Advanced prostate cancer remains challenging to treat, particularly after the development of resistance to androgen receptor-targeted therapies. Current options have significant limitations as Poly ADP-ribose polymerase (PARP) inhibitors benefit only tumors with homologous recombination deficiency, and radiation therapy is often unsuitable for metastatic disease. Genomic alterations common in advanced prostate cancer (e.g., TP53 loss, MYC amplification, BRCA2 mutations) increase replication stress, creating therapeutic vulnerability. Checkpoint kinase 1 (CHK1), a key regulator of replication stress response, is an emerging target. Prexasertib, a CHK1/2 inhibitor under clinical investigation in other cancers, has not been systematically studied in prostate cancer. Here, we evaluated prexasertib efficacy and explored molecular mechanisms of sensitivity. Prexasertib was tested as a monotherapy across 27 metastatic prostate cancer patient-derived xenograft (PDX) models with diverse histopathology and genomic backgrounds. Response was quantified by comparing tumor growth slopes between treated and vehicle groups, and classified as responder, intermediate responder, or non-responder. Pre-treatment PDX RNA-seq was used to identify transcriptional signatures associated with treatment response. To investigate mechanisms, we performed CRISPR/Cas9 knockout screens in PC-3, 22Rv1, and LNCaP cells using a custom sgRNA library targeting ∼1800 DNA damage response genes under prexasertib treatment at IC20. Prexasertib inhibited tumor growth in 26% (7/27) PDX models. RNA-seq analysis revealed enriched E2F signaling in sensitive tumors. CRISPR/Cas9 knockout screens identified key genes whose loss enhanced sensitivity, including Wee1-like protein kinase 1 (WEE1), a checkpoint kinase linked to CHK1 inhibitor resistance. Integration of transcriptomic and functional genomic data highlighted overlapping candidate genes currently under investigation to refine therapeutic strategies. Prexasertib demonstrated efficacy in a subset of metastatic prostate cancer PDX models. Combined transcriptomic and functional genomic analyses identified candidate mediators of sensitivity, providing a foundation for advancing CHK1/2 inhibitor-based therapies in prostate cancer. Jiachen Ji, Aliaa Alamoudi, Nadia Boufaied, Connor J. Sessions, Holly M. Nguyen, Ilsa M. Coleman, Maria C. Fernandez, Eva Corey, David P. Labbé. CHK1/2 inhibition with prexasertib reveals therapeutic vulnerabilities in advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A027.

There are 3.5 million prostate cancer survivors in the United States. While prostate cancer is the second leading cause of cancer death in men, individuals with prostate cancer have a higher risk of dying of cardiovascular diseases or other cancers than prostate cancer. The composition of dietary fats plays a key role in mortality as saturated and trans fats, and fats from animal sources, are associated with an increased risk of all-cause and cardiovascular mortality in the general population. This highlights the need for evidence-based recommendations for lifestyle interventions that improve survival overall among prostate cancer patients. We investigated dietary fat intake and mortality among 4,884 men diagnosed with clinical stage T1-T3 prostate cancer between 1986 and 2019 who were participants of the Health Professionals Follow-up Study. Dietary data collected every 4 years using validated semi-quantitative food frequency questionnaires (FFQ) were used to assess post-diagnosis intakes of saturated, polyunsaturated, monounsaturated, and trans fats, as well as fats from animal or vegetable sources. Post-diagnosis dietary fat intake was defined as the intake reported on the first questionnaire with FFQ collected at least 6 months after diagnosis. Multivariable Cox regression and nutrient-density models were used to investigate associations between dietary fat intake (in quintiles) after diagnosis and all-cause, prostate cancer, other cancer, and cardiovascular mortality through 2022. The median age at prostate cancer diagnosis was 70 years (IQR 65-74). The primary causes of death were due to prostate cancer (441 deaths), other cancers (499 deaths), and cardiovascular disease (803 deaths). Higher post-diagnostic saturated fat intake was associated with higher risk of all-cause mortality (HRQ5vQ1 1.28, 95% CI 1.10-1.50), cardiovascular mortality (HRQ5vQ1 1.45, 95% CI 1.06-1.98), and death from other cancers (HRQ5vQ1 1.46, 95% CI 0.98-2.18). Replacing 10% of calories from animal fats with carbohydrates (HR 0.91, 95% CI 0.83-1.00) or vegetable sources (HR 0.85, 95% CI 0.77-0.93) was associated with a lower risk of all-cause mortality. Replacing 5% of calories from saturated fat with monounsaturated fat was also associated with a lower risk of all-cause mortality (HR 0.80, 95% CI 0.71-0.91), primarily due to reductions in cardiovascular mortality. There were no associations between any fat intake and prostate cancer mortality in any models when comparing extreme quintiles of intake. Among participants with non-metastatic prostate cancer, higher intake of post-diagnostic saturated fat was associated with higher risk of all-cause mortality, driven by death from cardiovascular disease and other cancers, the primary causes of mortality in this patient group. Our results suggest that replacing saturated and animal fats with healthier plant fats may improve survival among prostate cancer patients. * YZ, MRS: Authors contributed equally ** ELG, DPL, LAM: Senior authors contributed equally Megan R. Shanahan, Yiwen Zhang, Hannah E. Guard, Jiachen Ji, Maria Celia Fernandez, Nadia Boufaied, Jane B. Vaselkiv, Binkai Liu, Chaoran Ma, Rebecca E. Graff, Stacy Loeb, Caroline Himbert, Yuan Ma, Edward L. Giovannucci, David P. Labbé, Lorelei A. Mucci. Post-diagnostic dietary fat intake and long-term survival among patients with stage T1-T3 prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B068.

The proto-oncogene MYC acts as a master regulator of diverse metabolic programs that fuel tumor initiation and progression, but the exact programs it activates depend heavily on context, tissue type, accompanying mutations, and the tumor microenvironment (TME). Furthermore, extrinsic influences, including diet and systemic metabolism, interact with MYC to reshape tumor and stromal cell metabolism, revealing a multifaceted metabolic landscape governed by MYC. This review focuses on MYC-driven in vivo metabolic addictions and discusses tissue-specific programs, TME interactions, and systemic influences to illustrate how MYC-driven metabolic reprogramming creates context-dependent vulnerabilities. These insights may uncover actionable targets and guide precision therapeutic strategies for MYC-driven cancers.

Importance There are 3.5 million prostate cancer survivors in the US, with a need for evidence-based lifestyle recommendations that improve survivorship. Objective To assess whether consumption of specific dietary fats after diagnosis is associated with long-term survival among patients with nonmetastatic prostate cancer. Design, Setting, and Participants This study, nested in the Health Professionals Follow-Up Study, a cohort of male health professionals from across 50 US states ongoing since 1986, included participants with confirmed nonmetastatic prostate cancer between 1986 and January 2019, followed up through December 2022. Statistical analysis was conducted from July 2024 to May 2026. Exposures Dietary data were collected every 4 years from validated food frequency questionnaires and used to estimate intake of saturated, polyunsaturated, monounsaturated, trans, plant, and animal fat after cancer diagnosis. Main Outcomes and Measures Main outcomes were all-cause mortality and death from prostate cancer, other cancers, cardiovascular disease, and other causes during a median 12.8 years (IQR, 8.1-16.8 years) of follow-up through 2022. Hazard ratios (HRs) and 95% CIs from multivariable Cox proportional hazards regression and multivariate nutrient-density models examined associations with mortality, adjusting for demographic, epidemiologic, and clinical factors. Results Among 4884 patients with nonmetastatic prostate cancer, the mean (SD) age at diagnosis was 69.5 (6.9) years. During follow-up, 3040 deaths from any cause were confirmed. When comparing patients in the highest quintile of saturated fat consumption with those in the lowest quintile, higher postdiagnostic saturated fat intake was associated with greater all-cause (HR, 1.24 [95% CI, 1.05-1.47), cardiovascular (HR, 1.42 [95% CI, 1.02-1.98]), and other cancer mortality (HR, 1.42 [95% CI, 0.93-2.17]). Animal fat, a major source of saturated fats, was also positively associated with all-cause mortality (HR, 1.14 [95% CI, 0.97-1.33]), as well as deaths from other cancers (HR, 1.49 [95% CI, 1.00-2.21]). Replacing 10% of calories from animal fats with plant-based fats (HR, 0.84 [95% CI, 0.76-0.93]) and replacing 5% of calories from saturated fats with monounsaturated fats (HR, 0.80 [95% CI, 0.70-0.91]) was associated with a decrease in all-cause mortality. There were no associations between dietary fats and prostate cancer mortality. Conclusions and Relevance In this cohort study of patients with nonmetastatic prostate cancer, saturated fats, including animal fats, were associated with greater all-cause mortality owing to deaths from cardiovascular disease and other cancers. Diets rich in monounsaturated and polyunsaturated fats and plant-based fats after prostate cancer diagnosis were associated with improved survival outcomes for patients. These findings support evidence-based recommendations for patients and clinicians around dietary fat consumption to improve survivorship outcomes in the clinical setting of nonmetastatic prostate cancer.

BACKGROUND:Reduced protein intake is associated with adverse outcomes in critically ill patients. Paradoxically, large-scale randomized controlled trials have failed to demonstrate a beneficial effect of protein supplementation, perhaps because the dose required to achieve an anabolic response is unknown, and because biological mechanisms that determine individual patient responses to nutrition are poorly understood. OBJECTIVES:The objective of this study was to determine the effect of exogenous protein dose on whole-body protein balance (WBPB) and associated biological markers of metabolic response. METHODS:We conducted a randomized controlled trial to determine the effect of high dose (2.5 g/kg/d by parenteral amino acid infusion for 48 h) compared with usual (0.8 g/kg/d) or moderate (1.75 g/kg/d) doses on WBPB. By measuring 13C-leucine stable isotope kinetics, whole-body protein synthesis and breakdown were evaluated before and after the intervention. As a comprehensive and well-annotated method to achieve untargeted biomarker identification, the blood transcriptome was interrogated by RNA sequencing every 12 h to identify molecular signatures associated with increases in WBPB during protein supplementation. RESULTS:Thirty-three patients were randomly assigned, and 25 completed the study. The increase in WBPB for the high-dose group was 10.0±3.7, and that for the moderate and usual-dose groups were 6.7±2.9 and 6.6±3.6, μmol/kg/h (mean±SEM) respectively. After adjusting for baseline WBPB, high dose (P = 0.036 vs. usual dose, P = 0.047 vs. moderate dose), but not moderate dose (P = 0.893 vs. usual dose) protein led to larger increases in WBPB. Increased WBPB was associated with lower baseline protein balance (R2 = 0.18, P = 0.03), and reduced expression of a distinct neutrophil bactericidal gene signature (normalized enrichment score = -1.613, Padj = 0.003). CONCLUSIONS:Larger increases in WBPB were observed in critically ill patients receiving a high-dose protein supplementation strategy, and these increases were associated with a biological program reflecting neutrophil-mediated bacterial killing. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT02865408.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype.

Prostate cancer (PCa) represents a worldwide leading cause of cancer-related mortality in men. Diabetes is also a highly prevalent and a rapidly growing pathology. Intriguingly, diabetes is associated with decreasing PCa incidence, and at the same time, it is linked to increased mortality rates for men already afflicted by the disease. A plausible mediator causing this effect are Advanced Glycation End Products (AGEs), products of the Maillard reaction, occurring between sugars and proteins at body temperature. AGEs, known to be elevated in diabetic patients, have been reported to increase the Extracellular Matrix (ECM) stiffness via ECM-crosslinking, potentially explaining the tumor-promoting effects of diabetes in cancer progression. Nonetheless, the protective role of diabetes in prostate cancer is not yet fully understood. Interestingly, we demonstrated that AGEs, produced by mixing sugars and an abundant circulating protein in the blood decreased PCa cell proliferation in vitro in a dose-dependent and irreversible manner across a panel of human PCa cell lines. Importantly, through transcriptomic analysis, we found that AGEs-mediated cell proliferation blocking correlate with a senescence transcriptional signature. Accordingly, treatment with AGEs lead to increased beta-galactosidase activity, a hallmark of senescence, and to the upregulation of senescent markers linked to cell cycle arrest (p21WAF1/Cip1) and pro-inflammatory cytokines (IL-8) at the transcriptional and translational levels. We also confirmed the expression of the senescence-associated secretory phenotype (SASP, e.g., IL, CXCL, CCL) in AGEs-treated PCa cells. Finally, our validation of key transcriptomics analysis confirmed the upregulation of HMOX1, an enzyme reported to be induced during cellular senescence, upon AGEs treatment. Altogether, our results suggest that AGEs-mediated senescence could underlie the lower incidence of PCa among diabetic patients. This sets the stage for combination treatments between AGEs and senolytics, drugs that selectively target and induce cell death in senescent cells, as a novel therapeutic strategy in PCa. Luisa Bacca, Tarek Hallal, Carole Luthold, Nadia Boufaied, François Bordeleau, David Labbé. Characterization of a senescence phenotype induced by advanced glycation end products in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 299.

Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, particularly in its advanced and metastatic stages. While various systemic therapies have improved clinical outcomes, therapy resistance and disease progression remain significant challenges. One critical, yet underappreciated, mechanism influencing treatment response is therapy-induced senescence (TIS), a stable form of cell cycle arrest triggered by anticancer treatments. In PCa, TIS can be elicited by chemotherapy, radiotherapy, hormonal therapies, and targeted agents, and is characterized by a complex interplay of tumor-suppressive and tumor-promoting effects, largely mediated through the senescence-associated secretory phenotype (SASP). This review explores the molecular mechanisms of senescence, the diverse therapeutic strategies that induce it, and the dual roles it plays in PCa progression and treatment resistance. We further discuss emerging approaches that combine senescence-inducing therapies with senescence-targeting strategies, such as senolytics and senomorphics, to mitigate the adverse consequences of persistent senescent PCa cells. Finally, we highlight ongoing clinical trials, translational barriers, and future directions in integrating senotherapy into the clinical management of PCa.

Supplementary Figure S8 shows migration assays of MYC-CaP cells treated with lactate or LDHA inhibitor FX11.

Excel file containing 19 supplementary tables

Supplementary Figure S1 shows the systemic effects of HFD.

Supplementary Figure S7 shows the output of mouse-based deconvolution models ImmuCC and mMCP.

Supplementary Figure S6 includes scRNA-seq data showing that Luminal (high Ly6d) cells in MYC-transformed DLP display glycolytic features.

Supplementary Figure S10 shows the output of human-based deconvolution model QuanTIseq.

Supplementary Figure S9 shows GSEA_Hallmark results in human PCa

Supplementary references for Materials and Methods