At 25 years old, Lourdes Monje was excited about starting the next chapter in their life. Monje, who identifies as nonbinary, was preparing to move from New York to Philadelphia to launch a new career. Then, one morning in October 2020, they felt a lump on their chest. When Monje was eventually diagnosed with stage 4 breast cancer, it was as if time—and their life—froze.  

“I felt my world stop. All my plans had to go out the window. It was just about getting this taken care of,” Monje explained in the AACR Cancer Progress Report 2024. “While I was watching my friends advance in their careers, and get married, and go into committed relationships, and have kids, I was spending a lot of time just navigating my diagnosis.” 

Stories like Monje’s are becoming more common as cases of early-onset cancer—typically defined as cancer in those between the ages of 15 and 49—are on the rise. From 2010 to 2019, a total of 2,020,829 individuals were diagnosed with early-onset cancer, according to a study published in the AACR journal Cancer Discovery. Among the 33 cancer types the study examined, 14 had a significant increase in early-onset incidence. 

So, which types of cancer are seeing more early-onset cases? What do we know about why more people under 50 are getting cancer? Is the rise of early-onset cases leading to more deaths from cancer? Several researchers are examining these very questions. 

Which Cancer Types Have Increasing Rates of Early-onset Incidence? 

In the Cancer Discovery study, Meredith Shiels, PhD, MHS, from the National Cancer Institute (NCI), and her colleagues used data from the United States Cancer Statistics database to analyze cancer incidence from 2010 to 2019. Cancer was considered early-onset if it was diagnosed in one of three age groups—15-29, 30-39, and 40-49—while the older-onset age groups consisted of those 50-59, 60-69, and 70-79.  

“Understanding which cancers are increasing in younger age groups, and whether those cancers are also increasing among those at older ages, will inform future studies focused on identifying the drivers of rising rates,” Shiels said in a press release.  

Five cancer types had an increase in at least one of the early-onset groups without any corresponding increase in the older-onset age groups: 

• melanoma;  
• plasma cell neoplasms;  
• cervical cancer;  
• stomach cancer; and  
• cancer of the bones and joints. 

Nine cancer types had an increase in at least one early-onset group and at least one older-onset age group: 

• female breast cancer; 
• colorectal cancer; 
• kidney cancer; 
• testicular cancer; 
• uterine cancer; 
• pancreatic cancer; 
• precursor B-cell non-Hodgkin lymphoma; 
• diffuse large B-cell lymphoma; and  
• mycosis fungoides/Sézary syndrome. 

Overall, the largest increases in the number of additional early-onset diagnoses in 2019 compared with 2010 were seen in female breast (4,834), colorectal (2,099), kidney (1,793), uterine (1,209), and pancreatic cancers (511). Together, these cancers accounted for more than 80% of the additional cancers diagnosed during this period.  

Another study published in the Annals of Internal Medicine found that early-onset incidence is also on the rise for appendix cancer. Previous studies have observed an increasing rate of appendix cancer cases overall, but Andreana Holowatyj, PhD, MSCI, from the Vanderbilt-Ingram Cancer Center and a 2019 AACR NextGen Star, wanted to better understand how incidence was changing across birth cohorts.  

Holowatyj and her colleagues used data from NCI’s Surveillance, Epidemiology, and End Results (SEER) Program and found 4,858 cases of appendiceal adenocarcinomas diagnosed between 1975 and 2019. But compared to those born in 1945, incidence rates more than tripled for those born in 1980 and more than quadrupled for those born in 1985. 

As for cancer types with decreasing early-onset incidence, Shiels and her colleagues found that Kaposi sarcoma, liver cancer, and Burkitt lymphoma had the largest decreasing rates while prostate, lung, and ovarian cancers had the largest decreases in the total number of cases.  

How Does Early-onset Cancer Differ by Sex? 

Beyond age, Shiels and her colleagues also broke down incidence based on sex. Overall, early-onset cases were more common in females, who were diagnosed with 63% of the cases. The most common types of early-onset cancer in females were breast cancer, thyroid cancer, and melanoma.  

For female breast cancer and uterine cancer, the researchers also examined how incidence differed based on cancer subtype. Estrogen receptor (ER)-negative breast cancer rates only increased significantly among those 20-29 while ER-positive breast cancer rates increased significantly among those 30-39 and 40-49. Increasing incidence of uterine cancer was limited to the more common endometrioid subtype, which saw higher rates across the three early-onset age groups. 

For males, the most common types of early-onset cancer were melanoma, colorectal cancer, and testicular cancer. 

Why Are More People Under 50 Getting Cancer? 

In brief, there aren’t yet any definitive answers as to what is causing the rise in early-onset cancers, but researchers have some ideas. 

Genetics plays at least some role, according to Zsofia K. Stadler, MD, from Memorial Sloan-Kettering Cancer Center. At the AACR Annual Meeting 2025, Stadler said that her group looked at the prevalence of high-penetrance germline mutations—such as BRCA1/2 and the Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) that carry an increased risk of certain cancers—in early-onset cases compared to average- and late-onset cases. They found that the overall prevalence of these hereditary mutations was 18.4% in early-onset, 15.6% in average-onset, and 12.3% in late-onset cancers.  

Even though genetics was found to have a stronger impact on early-onset cancers, Stadler said that still means around 80% of those with early-onset cancer don’t have a germline mutation. 

“Genetics [alone] cannot explain the rise that we have seen for early-onset cancers because our genome just doesn’t change so quickly over several decades,” Ulrike Peters, PhD, MPH, from Fred Hutchinson Cancer Center, explained during that same session. 

Instead, Peters suggested looking at the possibility of how gene-environment interactions contribute to the development of early-onset cancers. For example, she discussed more closely examining the impact of certain lifestyle and environmental factors such as pollutants, microplastics, ultraprocessed foods, forever chemicals (pre- and polyfluoroalkyl substances), extreme weather, sleep, stress, obesity, and gut dysbiosis.   

However, she cautioned that: “For many of these, there’s no strong epidemiological evidence that they are linked to early-onset cancers. This is really a research area that is just evolving.” 

She is excited by advances in geospatial datasets, multiomics, and wearable monitoring devices that are making it possible to conduct more comprehensive exposure assessments, which could lead to a better understanding of the connection between environmental/lifestyle factors and early-onset cancers. 

Are Cancer Mortality Rates Also Increasing? 

Overall, cancer mortality rates did not increase significantly across all cancers and age groups between 2010 to 2022, based on Shiels and her colleagues’ analysis of national death certificate data. However, out of the 14 cancer types with increased early-onset incidence, four of them had higher mortality rates in at least one early-onset age group: 

• testicular cancer among those 30-39; 
• uterine cancer among those 30-39 and 40-49; 
• colorectal cancer among those 30-39 and 40-49; and 
• cancer of the bones and joints among those 15-29. 

Notably, in a study presented at the AACR Annual Meeting 2025, Adetunji Toriola, MD, PhD, MPH, of Washington University School of Medicine, and colleagues found that deaths from breast cancer among women 20-49 declined significantly from 2010 to 2020. 

Toriola reported that across all breast cancer subtypes and racial/ethnic groups, incidence-based mortality in women 20-49 declined from 9.70 per 100,000 women to 1.47/100,000. For most of the breast cancer subtypes and racial/ethnic groups the researchers examined, the declines were most pronounced after 2016. Toriola explained that this likely reflects advancements in treatment options—such as the broader adoption of CDK4/6 inhibitors and optimization of endocrine therapy between 2015 and 2016—as well as expanded access to care and screening in women ages 40-49. 

“We must continue to perform impactful research to ensure further reduction in breast cancer mortality, including research into understanding the tumor biology and molecular mechanisms driving carcinogenesis and treatment response in younger women,” Toriola said in a press release.  

Monje is hopeful that their own contribution to clinical research can help others with cancer to live longer. After being treated with ribociclib (Kisqali) for six months and then palbociclib (Ibrance) for over two years, Monje joined a clinical trial to treat cancer that metastasized to their lungs.  

“The way I’ve been approaching this trial is knowing that it’s not just for me, it’s for other people who will come after me,” they said. “Because I know that the two medications that I had access to beforehand that are relatively new are because of people like me who went through clinical trials.” 

Throughout the trial, which concludes at the end of August, Monje’s cancer has remained stable. And thanks to each of these treatments, Monje also no longer feels as if their life is on hold.  

“I feel like I’m having as normal of a life as I can and creating the memories that I’ve wanted to.” 

Summer may be in full swing, but this month’s Editors’ Picks from the 10 peer-reviewed journals of the American Association for Cancer Research (AACR) summoned a different kind of heat map: one that pinpointed pockets across the United States where cancer mortality rates have flared up. One study dove into the ear, exploring the mechanisms through which chemotherapy can disrupt inner ear cells and promote hearing loss, while others highlighted new immunotherapy approaches, including a tumor‑derived vaccine platform and an antibody‑drug conjugate built to disarm the immunosuppressive grip of regulatory T cells. Rounding out this edition, a new special series in Cancer Research showcased a machine learning method to identify patients with breast and ovarian cancer who might benefit from PARP inhibition. 

Follow the links for the full text of each article, which are freely available for a limited time.  

Journal: Blood Cancer Discovery 

Single-cell Transcriptional Atlas of Human Hematopoiesis Reveals Genetic and Hierarchy-Based Determinants of Aberrant AML Differentiation 

Therapeutic targeting of acute myeloid leukemia (AML) is hampered by intra- and inter-tumoral cell state heterogeneity. To develop a more precise understanding of AML cell states, we constructed a reference atlas of human hematopoiesis from 263,159 single-cell transcriptomes spanning 55 cellular states. Using this atlas, we mapped more than 1.2 million cells spanning 318 leukemia samples, revealing 12 recurrent patterns of aberrant differentiation in AML. Notably, this uncovered unexpected AML cell states resembling lymphoid and erythroid progenitors that were prognostic within the clinically heterogeneous context of normal karyotype AML, independent of genomic classifications. Systematic mapping of genotype-to-phenotype associations revealed specific differentiation landscapes associated with more than 45 genetic drivers. Importantly, distinct cellular hierarchies can arise from samples sharing the same genetic driver, potentially reflecting distinct cellular origins for disease-sustaining leukemia stem cells. Thus, precise mapping of malignant cell states provides insights into leukemogenesis and refines disease classification in acute leukemia. 

Significance: We present a single-cell reference atlas of human hematopoiesis and a computational tool for rapid mapping and classification of healthy and leukemic cells. Applied to AML, this has enabled single-cell analysis at the scale of hundreds of patient samples, revealing the full breadth of derailment of differentiation in AML. 

This study was simultaneously presented at the AACR Annual Meeting 2025, highlighted in a press release, and covered on the AACR blog. A related commentary was also published in the July issue. 

Journal: Cancer Discovery 

Cytosolic Phospholipase A2 Determines Intercellular Heterogeneity of Stress Granules and Chemotherapy Response 

Cancer cell heterogeneity is a major therapeutic challenge. In this study, we identify that individual cells within cancer cell populations show significant heterogeneity in the levels of the stress-adaptive organelles, stress granules (SG), and demonstrate that SG heterogeneity is dictated by the cell cycle state. Specifically, SG formation is distinctively heightened in cells in the G2 phase because of the interplay between a nonapoptotic function of CASPASE-3 and calcium-dependent phospholipase A2 (cPLA2)–mediated production of the SG-promoting molecule, 15-deoxy-delta-prostaglandin-J2. We demonstrate that in the G1–S phase, CASPASE-3 cleaves and inactivates cPLA2, whereas in the G2 phase, CASPASE-3 activity is suppressed, resulting in enhanced cPLA2 activity and 15-deoxy-delta-prostaglandin-J2 upregulation. We show that cell cycle–dependent SG heterogeneity is a property of pancreatic ductal adenocarcinoma and targeting G2-SGs by inhibiting cPLA2 sensitizes pancreatic ductal adenocarcinoma to G2 arrest–inducing chemotherapeutics. Our findings highlight cell cycle–dependent SG formation as a fundamental property of SGs, a key aspect of cancer heterogeneity, and a target for cancer treatment. 

Significance: Because of their defective G1 checkpoint mechanisms, cancer cells often activate a G2 checkpoint, which leads to resistance to DNA-damaging chemotherapeutics. We identify an intercellular heterogeneity of SGs that is driven by the cell cycle, with SG formation being highest in the G2 phase. Targeting G2-specific SG formation sensitizes pancreatic tumors to G2 arrest–inducing chemotherapeutics. 

This article was featured on the cover of the July issue. 

Journal: Cancer Epidemiology, Biomarkers & Prevention 

Where Should the Cancer Control Interventions Target: A Geospatial Hotspot Analysis for Major Cancer Mortality 2018 to 2022 in the United States 

Background: Identifying changes in geographic disparities of cancer mortality reveals locations where cancer prevention and control efforts should be focused/targeted. We use recent cancer surveillance data to demonstrate the geographic disparity of major cancer mortality rates in the United States and its shift compared with previous data. 

Methods: This cross-sectional study used the 2018 to 2022 county-level mortality rates of colorectal, lung, breast, and prostate cancers from the Centers for Disease Control mortality data. Counties with suppressed death counts were imputed by spatial regression models. Getis–Ord Gi* statistics were used to evaluate the spatial clustering of county mortality. Identified hotspot counties were visualized and compared with literature for hotspot pattern change. 

Results: A total of 3,108 U.S. mainland counties were included. Cancer mortality rates were significantly higher in 244 counties for colorectal, 456 for lung, 147 for breast, and 180 for prostate cancers. Hotspot areas were central Appalachia (colorectal and lung cancers), Lower Mississippi Delta (colorectal, breast, and prostate cancers), Midwest (colorectal and lung cancers), north Michigan/Wisconsin (lung and prostate cancers), north Florida (lung cancer), and the West (prostate cancer). 

Conclusions: West central Appalachia and Lower Mississippi Delta continue to be hotspots for major cancer types, whereas previously identified eastern North Carolina/Virginia hotspots shrunk, east Oklahoma and North Florida emerged as new hotspots for lung cancer, and several hotspots emerged in the West for prostate cancer. 

Impact: This study updated the analyses for geospatial disparity in major cancer mortality since 2018, illustrating recent changes in the disparity pattern and pinpointing areas that cancer prevention and control efforts should target. 

Journal: Cancer Immunology Research 

First-in-Human Clinical Trial of Vaccination with WDVAX, a Dendritic Cell–Activating Scaffold Incorporating Autologous Tumor Cell Lysate, in Patients with Metastatic Melanoma 

The optimal means to prime for effective antitumor immunity in a patient with cancer remain elusive in the current era of checkpoint blockade. Crafting a strategy to amplify the number and function of CD8+ T cells while blocking regulatory cells should increase immunotherapy efficacy. Biomaterial carriers have been demonstrated in preclinical studies to amplify the effects of immunomodulatory agents, synergistically integrate the effects of different agents, and concentrate and manipulate immune cells in vivo. Herein, we report data from a phase I trial in patients with metastatic melanoma who received the cytokine GM-CSF and the innate Toll-like receptor 9 agonist CpG oligonucleotide admixed with autologous tumor lysate onto a microporous poly-lactide-co-glycolide matrix polymer scaffold that achieves precise control over the spatial and temporal release of immunostimulatory agents in vivo. This materials system (WDVAX) served as a physical antigen-presenting structure to which dendritic cells and other immune-stimulating cells are recruited and activated. In this first clinical trial of a macroscale biomaterial–based vaccine, WDVAX treatment was found to be feasible and to induce immune activation in patients with melanoma. 

This article was featured on the cover of the July issue. 

Journal: Cancer Prevention Research  

Cancer Incidence and Survival after Emergency Department Care in the U.S. Midwest: An Opportunity for Cancer Interception 

Historically, cancers diagnosed via the emergency department (ED) portend a poor prognosis. Recent data from the United States are sparse, and analyses of cancers detected in the years following ED visits are lacking. Thus, we analyzed data from nine rural U.S. Midwest counties included within the population-based Rochester Epidemiology Project (2015–2021). Participants without a history of cancer (N = 42,074) who did not receive ED care were matched 1:1 to ED participants on the date of ED visit, age, sex, race, ethnicity, and county of residence. Analyses were restricted to participants with records ≤2 years prior to ED or index visit and ≥30 days after. HRs and 95% confidence intervals (CI) comparing cancer incidence and deaths among ED and non-ED participants were estimated from Cox proportional hazards regression models, either unadjusted or adjusted for covariates. Cumulative cancer incidence curves accounting for competing risks of death and survival (all cause and cancer-specific) were estimated. The median follow-up was 6.3 years, with 2,719 (6.46%) cancers diagnosed among ED participants and 3,139 (7.46%) among non-ED participants. ED participants experienced lower cancer risk overall (HR_Adjusted = 0.70; 95% CI, 0.66–0.74; P = 8.89 × 10⁻³¹), specifically for breast cancer, prostate cancer, melanoma, and secondary cancers. Cancer-specific mortality was higher among ED participants (HR_Adjusted = 1.76; 95% CI, 1.49–2.08; P = 3.62 × 10⁻¹¹). Compared with non-ED participants, ED participants experienced a lower incidence of cancer but higher overall cancer-specific mortality, suggesting that subsets of ED patients may benefit from postvisit preventive interventions. 

Prevention Relevance: This cohort analysis shows that cancer incidence over 6 years was lower among participants after an ED visit than among matched non-ED participants, whereas cancer-specific mortality was higher in the ED group (HR_Adjusted = 1.76; 95% CI, 1.49–2.08; P = 3.62 × 10⁻¹¹), suggesting the potential benefit of preventive interventions. 

Journal: Cancer Research (July 1 Issue) 

HRProfiler Detects Homologous Recombination Deficiency in Breast and Ovarian Cancers Using Whole-Genome and Whole-Exome Sequencing Data 

Breast and ovarian cancers harboring homologous recombination deficiency (HRD) are sensitive to PARP inhibitors and platinum chemotherapy. Conventionally, detecting HRD involves screening for defects in BRCA1, BRCA2, and other relevant genes. Recent analyses have shown that HRD cancers exhibit characteristic mutational signatures due to the activities of HRD-associated mutational processes. At least three machine learning tools exist for detecting HRD based on mutational patterns. In this study, using sequencing data from 1,043 breast and 182 ovarian cancers, we trained Homologous Recombination Proficiency Profiler (HRProfiler), a machine learning method for detecting HRD using six mutational features. The performance of HRProfiler was assessed against prior approaches using additional independent datasets of 417 breast and 115 ovarian cancers, including retrospective data from a clinical trial involving patients treated with PARP inhibitors. Individual HRD-associated mutational signatures alone did not consistently detect HRD or predict clinical response across datasets. Notably, while all tools performed comparably for whole-genome–sequenced cancers, HRProfiler was the only approach that consistently identified HRD in whole-exome–sequenced breast and ovarian cancers, offering clinically relevant insights. Retrospective analyses provided strong evidence that HRProfiler could serve as a valuable tool for predicting HRD and clinical response in breast and ovarian cancers. This study provides the rationale for large-scale prospective clinical trials to validate the potential of HRProfiler as a routine predictive and/or prognostic HRD biomarker to guide clinical decision-making. 

Significance: HRProfiler is a machine learning approach that reliably identifies homologous recombination deficiency in whole-exome–sequenced breast and ovarian cancers, outperforming other tools and providing clinically useful insights. 

This article was featured on the cover of the July 1 issue, which also included a related commentary. The article was also included in the journal’s special series on “Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI.”

Journal: Cancer Research (July 15 Issue) 

A Machine Learning–Based Strategy Predicts Selective and Synergistic Drug Combinations for Relapsed Acute Myeloid Leukemia 

Combination therapies are one potential approach to improve the outcomes of patients with relapsed/refractory (R/R) disease. However, comprehensive testing in scarce primary patient material is hampered by the many drug combination possibilities. Furthermore, inter- and intrapatient heterogeneity necessitates personalized treatment optimization approaches that effectively exploit patient-specific vulnerabilities to selectively target both the disease- and resistance-driving cell populations. In this study, we developed a systematic combinatorial design strategy that uses machine learning to prioritize the most promising drug combinations for patients with R/R acute myeloid leukemia (AML). The predictive approach leveraged single-cell transcriptomics and single-agent response profiles measured in primary patient samples to identify targeted combinations that coinhibit treatment-resistant cancer cells individually in each sample of patients with AML. Cell type compositions evolved dynamically between the diagnostic and R/R stages uniquely in each patient, hence requiring personalized drug combination strategies to target therapy-resistant cancer cells. Cell population–specific drug combination assays demonstrated how patient-specific and disease stage–tailored combination predictions led to treatments with synergy and strong potency in R/R AML cells, whereas the same combinations elicited nonsynergistic effects in the diagnostic stage and minimal coinhibitory effects on normal cells. In preliminary experiments on clinical trial samples, the approach predicted clinical outcomes of venetoclax–azacitidine combination therapy in patients with AML. Overall, the computational–experimental approach provides a rational means to identify personalized combinatorial regimens for individual patients with AML with R/R disease that target treatment-resistant leukemic cells, thereby increasing their likelihood of clinical translation. 

Significance: A predictive model identifies patient-tailored combinations that coinhibit multiple drivers to selectively and synergistically target leukemia cells, which could reduce therapy resistance and enhance treatment outcomes in patients with advanced disease. 

This article was also featured in the journal’s special series on computational research, data science, and machine learning/AI. 

Journal: Clinical Cancer Research (July 1 Issue) 

Application of Neoadjuvant Docetaxel plus Cisplatin in Early-Stage Triple-Negative Breast Cancer (HELEN-001): Results from a Phase II Trial 

Purpose: This study investigated the effects of taxane–cisplatin combinations on pathologic complete response (pCR) rates and survival outcomes in triple-negative breast cancer (TNBC). 

Patients and Methods: The HELEN-001 trial enrolled patients ages 18 to 70 years with stage II–III TNBC, randomly assigning them to receive either docetaxel (75 mg/m²) plus cisplatin (75 mg/m²; TP) or docetaxel (75 mg/m²), doxorubicin (50 mg/m²), and cyclophosphamide (500 mg/m²; TAC). Treatments were administered every 3 weeks for six cycles, with the primary endpoint being pCR (ypT0/isN0) and secondary endpoints being event-free survival (EFS), overall response rate, breast-conserving surgery rate, and toxicity. 

Results: From November 2018 to June 2022, 212 Asian female patients were enrolled across six hospitals in China, with 106 patients in each group. The pCR rate was significantly higher for TP (51.9%) than for TAC (35.8%; P = 0.028). After a median follow-up of 40 months, EFS was 86.1% in the TP group and 80.0% in the TAC group (HR, 0.639; P = 0.196). In germline BRCA1/2 mutation carriers, EFS was significantly higher with TP than with TAC (100% vs. 53.8%; P = 0.008). Grade 3 or higher adverse events occurred in 54% of patients in the TP group and 48% in the TAC group. 

Conclusions: The TP regimen demonstrated significantly improved pCR rates with a manageable toxicity profile, suggesting the potential benefit of taxane plus platinum regimens in patients with TNBC. 

Journal: Clinical Cancer Research (July 15 Issue) 

Phase I/II Study of Tifcemalimab, an Anti–B- and T-lymphocyte Attenuator Antibody, in Combination with Toripalimab in Previously Treated Advanced Lung Cancer 

Purpose: Tifcemalimab is a recombinant humanized IgG4k monoclonal antibody targeting B- and T-lymphocyte attenuator. Co-blockade of B- and T-lymphocyte attenuator and programmed death-1 pathways improved outcomes in nonclinical models. This phase I/II trial evaluated the safety and preliminary efficacy of tifcemalimab plus toripalimab in advanced lung cancer. 

Patients and Methods: Eligible patients with pathologically confirmed advanced non–small cell lung cancer (NSCLC) without sensitive EGFR variation and anaplastic lymphoma kinase fusion who failed standard treatment including one PD-1/PD-L1 inhibitor or those with refractory extensive-stage small cell lung cancer (SCLC) received tifcemalimab (200 mg) and toripalimab (240 mg) every 3 weeks intravenously until disease progression or intolerable toxicity. The Simon two-stage optimal design was used in the expansion part. The primary endpoints included safety and objective response rate (ORR) per RECIST version 1.1. 

Results: Twenty-four patients with NSCLC and 43 with SCLC were enrolled (median age of all patients, 60.0 years). All patients with NSCLC and 14 (32.6%) with SCLC had received previous immunotherapy. Fifty-five (82.1%) patients experienced treatment-related adverse events, and five (7.5%) patients reported grade ≥3 immune-related adverse events. For NSCLC, the ORR was 4.3%, and disease control rate was 47.8%. The median progression-free survival and overall survival were 1.5 and 18.9 months, respectively. For SCLC, the ORR and disease control rate were 35.0% and 55.0%, respectively. The median duration of response, progression-free survival, and overall survival were 5.7, 2.8, and 12.3 months, respectively. 

Conclusions: Tifcemalimab plus toripalimab showed promising antitumor activities with acceptable safety, especially in advanced refractory SCLC. 

Journal: Molecular Cancer Research 

Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine-Resistant Multiple Myeloma 

Protein homeostasis is critical to the survival of multiple myeloma cells. Although this is targeted with proteasome inhibitors, mRNA translation inhibition has not entered trials. Recent work illustrates broad sensitivity of multiple myeloma cells to the translation inhibitor omacetaxine. We hypothesized that understanding how multiple myeloma becomes resistant will lead to the development of drug combinations to prevent or delay relapse. We generated omacetaxine resistance in H929 and MM1S multiple myeloma cell lines and compared them with parental lines. Resistant lines displayed decreased sensitivity to omacetaxine, with EC₅₀ > 100 nmol/L, compared with parental sensitivity of 24 to 54 nmol/L. As omacetaxine inhibits protein synthesis, we performed both RNA sequencing and ribosome profiling to identify shared and unique regulatory strategies of resistance. Transcripts encoding translation factors and containing a terminal oligopyrimidine sequence in their 5’ untranslated region were translationally upregulated in both resistant cell lines. The mTOR pathway promotes the translation of terminal oligopyrimidine motif–containing mRNAs. Indeed, mTOR inhibition with Torin 1 restored partial sensitivity to omacetaxine in both resistant cell lines. The combination was synergistic in omacetaxine-naïve multiple myeloma cell lines, and a combination effect was observed in vivo. Primary multiple myeloma cells from patient samples were also sensitive to the combination. These results provide a rational approach for omacetaxine-based combination therapy in patients with multiple myeloma, which have historically shown better responses to multiagent regimens. 

Implications: Through the use of ribosome profiling, our findings indicate mTOR inhibition as a novel combination therapy for partnering with the translation inhibitor omacetaxine in the treatment of multiple myeloma. 

Journal: Molecular Cancer Therapeutics 

PF-08046032: A Novel, Investigational CD25-Directed Antibody–Drug Conjugate Optimized for Selective Depletion of Regulatory T Cells in Advanced Malignant Tumors 

Regulatory T cells (Treg) are known to suppress antitumor immune responses, and their presence in the tumor microenvironment is associated with cancer progression; therefore, Treg depletion is a promising strategy to enhance cancer immunotherapy. PF-08046032 is a novel antibody–drug conjugate (ADC) designed to target Tregs in the tumor microenvironment via CD25, the α-chain of the IL-2 receptor frequently upregulated by intratumoral Tregs. PF-08046032 is composed of an affinity-detuned anti-CD25 antibody linked to monomethyl auristatin E, a potent cytotoxic agent. Affinity detuning increases PF-08046032 selectivity for CD25^high intratumoral Tregs while minimizing peripheral blood Treg depletion, thus reducing the risk of autoimmune toxicities. In preclinical experiments, PF-08046032 selectively depleted Tregs compared with CD8⁺ T cells and preferentially depleted Tregs with high CD25 expression. PF-08046032 showed dose-dependent antitumor activity in CD25-expressing human lymphoma xenograft models, whereas a similarly detuned anti-mouse CD25 surrogate ADC depleted intratumoral Tregs and drove CD8⁺ T-cell activation in murine tumor models. This effect resulted in robust antitumor activity as a single agent and in combination with anti-PD1 checkpoint inhibitor blockade. Lastly, PF-08046032 was well-tolerated in nonhuman primates and mitigated the persistent depletion of peripheral blood Treg that was observed with a high-affinity anti-CD25 ADC comparator, demonstrating the safety benefit of a detuned-affinity ADC format. PF-08046032 represents an innovative therapeutic approach for depletion of intratumoral Tregs that may offer an improved safety profile and efficacy over traditional Treg-depleting agents. 

This article was featured on the cover of the July issue. 

Journal: Cancer Research Communications 

Cisplatin-Induced APE2 Overexpression Disrupts MYH9 Function and Causes Hearing Loss 

Cisplatin remains a cornerstone chemotherapy for many solid tumors but is limited by dose-limiting toxicities, including nephrotoxicity, peripheral neuropathy, and ototoxicity—the latter of which disproportionately affects pediatric patients and lacks effective prevention strategies. Although therapeutic approaches to mitigate cisplatin-induced toxicity are urgently needed, the underlying mechanisms driving organ-specific injury remain incompletely understood. We previously identified apurinic/apyrimidinic endonuclease (APE) 2 as a critical mediator of cisplatin-induced acute kidney injury through disruption of mitochondrial integrity. In this study, we extend these findings to cisplatin-induced hearing loss (C-HL). We demonstrate that cisplatin selectively induces APE2, but not APE1, overexpression in murine and human outer hair cells. Using an inducible, outer hair cell–specific APE2 transgenic mouse model, we show that APE2 overexpression alone is sufficient to cause high-frequency hearing loss, accompanied by hair cell loss and stereocilia disorganization visualized by electron microscopy. Mechanistically, we identified a direct interaction between APE2 and MYH9, mapped the critical MYH9-binding domains, and demonstrated that APE2 knockdown preserved mitochondrial metabolism and protected cochlear cells from cisplatin-induced apoptosis. Notably, APE2 depletion activated an ATR–p53 signaling axis, promoting nuclear p53 localization and suppressing mitochondrial apoptotic pathways. Together, these findings reveal a noncanonical, APE2-dependent mechanism driving C-HL and suggest that targeting APE2 may offer a novel therapeutic strategy to prevent cisplatin-induced ototoxicity. 

Significance: These results reveal an unexpected role of APE2 via its interaction with MYH9, emphasizing the therapeutic promise of targeting APE2 for preventing C-HL in patients with cancer.

Cancer medicine has never been more powerful, or more complex. Modern drugs can melt tumors that once seemed unbeatable, and survival rates for many cancers keep climbing. Yet while newer treatments often have preferable side effect profiles compared to chemotherapy, they can affect some of the body’s most vital organs, including the heart.

Cardiotoxicity can come in many forms, and sometimes does not manifest until decades later, something Peter Wolf learned after a yearslong quest for answers related to valve disease rooted in radiation treatment for lymphoma in his teens.

Cancer and cardiovascular disease already claim the top two spots on the U.S. mortality list, and cancer survivors face about a 42% higher risk of heart problems compared with people who have never had cancer. The ultimate goal is not a Pyrrhic victory but a lasting one: eliminate the cancer and let patients enjoy a better quality of life with healthy hearts.

The Importance of Healthy Cardiovascular Highways

Think of the endothelium—the single-cell layer lining every artery, vein, and capillary—as the pavement of the body’s circulatory highways. When healthy, it keeps blood (and the circulating immune cells) gliding smoothly where they need to go, widening or narrowing lanes as necessary and preventing fender benders that could clog the road. But new generations of treatments for chronic myeloid leukemia (CML) can turn parts of a once-smooth pavement into hazard-filled stretches with potholes prone to pileups and clots.

Approved in 2001, imatinib (Gleevec) became the first small molecule precision therapy, and created a new class of treatments known as tyrosine kinase inhibitors (TKIs). Instead of indiscriminately targeting dividing cells, imatinib homes in on an abnormal fusion protein called BCR-ABL. This protein is created by the Philadelphia chromosome, an accidental DNA swap between two chromosomes that characterizes roughly 95% of CML cases. For many patients, imatinib transformed CML from a deadly disease into a long-term, manageable condition.

But cancer sometimes finds ways to escape; by acquiring BCL-ABL mutations that weaken the grip of imatinib, for example. Enter the next-generation TKIs. These treatments, such as dasatinib (Sprycel), nilotinib (Tasigna), and ponatinib (Iclusig), latch onto BCR-ABL differently and, in ponatinib’s case, can even overcome some mutations that provide resistance against other TKIs. However, they can also come with greatly increased risks of heart attack, stroke, or limb-threatening clots.

Why the difference?

According to Iris Jaffe, MD, PhD, the Elisa Kent Mendelsohn Professor of Molecular Cardiology and executive director of the Molecular Cardiology Research Institute at Tufts Medical Center, the trouble traces back to blood vessel inflammation.

At the AACR Annual Meeting 2025, Jaffe highlighted how endothelial cells exposed to ponatinib clung to platelets much more readily, and in mice that develop human-like atherosclerosis when fed a high-fat diet, ponatinib increased inflammation, immune cell trafficking (both T cells and myeloid cells), and unstable fatty plaques.

Most strikingly, ponatinib invariably led to cardiovascular events or death in a novel plaque rupture model, whereas imatinib caused similar fates only 20% of the time. Interestingly, asciminib (Scemblix), a new TKI and the first to target tyrosine kinase enzymes in CML in an allosteric fashion, meaning it doesn’t target the active binding site, led to similar survival rates as imatinib in mice, and also appeared to spare their endothelium.

In follow-up experiments, Jaffe and her colleagues revealed that blocking the inflammatory switch TNFR2 could calm the endothelial lining and protect against cardiovascular events, hinting at the possibility of strategies to neutralize this vascular toll without sacrificing anticancer power.

As far as how the different TKIs affect the signaling of specific tyrosine kinase pathways, no single kinase alterations stood out, so the team sought to capture the “fingerprints” left behind by different TKIs that reflect how they influence kinase activity more globally in these endothelial cells. By comparing these TKI fingerprints to those of 30 already approved cardiovascular drugs the researchers hope to identify therapies with opposing signatures that might be able to counteract specific TKI-induced cardiotoxicity, though distinct TKI signatures would likely demand different cardiotoxicity counterbalancing strategies.

Age is another factor that impacts risk, Jaffe noted. CML usually appears after midlife, and consequently, more than 60% of patients already have hypertension, diabetes, or coronary disease at the time of diagnosis. She noted that having just one of those risk factors doubles the likelihood of a drug-induced clot, meaning the treatment that rescues an older patient from leukemia can unmask a silent vulnerability in arteries already under strain.

“The Weakest Link”

Why are endothelial cells so fragile in the first place?

One answer, according to Kristopher Sarosiek, PhD, a principal investigator and associate professor at the Harvard T.H. Chan School of Public Health, might be their unique susceptibility to apoptosis, a built-in program that allows cells to quietly self-destruct if they sustain too much DNA damage, for example.

Picking up the thread where Jaffe left off during the “Cardio-Oncology: A Novel Platform for Investigation” Major Symposium, Sarosiek revealed how he and his colleagues used a method called BH3 profiling to learn that endothelial cells remain “primed” for apoptosis throughout the lifetime of mice. Heart-muscle fibers, liver cells, and other functional (parenchymal) cells, in contrast, seemed to grow tougher with age. That intrinsic sensitivity could explain why chemotherapy and radiation, which can damage DNA, often disrupt the vascular lining first. This makes them, in Sarosiek’s words “the weakest link” when it comes to toxicity.

In young mice—whose endothelial cells, in addition to their heart muscle cells, were particularly primed for apoptosis—the chemotherapy doxorubicin compromised heart function, unless the researchers disabled the BAX/BAK proteins that trigger apoptosis.

Shielding endothelial cells, whether by tweaking drug schedules, adding protective medications, or engineering smarter molecules, could allow doctors to preserve heart health without dialing back cancer-killing potency. To complement those potential solutions in the meantime, biomarkers that help predict who is most at risk of cardiotoxicity would be valuable in guiding vulnerable patients to avoid certain therapies, Sarosiek said.

When the Immune System Misfires on the Heart

Beyond endothelial damage due to cytotoxic drugs, immunotherapies like immune-checkpoint inhibitors (ICIs) can also unleash cardiovascular damage. ICIs unleash T cells by removing molecular brakes such as PD-1 or CTLA-4. While these immunotherapies have been transformative for many types of advanced cancers, in about 1% of recipients they trigger myocarditis, an inflammatory attack on the heart muscle itself.

That 1% looms large, however, as the cardiotoxicity proves fatal in roughly 40% of cases, making ICI-induced myocarditis the most lethal immune-related side effect, according to Javid Moslehi, MD, the University of California, San Francisco (UCSF) William Grossman Distinguished Professor in Cardiology and chief of cardio-oncology and immunology at UCSF Health. In addition to founding the UCSF Myocarditis Center, Moslehi also leads the International ICI-Myocarditis Registry that, as of April 2025, had tracked nearly 1,300 cases from 150 centers across 26 countries.

The registry’s analyses have linked increased risk to combination regimens, in particular the dual administration of ICIs targeting LAG-3 and PD-1. To unravel the biology, Moslehi and colleagues utilized mice missing one copy of CTLA-4 and both copies of PD-1, both crucial immune checkpoints. Every such mouse died of myocarditis, driven by T cells that mistook alpha-myosin, a heart-specific protein, for a target. The other arm of adaptive immunity also plays a role, with a study in the AACR journal Cancer Immunology Research showing that B cells contribute to ICI-induced cardiotoxicity through the production of heart-targeting antibodies.

Standard steroids often prove ineffective in patients with ICI-induced myocarditis, among other hurdles, so Moslehi and his collaborators have been exploring a two-drug, immune-modulating rescue approach previously highlighted on the AACR blog. During this session, Moslehi shared clinical updates from his colleague Joe-Elie Salem, MD, PhD, an associate professor at Sorbonne Université in Paris, that demonstrated a potentially valuable approach for patients with ICI-induced myocarditis: combining abatacept (Orencia), which is used to treat rheumatoid arthritis, with ruxolitinib (Jakafi/Opzelura), a drug with applications in graft-versus-host disease, dermatitis, and vitiligo.

Discussing the study in which myocarditis deaths were limited to about 2% in the first 90 patients using this combination, Moslehi said, “Again, not a randomized trial, but it’s perhaps a cocktail that one could use in our patients.”

Searching for Solutions for Long-term Survivors

Roughly 5.4% of the population in the United States—about 18.6 million people—are cancer survivors. Cardiovascular complications already rank as their second-leading cause of long-term death, and is the leading cause in long-term survivors of breast, colorectal, and prostate cancers. Even modest advances in cardio-oncology could bring huge gains in quality years. As the mechanisms mediating cardiovascular side effects become better understood, doctors will better be able to tailor their care, or at least monitor patients who might be at risk, to intervene early with any necessary countermeasures.

Throughout human history, food has required some degree of processing to make it edible, improve its taste, or prepare it for storage. But with the Industrial Revolution came lifestyle changes and sophisticated technologies that demanded greater convenience and enabled a whole new level of food processing. The food industry was no longer limited to chopping, seasoning, and cooking whole foods. Now, industrially made ingredients could make food more appealing and increase shelf life, all while lowering costs. These advances led to the birth of what we know as “ultraprocessed foods.”

The socioeconomic benefits of ultraprocessed foods are hard to dispute. They’re cheap, quick to prepare, long-lasting, and easy to find—making nutritious foods like whole-grain bread accessible to many Americans who don’t have the time or resources to regularly bake a homemade loaf or to buy one from an artisanal bakery.

The popularity of ultraprocessed foods has continued to rise, and today, they account for nearly 60% of the American diet. Such high consumption, however, has many concerned that these foods could be wreaking havoc on our health.

But does the evidence support this concern?

Are all ultraprocessed foods equally harmful?

And what does “ultraprocessed” mean anyway?

Experts continue to debate these topics, weighing the strengths and limitations of past studies and finding improved ways to study and define this group of foods. The issue has even caught the attention of the federal government, which recently launched the Nutrition Regulatory Science Program to examine the health impacts of ultraprocessed foods and announced that it would develop a new definition of ultraprocessed foods—a step that could have ramifications for a slew of policies and dietary guidelines.

What Are Ultraprocessed Foods?

From peeled vegetables to potato chips, nearly everything we consume is processed—but clearly not to the same extent. To better study the health effects of differentially processed foods, in 2016, Carlos Monteiro, MD, PhD, from the University of Sao Paulo in Brazil, and colleagues developed the now commonly used NOVA classification scale, which categorizes foods into one of four groups based on how processed they are.

Group 1 foods are those that are unprocessed or that have been minimally processed to remove inedible parts and/or to prepare the food for storage. Examples include fresh or frozen fruits and vegetables, meats, grains, eggs, nuts, and seeds.   

Group 2 foods are ingredients used in cooking, such as butter, oil, sugar, vinegar, and salt, among others. Unlike Group 1 foods, these ingredients are not immediately found in nature. Instead, they are derived from Group 1 foods through processes such as churning, extraction, or fermentation. Butter, for example, is produced by churning milk, oils can be extracted from seeds, and vinegar can be produced from fermenting grapes.

Group 3 foods are processed foods produced by combining Group 1 and Group 2 ingredients and, in some cases, have been preserved via canning, bottling, or fermentation. Group 3 foods include sauteed vegetables, cheese, canned beans, and homemade bread.

Finally, Group 4 foods represent ultraprocessed foods, which are generated using ingredients and/or processes not found in a typical home kitchen, such as high-fructose corn syrup or hydrogenated oils. Because these foods are made with lower-quality ingredients, they often include flavorings, artificial colors, and other additives to improve their taste and appearance—things like butylated hydroxyanisole, xylitol, or red no. 40, to name just a few. Examples of Group 4 foods include soda, candy, most fast foods, breakfast cereal, chicken nuggets, lunch meat, packaged breads, plant-based milk, flavored yogurt, and meat substitutes.

How Do Ultraprocessed Foods Impact Health?

Using the NOVA scale, researchers have found correlations between ultraprocessed foods and a variety of metabolic and cardiovascular diseases. As one example, a meta-analysis of 25 studies found that high intake of ultraprocessed foods was associated with an increased risk of diabetes, high blood pressure, obesity, unhealthy cholesterol levels, and high triglycerides. The degree to which the risks increased, however, varied widely between studies due to differences in how each was performed.

Building on this type of correlative data, a randomized trial conducted at the National Institutes of Health by Kevin D. Hall, PhD, and colleagues demonstrated that switching from a minimally processed diet to an ultraprocessed diet increased consumption and weight gain—lending credence to the notion that ultraprocessed foods are not just correlated with obesity but may in fact cause it.

But, as many experts have noted, it is still not known whether the effects are due to the ultraprocessing per se, or just a result of these foods often having higher levels of sugar, salt, and fat. And while some have suggested that ultraprocessed foods could be addictive, a separate study by Hall and colleagues disputed this theory, indicating that alternative factors could be to blame for the common overconsumption of these foods.

Do Ultraprocessed Foods Increase Cancer Risk?

Whether directly or indirectly, the idea that ultraprocessed foods are associated with increased risk of metabolic and cardiovascular diseases is well supported, but what about cancer?

Studies have shown associations between ultraprocessed foods and increased cancer risk, and a meta-analysis found that these foods were, on average, associated with a 12% increased risk of total cancer incidence. However, the association was considered “suggestive” and based on “very low quality” evidence.

Among the individual cancer types examined in the meta-analysis, the researchers reported that only colorectal cancer was consistently associated with consumption of ultraprocessed foods.

As with other diseases, it remains to be seen whether it is the ultraprocessed nature of these foods that increases risk of cancer—for example, through additives or carcinogens derived from food processing methods—or whether the impact is primarily due to the higher levels of fat, salt, and sugar. These components could indirectly lead to cancer by promoting obesity, inflammation, and disruption of the gut microbiome or metabolic processes.

Substitution effects may also be at play, as eating a lot of ultraprocessed foods often means eating fewer of the unprocessed or minimally processed foods known to decrease cancer risk, such as fruits and vegetables.

Another important question is whether ultraprocessed foods as a whole are associated with cancer risk or whether the impact is driven by specific foods.

Interestingly, an analysis by Mingyang Song, ScD, from Harvard University, and colleagues found that high intake of ultraprocessed foods was associated with higher colorectal cancer risk for men but not for women. Song noted that the sex-specific impact could be due, in part, to differences in the types of foods men and women consumed.

“Ultraprocessed food is a very complex mixture of different food groups,” said Song during a presentation at the AACR Annual Meeting 2025, held this past April. “That makes the measurement and risk assessment particularly challenging.”

Certain ultraprocessed foods, including processed meat and sweetened beverages, have been convincingly associated with an increased risk of cancer, but most studies to date have not examined the impact of specific foods or individual ingredients and instead have treated ultraprocessed food as a monolith.

Much of this stems from the indiscriminate way that ultraprocessed foods are defined. Of note, the NOVA classification system is based solely on how processed a food is and does not account for a food’s nutritional value. As a result, foods like store-bought whole-grain breads—which provide fiber, complex carbohydrates, and other nutrients known to decrease cancer risk—are classified in the same category (Group 4) as soda—which has little to no nutritional value and is associated with liver cancer.

Experts argue that this feature of the NOVA system complicates interpreting the risks and benefits of ultraprocessed food consumption and may unfairly demonize otherwise nutritious foods.

“We believe that by considering both the food processing and nutrient profiles, we can better classify ultraprocessed foods,” Song said.

Should We Stop Eating Ultraprocessed Foods?

It’s still up for debate whether we should eliminate ultraprocessed foods from our diets. Some experts recommend limiting their consumption, pointing to the many studies linking these foods to poor health outcomes. Others argue that there isn’t convincing evidence yet to show that ultraprocessing itself, rather than individual ingredients commonly found in these foods, is inherently harmful.

Regardless of their views on ultraprocessing, experts agree on the importance of prioritizing nutritious foods and limiting those high in sugar, salt, and fat, which are linked to many diseases, including cancer.

Experts also agree on the need for more research.

To tease apart the contribution of specific ultraprocessed foods and ingredients on disease risk, researchers need to develop a more nuanced definition of ultraprocessed food that incorporates nutrient profiles, Song said.

In addition, identifying biomarkers of ultraprocessed food consumption and following large cohorts over many years will help researchers better understand the impact on cancer, and studies that examine how dietary changes and other interventions impact cancer risk will be required to demonstrate causality.

Acknowledging some of the lifestyle benefits of ultraprocessed foods, Song noted, “I don’t think it’s realistic for us to eliminate ultraprocessed foods from our diet.”

However, he hopes that “further research to improve the assessment of ultraprocessed foods and identify specific ingredients in ultraprocessed foods that may increase cancer risk … will inform future regulatory and policy changes.”

Douglas Hanahan, PhD, FAACR—the recipient of the 2025 Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research—is no stranger to pivotal moments in oncology. And he thinks we may be on the brink of more breakthroughs against hard-to-treat tumors like uterine cervical cancer and glioblastoma, an aggressive form of brain cancer, thanks to his latest research on finding ways to overcome immunosuppression.

A quarter of a century ago, Hanahan published “The Hallmarks of Cancer,” a conceptual framework that gave researchers a common language for the traits that enable cancers to become malignant. In two subsequent updates, most recently in the AACR journal Cancer Discovery in 2022, he has expanded on the original foundation and incorporated the latest science to help move the field forward. (Read more about each iteration of the hallmarks of cancer in this past blog post.) Hanahan is currently the president emeritus of the Swiss Federal Institute of Technology and a distinguished scholar with the Ludwig Institute for Cancer Research in Lausanne, Switzerland.

In an effort to “move basic cancer biology toward cancer medicine,” Hanahan unveiled two lines of work in his lecture that dive deeper into one of the hallmarks of cancer first acknowledged in the 2011 update: avoiding immune destruction. Specifically, he revealed how tumors sabotage immune responses far beyond their own borders and how an old antidepressant might turn one of oncology’s most intractable cancers into an immunotherapy target.

Short-circuiting Systemic Immunosuppression

The centerpiece of his talk focused on human papillomavirus type 16 (HPV16)-driven cancers, especially cervical cancer. While cervical cancers that express HPV16-specific oncoproteins might seem like ideal candidates for vaccine therapy, Hanahan noted that therapeutic vaccines have often floundered in both mice and humans.

His group suspected the problem lay outside the tumor microenvironment and were a result of systemic immunosuppression. In a Cancer Discovery article published simultaneously during the conference, the team performed multiomic screens of cervical tumor tissue, as well as the bone marrow, spleen, and blood, to identify molecules and pathways that maintain systemic immunosuppression. Three cytokines from the interleukin-1 (IL-1) family leapt out as significant: IL-1alpha, IL-33, and IL-36beta. While these IL-1 family cytokines bind different receptors on the surface of cells, the downstream signaling of all three relies on the IL1RAP coreceptor component expressed mainly by developing neutrophils.

When the IL-1 family trio engages IL1RAP, bone marrow output skews toward neutrophils, spleens swell, and those neutrophils migrate to lymph nodes and tumors where they paralyze the T-cell response a vaccine needs to elicit tumor elimination. In the lab, T cells grown with splenocytes from tumor-bearing mice had significantly reduced proliferation, helping to explain why a vaccine alone is typically ineffective.

Fortunately, blocking IL1RAP can break the spell. A mouse antibody against IL1RAP reduced neutrophil counts, shrank spleens, and—paired with a nanoparticle vaccine targeting the E7 HPV oncoprotein—sparked T-cell infiltration and rapid tumor regression, and significantly improved survival. Somewhat surprisingly, CTLA-4 immunotherapy, but not PD-L1 immunotherapy, widened the survival gap further.

The clinical relevance of this approach looks promising, according to Hanahan, whose team mined data from The Cancer Genome Atlas (TCGA) to build a 10-gene systemic immunosuppression score that included IL-1alpha, IL-33, and IL-36beta, among other molecules. Tumors that scored high—whether cervical, head and neck, or lung cancer—were linked to poorer prognosis, hinting that IL-1-driven systemic immunosuppression may be a common escape route.

 “We believe that a triplet of this HPV16 oncoprotein vaccine, anti-IL1RAP … plus anti-CTLA-4 warrants consideration for clinical trials,” Hanahan concluded.

Early data from a first-in-human trial provides some support, though PD-1 immunotherapy appeared beneficial in this clinical context. When nadunolimab, a humanized antibody against IL1RAP, was combined with PD-1 blockade, elevated neutrophil counts normalized in patients with lung and pancreatic cancers. This positions IL1RAP blockade as a practical path to disarm systemic immunosuppression and potentially enhance the effects of various immunotherapies, though the distinct effects of combinations involving different immune checkpoint inhibitors must be further clarified.

Antidepressant Flips Macrophages’ Mood Against Tumors

Hanahan next offered a glimpse into cancer neuro-immunology. His lecture’s closing act shifted to glioblastoma, where imipramine, a 60-year-old tricyclic antidepressant, emerged as an unlikely ally. In mouse glioblastoma models, the antidepressant turbocharged autophagy in tumor cells and flipped macrophages from a tumor-supporting to a tumor-attacking state.

Combined with VEGF blockade, the drug normalized aberrant blood vessels and cleared a path for adaptive immune cells to more efficiently enter tumors. Yet most mice eventually relapsed, until an anti-PD-L1 antibody was added to the mix. The triple therapy flooded tumors with T cells and doubled survival compared to the antidepressant plus VEGF inhibition. A Swiss pilot study, PHENIX, will soon test imipramine, the VEGF-A antibody bevacizumab (Avastin), and the anti-PD-1 antibody cemiplimab (Libtayo) in patients with recurrent glioblastoma.

Both stories extend Hanahan’s original hallmarks. Immune evasion is not just a skirmish at the tumor rim; it can be a body-wide blockade or a brain-tuned switchboard. But each defense reveals a seam: IL1RAP antibodies for HPV cancers, an antidepressant-anchored cocktail for glioblastoma. For a scientist whose frameworks have guided oncology for decades, the 2025 Pezcoller Foundation-AACR International Award lecture felt less like the closing of a chapter than the opening of a new front in the effort against cancer.

Summer is heating up, so why not keep cool by reading about some of the hottest topics in cancer research? This month’s Editors’ Picks from the 10 peer-reviewed journals of the American Association for Cancer Research (AACR) include studies on pancreatic cancer interception, breast cancer risk prediction, the tumor microenvironment, and more.

Read the abstracts of the selected articles below, and follow the links to access the full-text articles, freely available for a limited time.

Journal: Blood Cancer Discovery

A Model of Intratumor and Interpatient Heterogeneity Explains Clinical Trials of Curative Combination Therapy for Lymphoma

Models of tumor drug response have illuminated important concepts in oncology, but there remains a need for theory that combines intratumor and interpatient heterogeneity to explain patient outcomes, especially for curative treatments. In this study, we present a mathematical model of multidrug therapy that describes both cell-to-cell and patient-to-patient heterogeneity as distributions of drug sensitivity and apply it to simulate curative combination therapies for diffuse large B-cell lymphoma (DLBCL). Simulated trials reproduced progression-free survival and changes in ctDNA observed under standard therapy and accurately predicted success or failure of nine randomized trials of first-line combinations based on drug efficacies in relapsed/refractory DLBCL. Finally, we used the model to explore how drug synergies, biomarkers, and subtype-specific endpoints could improve the chance of success of targeted combination therapies. This study offers a quantitative model of curative drug combinations and suggests that predictive simulations could aid the design of new regimens with curative intent.

Significance: A new model of intratumor and interpatient heterogeneity in response to drug combinations explains and predicts the results of clinical trials of curative-intent treatments for DLBCL. This model can be used to understand and inform optimal design of curative drug combinations and clinical trials.

A related commentary was published in the May issue.

Journal: Cancer Discovery

Long-Term Latency of Highly Mutated Cells in Normal Mouse Skin Is Reversed by Exposure to Tumor Promoters and Chronic Tissue Damage

Historical studies performed nearly a century ago using mouse skin models identified two key steps in cancer evolution: initiation, a likely mutational event, and promotion, driven by inflammation and cell proliferation. Initiation was proposed to be permanent, with promotion as the critical rate-limiting step for cancer development. In this study, we carried out whole-genome sequencing to demonstrate that initiated cells with thousands of mutagen-induced mutations can persist for long periods and are not removed by cell competition or by immune intervention, thus mimicking the persistence of cells with cancer driver mutations in normal human tissues.

In the mouse, these cells do not give rise to tumors unless exposed to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Tissue damage and regenerative proliferation, but not normal cell turnover, consistently trigger tumor formation. Wounding, promoter treatment, and obesity enhance promotion without increasing mutational burden, supporting the possibility of future cancer prevention efforts directed at promotional risk factors.

Significance: Using historical skin cancer models, we reveal that mutated cells can persist without tumor formation and give rise to cancer upon exposure to tumor promoters, underscoring the importance of tumor promotion over initiation as the rate-limiting step in carcinogenesis and the need for cancer prevention strategies targeting promotional factors.

This article was featured on the cover of the June issue, which also included a related commentary.

Journal: Cancer Epidemiology, Biomarkers & Prevention

The Breast Tumor Immune Microenvironment of DNA Double-Strand Break Repair Pathogenic Variant Carriers Is Enriched with Tumor-Associated Macrophages

Background: Approximately 5% of patients with breast cancer have a rare pathogenic germline genetic variant that is associated with increased breast cancer risk. Mutations in more than 12 genes have been associated with hereditary breast cancer risk, many of which are involved in genome stability pathways, including DNA double-strand break (DSB) repair. We hypothesized that carriers of DSB repair–related pathogenic variants (PV) may have a distinct tumor immune environment that differs from that of noncarriers.

Methods: We utilized tumor transcriptome data from 559 participants with invasive breast cancer from the Nurses’ Health Studies and Nurses’ Health Studies II to infer immune-related gene expression signatures and immune cell abundance.

Results: Thirty-three (5.9%) individuals had germline DSB repair–related PVs in one or more of the following genes: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FANCC, FANCM, NBN, PALB2, RAD50, RAD51C, and/or RECQL. In covariate-adjusted analyses, DSB repair–related PV carrier status was positively associated with both a STAT1 signature (standardized β = 0.59; P = 3.5 × 10⁻³) and inferred M1 macrophage infiltration (standardized β = 0.56; P = 1.4 × 10⁻³). Furthermore, these immune features correlated with other features related to tumor IFN response signaling, suggesting that this enrichment is occurring in an inflammatory context.

Conclusions: These results indicate that breast tumors of DSB repair–related PV carriers have distinct immune features, which may have therapeutic implications in this high-risk population.

Impact: These results support further characterization of macrophage characteristics and abundance in the breast tumor microenvironment of DSB repair–related PV carriers.

Journal: Cancer Immunology Research

Mesenchymal Stem Cells and Fibroblasts Contribute to Microvascular Proliferation in Glioblastoma and are Correlated with Immunosuppression and Poor Outcome

Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma and other World Health Organization grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single-cell RNA sequencing on paired CD45⁻CD105⁺ vascular/perivascular stromal cells (PVSC) and CD45⁺CD105^± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally related mesenchymal stem cells alongside cancer-associated fibroblasts, pericytes, fibromyocytes, and smooth muscle cells within the CD45⁻CD105⁺ compartment. RNA velocity analysis identified PDGFRB as a putative driver gene guiding mesenchymal stem cells toward more mature PVSCs in the context of MVP. Signaling network analysis and digital spatial profiling uncovered interactions between PDGFRB⁺ PVSCs and immunosuppressive myeloid cell subsets enriched in the perivascular niche, suggesting targetable receptor–ligand interactions. Additionally, a gene signature of MVP-associated PVSCs from gliomas predicted worse prognosis in multiple other solid tumors. This study provides a transcriptomic cell atlas of PVSCs and immune cells in glioma, helping to refine the biological model of MVP which has traditionally focused on endothelial cells.

This article was featured on the cover of the June issue.

Journal: Cancer Prevention Research

Deriving a Mammogram-Based Risk Score from Screening Digital Breast Tomosynthesis for 5-Year Breast Cancer Risk Prediction

Screening digital breast tomosynthesis (DBT) aims to identify breast cancer early when treatment is most effective, leading to reduced mortality. In addition to early detection, the information contained within DBT images may also inform subsequent risk stratification and guide risk-reducing management. Using transfer learning, we refined a model in the Joanne Knight Breast Health Cohort at Washington University, a cohort of 5,066 women with DBT screening (mean age, 54.6), among whom 105 were diagnosed with breast cancer (26 ductal carcinoma in situ). We applied the model to external data from the Emory Breast Imaging Dataset, a cohort of 7,017 women free from cancer (mean age, 55.4), among whom 111 pathology-confirmed breast cancer cases were diagnosed more than 6 months after initial DBT (17 ductal carcinoma in situ). We obtained a 5-year AUC of 0.75 [95% confidence interval (CI), 0.73–0.78] in the internal validation. The model validated in external data gave an AUC of 0.72 (95% CI, 0.69–0.75). The AUC was unchanged when age and Breast Imaging-Reporting and Data System density were added to the model with synthetic DBT images. The model significantly outperforms the Tyrer-Cuzick model, with a 5-year AUC of 0.56 (95% CI, 0.54–0.58; P < 0.01). Our model extends risk prediction applications to synthetic DBT, provides 5-year risk estimates, and is readily calibrated to national risk strata for clinical translation and guideline-driven risk management. The model could be implemented within any digital mammography program.

Prevention Relevance: We develop and externally validate a 5-year risk prediction model for breast cancer using synthetic DBT and demonstrate clinical utility by calibrating to the national risk strata as defined in breast cancer risk management guidelines.

Journal: Cancer Research (June 1 issue)

FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development

Activating KRAS mutations are a key feature of pancreatic ductal adenocarcinoma (PDAC) and drive tumor initiation and progression. However, mutant KRAS by itself is weakly oncogenic. Defining the pathways that cooperate with mutant KRAS to induce tumorigenesis could identify prevention and treatment strategies. Analyzing organoids and murine and human pancreatic specimens, we found that the receptor tyrosine kinase FGFR2 was progressively upregulated in mutant KRAS-driven metaplasia, precancerous lesions, and classical PDAC. In genetic mouse models, FGFR2 inactivation impeded mutant KRAS-driven transformation of acinar cells by reducing proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, FGFR2 collaborated with EGFR, and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced precancerous lesion formation. Together, these data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic tumorigenesis, paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception.

Significance: FGFR2 inhibition reduces mutant KRAS signaling, which can impair mutant KRAS-expressing pancreatic cancer precursor lesions that are prevalent in the average healthy adult and delay pancreatic ductal adenocarcinoma progression.

This article was featured on the cover of the June issue and highlighted in an AACR press release.

Journal: Cancer Research (June 15 issue)

Immunological Tolerance to Luciferase and Fluorescent Proteins Using Tol Mice Enables Development of Improved Tumor Models for Investigating Immunity and Metastasis

There is a continuing need for improved preclinical mouse models of cancer that more accurately predict therapy outcomes for future clinical translation. Luciferase and bioluminescence have long been utilized to generate models conducive to noninvasive imaging to monitor tumor growth, disease progression, and response to therapy. However, luciferase, as well as fluorescent reporter proteins, are highly immunogenic, limiting their use in some syngeneic tumor models in immunocompetent mice. In this study, we described the utility of transgenic mice engineered to have tolerance to luciferase and several other reporter proteins, known as Tol mice, in cancer immunology research. Some tumor cell lines expressing both luciferase and GFP were completely rejected in wild-type mice but maintained robust growth in Tol mice. Additionally, Tol mice allowed the development of an experimental brain metastasis model and a postsurgical resection spontaneous metastasis model. Importantly, even when certain cell lines carrying reporter proteins successfully formed tumors in immunocompetent wild-type mice, underlying immunity existed that could be reinvigorated by immune checkpoint inhibitors. Therefore, caution is needed when using such models in wild-type mice, as exaggerated effects may be induced by immunotherapy. Tol mice circumvent this problem and will likely widen the number of orthotopic and metastatic tumor models that can be used in immunotherapy studies in both C57Bl/6 and BALB/c mice.

Significance: Tol transgenic mice, tolerant to reporter proteins like luciferase and GFP, can be used to develop improved tumor models for studying metastasis and immunotherapy, avoiding immune rejection issues in immunocompetent mice.

A related commentary was published in the June 15 issue.

Journal: Clinical Cancer Research (June 1 issue)

A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor–Positive Advanced or Recurrent Endometrial Cancer

Purpose: Inhibition of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer are suboptimal, perhaps due to genomic alterations that promote estrogen receptor–independent cyclin D1–CDK4/6 activation. We hypothesized that the addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant would be an effective therapeutic strategy in patients with advanced or recurrent endometrial cancer.

Patients and Methods: In this phase II study, patients with advanced or recurrent endometrial cancer received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included estrogen receptor or progesterone receptor expression ≥1% by IHC, measurable disease, ≤2 prior lines of chemotherapy, and ≤1 prior lines of hormonal therapy. The primary endpoint was the objective response rate by RECIST v1.1.

Results: Twenty-seven patients initiated therapy, and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number–low/no specific molecular profile tumors, 1 response (9%) was in a microsatellite instability–high tumor, and no responses were observed in copy number–high/TP53 abnormal tumors. The objective response rate was 44% (90% confidence interval, 27.0%–62.1%). The median duration of response was 15.6 months. The median progression-free survival was 9.0 months (90% confidence interval, 1.8–20.4). The most common grade ≥3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified.

Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent endometrial cancer; a randomized trial is planned.

A related commentary was published in the June 1 issue.

Journal: Clinical Cancer Research (June 15 issue)

Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-Doublet Chemotherapy for Non–Small Cell Lung Cancer Harboring EGFR Mutation

Purpose: This study was performed to confirm the superiority in overall survival (OS) of EGFR tyrosine kinase inhibitor (TKI gefitinib or osimertinib) monotherapy versus EGFR TKI with intercalation of cisplatin plus pemetrexed as the first-line treatment for patients with advanced non-squamous non–small cell lung cancer (NSqNSCLC) harboring EGFR mutation.

Patients and Methods: This was an open-label, multicenter, randomized phase III study. Patients with chemotherapy-naïve advanced or recurrent NSqNSCLC harboring EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were randomly assigned (1:1) to EGFR-TKI monotherapy or the EGFR TKI plus intercalated chemotherapy group. The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS).

Results: From December 2015 to October 2020, 501 patients were randomized. The EGFR TKI was changed from gefitinib to osimertinib in October 2018 (gefitinib cohort: n = 308 and osimertinib cohort: n = 193). There was no survival advantage in the EGFR TKI plus intercalated chemotherapy group; the median survival time of both groups was 48.0 months (HR, 0.985; 91.4% confidence interval, 0.796–1.219; one-sided P = 0.4496). The median PFS time was 12.0 months in the EGFR-TKI monotherapy group and 18.0 months in the EGFR TKI plus intercalated chemotherapy group (HR, 0.762; 95% confidence interval, 0.628–0.925; one-sided P = 0.003). The OS and PFS trends in both gefitinib and osimertinib cohorts were identical to those in the entire population.

Conclusions: The intercalation of cisplatin plus pemetrexed after the response to EGFR TKI improved PFS but not OS compared with EGFR TKI monotherapy as the first-line treatment for patients with advanced NSqNSCLC harboring EGFR mutation.

Journal: Molecular Cancer Research

SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT

An atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of SMARCB1, which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors cooperate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single-cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We used a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost because of SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the in vivo efficacy of a clinically relevant inhibitor demonstrating SIRT2 inhibition as a potential therapeutic strategy. We concluded that SIRT2 is a critical dependency in SMARCB1-deficient ATRT cells and acts by controlling the pluripotency–differentiation switch. Thus, SIRT2 inhibition is a promising therapeutic approach that warrants further investigation and clinical development.

Implications: SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors.

Journal: Molecular Cancer Therapeutics

Development of a Novel Bifunctional Anti-CD47 Fusion Protein with Improved Efficacy and a Favorable Safety Profile

Therapeutic anti-CD47 monoclonal antibodies (mAbs) are designed to block the CD47–SIRPα checkpoint and promote immune-mediated recognition and elimination of cancer cells. However, current anti-CD47 mAbs have limitations, including off-tumor toxicity and reduced effectiveness in advanced cancers. Additionally, CD47 serves as a death receptor that mediates programmed cancer cell death (PCCD), a mechanism that has not been fully explored in current therapies. In this study, we introduce CO-001, a chimeric bifunctional IgG4 mAb, and its optimized variant CO-005, a bivalent humanized single-chain fragment variable–fragment crystallizable fusion protein. Both CO-001 and CO-005 promoted phagocytosis and PCCD. CO-005, specifically engineered to overcome the safety limitations associated with anti-CD47 antibodies, demonstrates a superior hematologic safety profile in vitro and ex vivo compared with benchmark anti-CD47 antibodies. Notably, CO-005 exhibited no binding to red blood cells, limited binding to white blood cells, and showed no hemagglutination activity. In preclinical models, CO-005 demonstrated potent antitumor activity in B-cell precursor acute lymphoblastic leukemia and Raji lymphoma xenograft models through the dual action of PCCD induction and enhancement of phagocytosis. The ability of CO-005 to trigger strong PCCD while preserving conventional immune responses provides a novel and promising approach for CD47-targeted cancer therapy. Its favorable safety profile, observed in both in vitro and ex vivo studies, positions CO-005 as a promising candidate with potential therapeutic advantages over existing anti-CD47 treatments.

Journal: Cancer Research Communications

Breast Cancer Risk Modification in Women with Pathogenic Variants in BRCA1, BRCA2, ATM, CHEK2, and PALB2

There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers.

Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

In 2017, Stuart Sherrow had surgery to remove an aggressive soft tissue sarcoma called dedifferentiated liposarcoma from his abdomen. Three months later, he felt a mass growing in the same spot. His doctors suggested chemotherapy followed by an additional surgery, but they said the cancer would likely keep coming back. “At the time, I didn’t have many options or choices,” Sherrow says. Then his doctors suggested he enroll in a clinical trial investigating whether immunotherapy given before surgery could help shrink the tumor and train his immune system to keep the disease at bay. Sherrow’s cancer responded to the treatment, and he had a second surgery. Today, more than seven years later, Sherrow has no evidence of disease. 

Sherrow’s story illustrates how oncologists are increasingly using immunotherapy before surgery in people with early-stage and locally advanced disease with the goal of improving the body’s long-term ability to fight cancer. “We’ve found that some of these patients who traditionally would be considered incurable appear to be cured,” says Mark Yarchoan, MD, a medical oncologist at the Johns Hopkins Kimmel Cancer Center in Baltimore. The latest issue of Cancer Today, a magazine and online resource for cancer patients, survivors, and caregivers published by the American Association for Cancer Research (AACR), explores the potential benefits of neoadjuvant immunotherapy, as well as questions that remain about the approach. 

Treating Prostate Cancer With PSMA-targeted Therapy  

Another article in Cancer Today’s summer issue details how oncologists incorporate prostate-specific membrane antigen (PSMA)-targeted therapy into care for people with metastatic prostate cancer. While the disease remains incurable, PSMA-targeted therapy is another tool in the oncologist’s toolbox when the prostate cancer stops responding to other treatments. Researchers also are exploring other ways the therapy could be incorporated in care. “There are many, many trials looking at PSMA now,” Praful Ravi, MB, BChir, a medical oncologist at Dana-Farber Cancer Institute in Boston, tells Cancer Today. “They’re looking at targeted agents all across the disease spectrum and not just in the advanced setting.” 

Overcoming Shame, Finding Support, and More Advice for Cancer Patients 

In the same issue, Cancer Today explores how people with cancer often feel shame about their diagnosis—whether because it is an “embarrassing” type of cancer or they feel they’re responsible for their disease. Researchers have found that people who feel shame about their cancer may delay medical care or withhold details from their oncologist. As researchers become more aware of how shame can be detrimental to cancer care, they are developing ways to help patients overcome those negative feelings. 

Additionally, Cancer Today highlights Lorrinda Gray-Davis, a liver cancer survivor who received a liver transplant in 2018. Since her surgery, Gray-Davis has hosted support groups that create a community for transplant recipients—something she wishes she’d had during treatment. “That was the worst part of my journey—that lack of knowing anyone who knew what I was going through,” she says. 

Cancer Today’s latest issue also provides practical information for patients, including analysis of the recent approval of a T-cell receptor therapy for synovial sarcoma. Articles also offer advice on topics ranging from how to prevent treatment-related bone damage to dealing with cancer ghosting. Plus, William G. Nelson, MD, PhD, director of the Johns Hopkins Kimmel Cancer Center and Cancer Today’s editor-in-chief, provides commentary about the link between air pollution and lung cancer risk. 

The AACR offers Cancer Today free of charge to those affected by cancer. To view content from the summer issue, visit Cancer Today’s website or read the digital edition.  

To stay up to date with the latest in cancer research and care, subscribe to the magazine or sign up to receive Cancer Today’s e-newsletter released twice a month. 

Ten years ago, the American Association for Cancer Research (AACR) launched Project GENIE (Genomics Evidence Neoplasia Information Exchange) with the goal of providing cancer researchers with access to real-world, clinico-genomic data from multiple institutions that they couldn’t find in any one place—the type of data necessary to fulfill many researchers’ wishes of being able to study rare genetic variants.  

“Our initial founding principle was the idea that we had to combine data because no single institution would’ve had enough information on rare variants or rare cancers to really make a meaningful impact using just their own data,” said Shawn M. Sweeney, PhD, senior director of the AACR Project GENIE Coordinating Center. 

By January 2017, eight institutions had contributed to this new publicly accessible data registry. Today, 20 institutions worldwide have contributed more than 200,000 total samples to AACR Project GENIE, with new releases of additional sequencing data announced every six months. 

“I don’t think there is any other dataset that’s collected as many genomic sequenced samples as AACR Project GENIE has,” said Kenneth L. Kehl, MD, MPH, from Dana-Farber Cancer Institute, the current chair of AACR Project GENIE. “And that enables a number of different types of analyses that wouldn’t otherwise be possible.” 

At the AACR Annual Meeting 2025, held April 25-30, such possibilities were on full display. Researchers showcased using AACR Project GENIE data in a number of different ways, including to identify potential therapeutic opportunities for a rare cancer, test out an artificial intelligence (AI) platform that provides insights on colorectal cancer, develop a new targeted tumor-agnostic therapy, and understand the differences between early-onset and late-onset gastroesophageal cancers. 

A Deeper Understanding of a Rare Kidney Cancer 

While targeted therapies and immunotherapies have shown promise for common forms of kidney cancer, options are much more limited for patients with a rare and aggressive kidney cancer subtype called collecting duct carcinoma (CDC). 

A deeper understanding of the molecular underpinnings of CDC is needed to identify new therapeutic opportunities, said Xiaofan Lu, PhD, of the University of Strasbourg.  

“There is limited data published for rare cancers,” said Lu. “But we found that there’s a lot of data about rare cancers in the [AACR Project GENIE] database, which was very useful for our study to validate the findings.” 

In the study he presented, Lu performed whole exome sequencing, RNA sequencing, and DNA methylation profiling to characterize the gene mutation and expression patterns of 22 cases of CDC. He then validated the findings against 25 CDC samples housed in the AACR Project GENIE database. 

Lu’s analyses revealed that mutations in the NF2, LZTR1, and SMARB1 genes, found on chromosome 22q, were common in CDC and that copy number loss of chromosome 22q occurred in more than half of the cases examined. In addition, Hippo signaling was frequently dysregulated due to mutations in the NF2, SAV1, and WWC1 genes, leading to overexpression of the YAP gene signature. Further, CDC was found to have upregulation of cell cycle and immune cell enrichment signatures that were not found in other kidney cancer subtypes.  

Lu also examined the tumor microenvironments of CDC, finding that immunologically “hot” tumor microenvironments were enriched for CD8 T cells, B cells, tertiary lymphoid structure signatures, and mutations in DNA damage response genes. Conversely, immunologically “cold” tumors frequently had copy number loss of chromosome 22q and overexpression of the YAP gene signature.  

He also demonstrated that the loss of chromosome 22q and mutations in DNA damage response genes were effective biomarkers to predict tumor response to immune checkpoint inhibition. 

“We added to the knowledge of pathogenesis of this disease, including, for example, chromosome 22q loss … which was never reported before,” said Lu. “We also identified … a subset of [CDC] that might respond to immune checkpoint inhibitors. We think our study would be beneficial to those patients diagnosed with this challenging disease.” 

Validating a Conversational AI System  

Enrique Velazquez-Villarreal, MD, PhD, MPH, of City of Hope, had a wish: a conversational AI platform that researchers could use to query datasets with simple natural language to help in their quests to advance precision medicine. But using publicly available platforms resulted in issues, including hallucinations. One example he provided: asking about the TAILORx clinical trial and getting a citation about Taylor Swift. So, Velazquez-Villarreal and his team built a new platform from scratch.  

Called the Precision Medicine AI Agent (PM-AI), their model turns clinical, social determinants of health, and genomic data into tokens that can be more easily analyzed using AI. Users can then conduct integrative data analysis by querying with pertinent questions, such as potential molecular biomarkers, how patients from different socioeconomic backgrounds or ethnic groups react to different therapeutics, or treatment strategies for patients with different KRAS mutations. The program can supply analysis within hours, compared to the weeks or months it can take to get a similar analysis using other platforms.  

To validate the platform, Velazquez-Villarreal’s team conducted a case-control study using data from The Cancer Genome Atlas (TCGA), cBioPortal for Cancer Genomics, and AACR Project GENIE. PM-AI was asked to compare how patients with colorectal cancer respond to FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) depending on whether they have RAS mutations. The platform identified KRAS as a predictor of poorer response and increased risk of recurrence, which is consistent with published findings.  

Velazquez-Villarreal said that in addition to publicly available data sources, researchers can also use PM-AI to query their own data. 

“We want to help researchers take advantage of this AI revolution,” Velazquez-Villarreal explained. “By using the AACR Project GENIE dataset, we are able to provide researchers with an opportunity to interact with this AI agent for the first time and feel confident about how the technology works before they work to adopt or improve upon this open-source model for their own purposes.” 

Reigning in a Rogue Genome Guardian 

As the guardian of the genome, the p53 tumor suppressor pathway is one of the body’s most important defenses against cancer. When cells are damaged, p53 springs into action to help them fix themselves or, if the damage is too severe, to trigger them to self-destruct. But when p53 itself mutates, cells lose their brakes and threaten runaway malignancy. One such variation results from the R175H missense mutation that changes the shape and function of the p53 protein. 

With the aid of AACR Project GENIE, a team at Clasp Therapeutics led by Kristen McEachern, PhD, analyzed genomic data from over 180,000 tumor samples to determine the frequency of this mutation that cripples p53’s protective power. Overall, R175H mutation occurred in about 2% of all tumors and more often in tough-to-treat diseases like colorectal, pancreatic, and ovarian cancer. This allowed them to estimate how many patients might benefit from new targeted therapies like CLSP-1025, thus defining an addressable population 

CLSP-1025 is a bispecific T-cell engager designed to direct immune assassins to cancer cells that possess this altered version of p53.  

One end of the diabody drug recognizes a peptide fragment unique to the R175H mutant, so long as it is presented in the context of a complex called HLA-A*02:01, which about 41% of people in the United States carry, according to the researchers. The other end of CLSP-1025 binds and activates T cells, triggering their cancer-killing function. 

Going after any form of mutant p53 has been hard because the full protein is expressed only inside of cells. But by using an antibody that connects the immune cells to cancer cells that express the mutant p53-HLA combo on their surface, this treatment turns this previously “undruggable” protein into a precision immunotherapy target. Thus far, the approach has shown promise preclinically, and the investigators have launched GUARDIAN-101, the first-in-human trial of CLSP-1025, earlier this year in patients with solid cancers. 

McEachern explained that the GENIE database “helped us to define a clear patient population for our ongoing phase I trial and support a tumor agnostic approach so that we can bring this important therapy to as many patients as possible.” 

Understanding the Molecular Landscape of Early-onset Cancers 

With cancer becoming increasingly common in younger populations, identifying the factors underlying early-onset cancers will be critical to developing successful prevention and therapeutic strategies. 

To this end, Ronan McLaughlin, MBBCh, BAO, of Princess Margaret Cancer Centre, used data from AACR Project GENIE to understand how molecular and clinical features differ between early-onset and late-onset gastroesophageal cancers (GEC). He examined data from 5,897 patients, 943 (16%) of whom had been diagnosed with GEC at age 50 or younger. 

The analysis benefited from data collected across 17 different institutions, McLaughlin noted, and it identified 26 genes that were differentially mutated between early-onset and late-onset GEC. All but two of these genes were more frequently mutated in late-onset GEC and included potentially actionable mutations, such as those in the CDKN2A, KRAS, FGF4, and FGFR3 genes. 

The genes CDH1 and CCNE1 were significantly more likely to be mutated in early-onset GEC than in late-onset cases. McLaughlin noted that CDH1 and CCNE1 mutations were previously found to be associated with hereditary gastric cancer syndromes, aggressive disease, and poor survival.  

Compared with the late-onset GEC cohort, the early-onset cohort had a higher proportion of female patients and a higher percentage of Asian patients. Survival analyses did not reveal statistically significant differences between the cohorts; however, patients with early-onset GEC had numerically shorter progression-free survival. 

“Looking at somatic mutations has allowed us to identify two mutations that are identified more commonly and enriched in that younger-onset group,” McLaughlin said. “[The findings] will allow us to develop targeted therapies, design future clinical trials, and ultimately [impact] patient outcomes.”