e18124 Background: Social determinants of health (SDOH), encompassing socioeconomic and environmental factors, are pivotal in modulating cancer outcomes, yet their long-term implications in head and neck cancers, particularly cancers of the lip, oral cavity, and pharynx (CLOP), remain inadequately characterized amid rising disparities in oncology care. This study investigates the association between adverse SDOH and clinical outcomes in patients with CLOP. Methods: This retrospective, propensity score-matched cohort study utilized data from the TriNetX network, comprising electronic medical records from 88 healthcare organizations. Adults (aged ≥18 years) with CLOP (ICD-10-CM: C00-C14) were stratified into cohorts without (n = 265,544) and with (n = 6,235) adverse SDOH (ICD-10-CM Z59/Z60 codes for housing instability, food insecurity, low income, transportation barriers, and social environment issues). Propensity score matching (1:1) balanced cohorts (n=5430 each) on demographics, BMI, comorbidities, and Eastern Cooperative Oncology Group performance status. The index event was initial CLOP diagnosis and outcomes were assessed from 1-day post-index onward. Analyses included measures of association, Kaplan-Meier survival with log-rank tests and hazard ratios (HRs; Cohort 2 [SDOH] vs Cohort 1 [non-SDOH]), with statistical significance at p<0.05. Results: Matched cohorts were balanced (mean [SD] age, 64 [14] years; 66% male; 63% White). Adverse SDOH was associated with increased mortality (risk, 30.3% vs 25.4%; risk difference, 0.050 [95% CI, 0.032-0.067]; P < .001; HR, 1.76 [95% CI, 1.63-1.89]; P = .038; median survival, 2057 vs 5111 days). Severe sepsis risk was higher with SDOH (6.7% vs 5.7%; risk difference, 0.010 [95% CI, 0.000-0.019]; P = .04; HR, 1.69 [95% CI, 1.44-1.98]; P = .035). Multiple conditions demonstrated comparable associations with worse survival: respiratory disease (HR, 1.23 [95% CI, 1.10-1.39]; P = .38), malnutrition (HR, 1.30 [95% CI, 1.17-1.45]; P = .62), acute kidney failure/CKD (HR, 1.39 [95% CI, 1.24-1.56]; P = .006), infectious diseases (HR, 1.47 [95% CI, 1.33-1.62]; P = .66), and metabolic disorders (HR, 1.27 [95% CI, 1.13-1.42]; P = .11). Dysphagia risk was lower with SDOH (25.6% vs 32.0%; risk difference, -0.064 [95% CI, -0.086 to -0.043]; P < .001; HR, 0.88 [95% CI, 0.81-0.97]; P = .073). Mental/behavioral disorder risk was lower with SDOH (25.4% vs 28.8%; risk difference, -0.034 [95% CI, -0.065 to -0.003]; P = .04; HR, 1.22 [95% CI, 1.06-1.40]; P = .03). Conclusions: Adverse SDOH significantly worsen long-term survival and select morbidity risks in CLOP patients, highlighting the need for multifaceted interventions integrating social support into oncologic frameworks to mitigate disparities and improve equitable oncology care.

MECOM suppression enhances spheroid inhibition and apoptosis

Abstract Immune checkpoint inhibitors (ICIs), including anti-PD-1 antibodies, have transformed the management of genitourinary malignancies, yet a substantial proportion of patients exhibit primary or acquired resistance. Resistance to PD-1 blockade has been associated with an immunosuppressive tumor microenvironment characterized by elevated regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Histone deacetylase inhibitors (HDACi) such as vorinostat may overcome these barriers by reprogramming immune and chromatin landscapes to favor antitumor activity. In this study, we integrated transcriptomic, epigenomic, and immunogenetic analyses from a Phase I/IB clinical trial of vorinostat plus the PD-1 inhibitor pembrolizumab and a preclinical mouse model to investigate the mechanisms driving response. ATAC-seq of peripheral blood mononuclear cells (PBMCs) revealed that patients with clinical response maintained global chromatin accessibility from baseline to on-treatment, including at promoter regions of immune activation genes such as IRF1, IRF4, and IRF8. Gene Ontology and motif enrichment analyses demonstrated enrichment of IRF-family transcription factor motifs within regions of increased accessibility. Corresponding RNA-seq analyses showed upregulation of IRF4 and reduced expression of immunosuppressive genes including FOXP3 and TIGIT, consistent with a less suppressive immune phenotype and enhanced effector activation. Interestingly, HLA genotyping identified an overrepresentation of HLA-B44 supertype alleles among responders, suggesting a potential immunogenetic predictive marker. Building on the immune profiling results, we next examined how the combination therapy of vorinostat and anti-PD-1 shaped immune programs in a murine model of kidney cancer (RENCA). We observed significantly reduced tumor burden, decreased metastases, and improved overall survival relative to monotherapies. Single-cell RNA-seq of splenocytes revealed downregulation of myeloid-associated immunosuppressive genes (Saa1, Saa3, S100a8, S100a9) in the combination group, implicating HDAC inhibition in the attenuation of MDSC and neutrophil-mediated resistance pathways. Flow cytometry studies are ongoing to further characterize the immune cell composition and validate these transcriptomic findings at the protein level. In summary, these findings suggest that HDAC inhibition may enhance PD-1 blockade efficacy by maintaining chromatin accessibility at immune activation loci, reducing immunosuppressive signaling, and potentially interacting with host HLA genotype to shape therapeutic outcome. These results support further exploration of HDAC inhibitors as a rational combination strategy to overcome immune resistance in cancer. Citation Format: Otega Oviri, Tyler Gross, Md Imran Khan, Sean Henry Colligan, Jonathan E. Bard, Roberto Pili. Epigenetic induced increased chromatin accessibility of immune activation loci is associated with response to anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1552.

Functional studies confers the role of MECOM in regulation of AR activity and survival transcriptional programs

12119 Background: Social determinants of health (SDOH) such as housing instability, food insecurity, and low income are known to influence health outcomes, but their long-term effects on prostate cancer (PCa) patients remain underexplored. To compare long-term outcomes, including mortality, sepsis, sexual dysfunction, and comorbidities across major organ systems, between prostate cancer patients with and without adverse SDOH. Methods: Retrospective cohort study using the TriNetX federated database (deprecated COVID-19 Research Network, 88 healthcare organizations). Cohort 1 included adults (≥18 years) with PCa (ICD-10-CM C61) and at least one adverse SDOH code (n = 14,595). Cohort 2 included PCa patients without SDOH codes (n = 875,545). Propensity score matching (1:1) balanced cohorts on demographics, external morbidity causes, ECOG status, and BMI (final n = 12,626 per cohort). The index event was the first prostate cancer diagnosis (with SDOH for Cohort 1). Outcomes assessed from 1-day post-index onward (up to 20 years prior exclusion). Risk ratios (RR), hazard ratios (HR) from Kaplan-Meier survival, and mean instances via t-tests for mortality, severe sepsis, sexual dysfunction, and diseases of genitourinary, circulatory, endocrine/metabolic, respiratory, digestive, and infectious systems. Results: After matching, cohorts were balanced (mean age ~72 years, ~56% White, ~25% Black). PCa with adverse SDOH had higher mortality risk (22.0% vs 17.3%; RR 1.272 [95% CI, 1.209-1.338]; p < 0.001) and worse survival (median 2821 vs 5246 days; HR 2.018 [95% CI, 1.906-2.137]; p < 0.001). Severe sepsis risk was elevated (5.6% vs 4.7%; RR 1.199 [95% CI, 1.074-1.339]; p < 0.001; HR 1.824 [95% CI, 1.626-2.047]; p < 0.001). Sexual dysfunction risk was lower (0.2% vs 0.4%; RR 0.493 [95% CI, 0.305-0.794]; p = 0.003). For comorbidities, PCa with adverse SDOH showed mixed risks—genitourinary diseases had a lower risk but poorer survival (HR 1.113, 95% CI 1.017-1.218, p = 0.020); circulatory diseases showed equivalent risk but worse survival (HR 1.223, 95% CI 1.089-1.374, p = 0.001); endocrine/nutritional/metabolic conditions had similar risk but reduced survival (HR 1.277, 95% CI 1.151-1.418, p < 0.001); respiratory diseases had equivalent risk but poorer survival (HR 1.531, 95% CI 1.416-1.656, p < 0.001); digestive diseases demonstrated lower risk with worse survival (HR 1.308, 95% CI 1.200-1.425, p < 0.001). Conclusions: Adverse SDOH are associated with increased mortality and poorer survival in prostate cancer, alongside heightened sepsis risk and differential comorbidity patterns. Interventions targeting SDOH may improve long-term outcomes.

Pathways enriched by SE-driven genes

Reprogramming of the androgen receptor (AR) cistrome is associated with prostate cancer progression, and advanced castration-resistant prostate cancers (CRPC) tend to rely on reprogrammed/noncanonical AR signaling that remains active under treatment with AR signaling inhibitors (ARSI). In this study, we identified ecotropic viral integration site 1 (EVI1), an oncogenic nuclear transcription factor (TF) encoded by MECOM, as an AR-recruited coactivator of noncanonical signaling. In prostate cancer, MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus. MECOM depletion in prostate cancer cells decreased proliferation, altered cell survival transcriptional programs, and reduced the number of super-enhancers (SE), leading to a dynamic change in the SE landscape and a decrease in the expression of SE-regulated oncogenic TFs, along with increased proapoptotic signatures. Notably, cells overexpressing MECOM and its protein, EVI1, were susceptible to PARP inhibitors (PARPi) regardless of their DNA damage response or homologous recombination repair (HRR) gene mutation status. These insights reveal the crucial role of EVI1 in regulating cell survival within the context of an AR-reprogrammed chromatin landscape. More importantly, the findings suggest that MECOM overexpression may be another biomarker that could significantly broaden the use of PARPis beyond those with HRR gene mutations. SIGNIFICANCE:MECOM is a driver of androgen receptor inhibitor resistance in castrate-resistant prostate cancer that promotes susceptibility to PARP inhibition, positioning MECOM as a biomarker in patients without homologous recombination repair gene mutations.

e21599 Background: Immune checkpoint inhibitors have transformed melanoma treatment, but comorbidities like periodontal disease—pre-existing or immune-related adverse events—may modulate efficacy and toxicity through systemic inflammation and immune dysregulation. This study examined associations between periodontal disease (any-time diagnosis) and clinical outcomes, including mortality and systemic complications, in melanoma patients receiving immunotherapy. Methods: This retrospective cohort study used the TriNetX federated network of deidentified electronic medical records from 88 healthcare organizations. Adults (aged ≥18 years) with melanoma (ICD-10-CM C43-C44) receiving immunotherapy (pembrolizumab or antineoplastic immunotherapy encounter) were stratified by presence (n = 703) or absence (n = 37,419) of periodontal disease (ICD-10-CM K05). Propensity score matching (1:1) balanced race, communicable disease hazards, body mass index, and Eastern Cooperative Oncology Group performance status, yielding 698 patients per group. Analysis was performed January 24, 2026. The primary outcome was all-cause mortality, with secondary outcomes of circulatory (I00-I99), endocrine/metabolic (E00-E89), respiratory (J00-J99), and digestive (K00-K95) diseases; fever of unknown origin (R50); and symptoms involving food/fluid intake (R63), circulatory/respiratory systems (R00-R09), and digestive system/abdomen (R10-R19). Outcomes were assessed from 1 day post-index event (melanoma diagnosis) onward. Analyses included risk differences, ratios, odds ratios, Kaplan-Meier survival (log-rank), Cox hazard ratios, and instance counts excluding prior events. Results: Post-matching, mortality was higher in the periodontal group (41.7% vs 34.8%; risk difference −0.069 [95% CI, −0.120 to −0.018]; P = .008; risk ratio 0.835 [95% CI, 0.730-0.955]; odds ratio 0.746 [95% CI, 0.601-0.927]) with shorter median survival (1271 vs 1626 days; log-rank P = .002; hazard ratio 0.763 [95% CI, 0.643-0.906]; P = .016). Significant associations included fever of unknown origin (hazard ratio 0.682 [95% CI, 0.495-0.939]; log-rank P = .018) and food/fluid intake symptoms (22.3% vs 14.8%; risk difference −0.075 [95% CI, −0.125 to −0.024]; P = .003; hazard ratio 0.603 [95% CI, 0.445-0.817]). No significant differences emerged for circulatory (P = .288), endocrine/metabolic (P = .268), respiratory (P = .999), or digestive symptoms (P = .756 for digestive symptoms; disease analysis precluded due to 0 events in periodontal group). Conclusions: Periodontal disease is linked to poorer survival and select complications in immunotherapy-treated melanoma patients. These findings advocate for routine periodontal evaluation and intervention to potentially enhance oncologic outcomes.

Purpose Limited research has evaluated the success criteria and priorities for symptom improvement of patients with cancer to inform patient-centered care. In this study, we adapted and tested a measure of these constructs, the Patient-Centered Outcomes Questionnaire (PCOQ), for patients with advanced prostate cancer. We compared acceptable symptom severity levels following symptom treatment across 10 symptoms and identified patient subgroups based on symptom importance. Methods Patients with advanced prostate cancer (N = 99) participated in a one-time survey, which included a modified version of the PCOQ, standard symptom measures, and additional clinical characteristics. Results The modified PCOQ demonstrated construct validity through its correlations with related theoretical constructs. There was a moderate correlation between symptom severity and importance. Acceptable symptom severity levels were generally low, with sexual dysfunction having a higher acceptable severity than most other symptoms. Three patient subgroups were identified: (1) those who rated all symptoms as low in importance (n = 43); (2) those who rated all symptoms as moderately important (n = 33); and (3) those who rated all symptoms as highly important (n = 18). Subgroups were associated with functional status, fatigue, sleep problems, pain, and emotional distress. Conclusion The modified PCOQ demonstrated preliminary evidence of construct validity. Patients generally considered low symptom severity to be acceptable, with variations across symptoms. Results suggest that symptom severity and importance are related but distinct aspects of the symptom experience in advanced prostate cancer. Patients’ diverse priorities for symptom improvement point to the need for individualized treatment plans.

Enriched Pathways from genes closest to AR_unique sites

Abstract Tyrosine kinase inhibitors (TKIs) are critical to the treatment of renal cell carcinoma (RCC). However, recurrent and metastatic RCC frequently develop resistance to TKIs, limiting therapeutic options. Understanding the molecular mechanisms underlying this resistance is crucial for improving patient outcomes. Our previous studies have identified EZH2 and the androgen receptor (AR) as key regulators of acquired resistance to the TKI . Inhibiting EZH2 or AR restores sunitinib sensitivity in vitro and in vivo, highlighting these molecules as therapeutic targets potentially shared across TKIs .To investigate the interplay between EZH2 and AR, we compared sunitinib-resistant 786-0 cells (786-0RS) with drug-naive 786-0 cells overexpressing AR (786-0AR). Chromatin immunoprecipitation sequencing revealed that AR and EZH2 co-occupy genomic loci exclusively in resistant cells. Sunitinib treatment induced nuclear translocation of AR in 786-0AR, with AR binding at EZH2-occupied sites. Mass spectrometry further showed high phosphorylation of AR at S81 and S213, markers of ligand-independent activation, in 786-0RS, which was absent in 786-0AR.786-0RS cells undergo EZH2-dependent reprogramming of the tyrosine kinome via a likely non-canonical mechanism. Co-expression of a phosphomimetic EZH2 mutant (S21D) with AR promoted sunitinib resistance, whereas wild-type or phosphonull (S21A) EZH2 did not. Expanded phosphoproteomic analyses revealed extensive rewiring of serine/threonine signaling networks in sunitinib resistant cells, including enrichment of EGFR-driven MAPK and AKT pathways. Interestingly, preliminary data indicate that cabozantinib does not induce AR and EZH2 upregulation like other TKIs such as lenvatinib. Moreover, cabozantinib appears to prevent compensatory pathway activation triggered by lenvantinib, suggesting a distinct resistance profile. Consistently, AR expression is observed in RCC lines resistant to sunitinib, dovitinib, and lenvatinib, but not with cabozantinib treatment. Ongoing phosphoproteomic analysis will dissect the difference across the TKIsdrugs. Overall, our findings suggest that EZH2-dependent kinase reprogramming drives AR phosphorylation and activation, contributing to drug resistance to selective TKIs. Cabozantinibunique ability to bypass AR/EZH2 upregulation underscores the need to explore alternative resistance pathways. Citation Format: Christian Migliarese, Abbas Jawadwala, Sabrina A. Orsi, Stephanie Metcalf, Saranya Rajendran, Peter C. Hollenhorst, Roberto Pili. EZH2-AR non-canonical axis activation in TKI-resistant RCC: Differential effects of lenvatinib and cabozantinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5291.

e21600 Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for advanced malignant melanoma, but immune-related adverse events (irAEs) such as stomatitis may impact long-term outcomes. The association between stomatitis and subsequent morbidity, including mortality and systemic irAEs, remains underexplored. To evaluate the long-term effects of stomatitis on mortality and other adverse outcomes in melanoma patients receiving ICIs. Methods: Retrospective cohort study using the TriNetX federated database (deprecated COVID-19 Research Network, 88 healthcare organizations). Patients aged ≥18 years with malignant melanoma (ICD-10-CM C43) receiving ICIs (pembrolizumab, nivolumab, or ipilimumab) were divided into cohorts with (n = 1,719) and without (n = 22,228) stomatitis (ICD-10-CM K12). Propensity score matching (PSM) balanced cohorts on demographics, BMI, ECOG score, and comorbidities, yielding 1,708 patients per group. Exposures included-Stomatitis during ICI therapy. Main Outcomes and Measures--Primary outcome: all-cause mortality. Secondary outcomes: respiratory diseases, dysphagia, malaise/fatigue, trismus, fever, circulatory/respiratory symptoms, endocrine/metabolic diseases, circulatory diseases, and digestive diseases. Analyses included risk ratios (RRs), odds ratios (ORs), hazard ratios (HRs) from Kaplan-Meier survival, and mean instances, starting 1 day post-index event (first ICI administration). Results: After PSM, the stomatitis cohort had a higher mortality risk (37.3% vs 31.4%; RR, 0.842 [95% CI, 0.765-0.926]; HR, 0.829 [95% CI, 0.737-0.933]; P = 0.002 for log-rank). Respiratory diseases were more common (53.3% vs 43.3%; RR, 0.813 [95% CI, 0.721-0.917]; P = 0.001; HR, 0.711 [95% CI, 0.600-0.842]; P < 0.001). Dysphagia instances were higher (mean 2.913 vs 2.121; P = 0.023), though risk was borderline (11.2% vs 9.1%; RR, 0.806 [95% CI, 0.648-1.003]; P = 0.053). Circulatory/respiratory symptoms (49.2% vs 42.3%; RR, 0.860 [95% CI, 0.758-0.975]; P = 0.020) and circulatory diseases (59.5% vs 51.5%; RR, 0.866 [95% CI, 0.757-0.990]; P = 0.041; HR, 0.690 [95% CI, 0.562-0.847]; P < 0.001) were elevated in the stomatitis group. No significant differences for malaise/fatigue, trismus, fever, endocrine, or digestive diseases. Conclusions: Stomatitis during ICI therapy for melanoma is associated with increased long-term mortality and select irAEs, particularly respiratory and circulatory complications. These findings suggest stomatitis may signal broader immune dysregulation, warranting closer monitoring.

MECOM Overexpression CRPC are vulnerable to PARP inhibitors and inhibitors of the DNA repair pathway irrespective of HRR or DDR genes mutation status

Abstract The Androgen Receptor (AR) pathway is a primary target for metastatic castration-resistant prostate cancer (mCRPC) treatment, and AR blockade with enzalutamide is a well-established therapeutic option for targeting the AR pathway in mCRPC. However, prostate cancer cells can bypass AR blockades through induction of other pathways for survival, and recently numerous preclinical studies have made the PI3K-AKT pathway a target of interest for the treatment of drug-resistant mCRPC. The PI3K-AKT pathway has pleiotropic effects, and its inhibition has long been of interest in the management of prostate cancer. We previously reported that AKT inhibition (Ipatasertib) significantly decreases cell proliferation, increases canonical AR activity, and remodels the chromatin landscape in vitro and in vivo. However, the effects of AKT inhibition on chromatin accessibility remain poorly understood. This study aims to assess chromatin landscape modifications under PI3K-AKT pathway inhibition. In this study, LuCaP 167 patient-derived organoid (PDO) models were treated with AKT inhibitors (Ipatasertib and MK2206), and the chromatin landscape was studied using ATAC-seq. Preliminary results reveal that both Ipatasertib and MK2206 significantly altered chromatin accessibility in LuCaP 167 PDO compared with the non-treated control group. Interestingly, footprinting and motif analysis revealed several transcription factor motifs enriched by AKT inhibition, including KLF15, a tumor suppressor. While the results are preliminary, our data provide additional insights into AKT's influence on chromatin accessibility. Citation Format: Sasikumar Ponnusamy, Surendra Gulla, Tej Sharma, Ephraim Jeremiah Gardner, Abbas Jawadala, Adaora Amobi, Maddie Aust, Tobi Ogunbowale, Roberto Pili, Remi M. Adelaiye-Ogala. Impression of AKT inhibitor in chromatin accessibility in mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 521.

e24205 Background: Stomatitis and related oral lesions are common adverse effects of antineoplastic therapies in lung cancer patients, but their long-term implications remain understudied. This study compares long-term outcomes between lung cancer patients with and without stomatitis who underwent chemotherapy and/or immunotherapy. Methods: Using data from the TriNetX federated health research network (88 healthcare organizations), we conducted a propensity score-matched comparative outcomes analysis. Cohort 1 included 8,350 adult patients with lung cancer (ICD-10: C34), stomatitis (ICD-10: K12), and antineoplastic therapy (ICD-10: Z51.1). Cohort 2 comprised 8,350 matched patients without stomatitis. Outcomes assessed post-index event (starting 1 day after therapy initiation, with no end date) included mortality, severe sepsis, malaise/fatigue, respiratory diseases, cardiac arrhythmias, pneumonia, dysphagia, and skin diseases. Analyses encompassed risk measures, Kaplan-Meier survival, and instance counts, excluding prior outcomes where specified. Results: After matching for demographics, comorbidities, and performance status, the stomatitis cohort exhibited a significantly higher hazard for mortality (HR 1.078, 95% CI 1.032-1.126, p < 0.001; median survival 807 vs. 899 days) and severe sepsis (HR 1.118, 95% CI 1.010-1.238, p = 0.032). Risks were elevated for dysphagia (RR 1.186, 95% CI 1.088-1.293, p < 0.001; HR 1.270, 95% CI 1.157-1.394, p < 0.001) and skin diseases (RR 1.119, 95% CI 1.046-1.196, p = 0.001; HR 1.235, 95% CI 1.139-1.338, p < 0.001). Stomatitis in lung cancer patients showed no significant effects on malaise/fatigue (RR 0.974, 95% CI 0.923-1.029, p = 0.346; HR 1.025, p = 0.167), respiratory diseases (RR 1.028, p = 0.394; HR 1.100, p = 0.522), cardiac arrhythmias (RR 0.967, p = 0.468; HR 1.021, p = 0.927), or pneumonia (RR 0.990, p = 0.731; HR 1.032, p = 0.666). Conclusions: Stomatitis in lung cancer patients on chemotherapy/immunotherapy is associated with increased long-term risks of mortality, severe sepsis, dysphagia, and skin diseases, highlighting the need for proactive oral care and monitoring to mitigate these effects and improve quality of life. Further prospective studies are warranted to explore causal mechanisms and interventions.