Background: Immune checkpoint inhibitors and adoptive T-cell therapies have substantially improved cancer treatment outcomes, but their use is often limited by immune-related toxicities, including cytokine release syndrome. The role of interleukin (IL)-17A in tumor immunity remains controversial, hindering its therapeutic applications in cancer. A concern is that application of IL-17 blocking agents to release cytokine storms caused by tumor immunotherapy reverses anti-tumor immunity. Methods: In this study, we evaluated the effect of IL-17A blockade alone and in combination with anti-PD (programmed cell death)-1 therapy or tumor-specific CD8+ T cells in melanoma, colon, and lung tumors, and in UVB-induced skin carcinogenesis. Results: Our results showed that blocking IL-17A inhibited tumor development, and did not impair the efficacy of tumor immunotherapies with checkpoint inhibitors or tumor-specific T cells. Combined treatment with anti-IL-17A and anti-PD-1 antibodies significantly enhanced tumor suppression compared to single-agent therapies in all tested tumor models. Moreover, IL-17A blockade improved the efficacy of adoptive CD8+ T-cell therapy. Mechanistic analyses revealed that the combination therapy increased infiltration of activated antigen-specific CD8+ T cells in tumors. In none of the tested tumor models did IL-17A blockade negatively affect the efficacy of tumor immunotherapy with checkpoint inhibitors or T-cell therapy. Conclusions: These findings suggest that the combined application of anti-IL-17A blocking agents with current tumor immunotherapy at the same time is a promising strategy to enhance the efficacy and potentially diminish immune-related adverse effects.

sex, race, and timeliness of treatment on CRC mortality

Abstract Background: The optimal surgical approach for early-stage cervical cancer remains debated, especially after the Laparoscopic Approach to Cervical Cancer (LACC) trial raised concerns about minimally invasive surgery (MIS). This study evaluates the association between surgical approach (robotic/MIS vs. open surgery) and five-year survival, accounting for demographic, facility, and clinical factors. Methods: We analyzed data from the National Cancer Database (NCDB) for patients diagnosed with AJCC stage I-IIA cervical cancer from 2004-2022 who underwent surgery. Patients were classified as cases (died within five years) or controls (alive at five years). Multivariable logistic regression assessed the association between surgical approach and five-year mortality, adjusting for age, race, insurance, facility type, geographic region, distance traveled, tumor grade, comorbidity, adjuvant therapy, length of stay, and 30-day readmission. Results: Among 18,849 patients, 2,263 (12.0%) died within five years. Robotic/MIS was associated with lower five-year mortality compared to open surgery (adjusted OR: 0.86; 95% CI: 0.76-0.99). Higher mortality was independently associated with receipt of adjuvant therapy (aOR: 1.79), older age (aOR per year: 1.05), Black race (aOR: 1.40), public insurance (aOR: 1.41), treatment at comprehensive community cancer centers (aOR: 1.38), travel >50 miles (aOR: 1.35), higher tumor grade (aOR: 2.66), and greater comorbidity burden (aOR: 2.30). Readmission rates did not differ significantly by surgical approach. Conclusions: Robotic/MIS was significantly associated with improved five-year survival compared to open surgery in early-stage cervical cancer. However, demographic, facility, and clinical factors, including race, insurance, facility type, and comorbidities, were also strong predictors of mortality, highlighting persistent disparities. These findings underscore the need to address healthcare inequities and optimize care delivery. Future research should further explore how patient and systemic factors modify survival outcomes. Citation Format: Vishruti Pandya, Marguerite R. Irvin, Sharad Ghamande, Charles A. Leath, Chenguang Wang, Steve Coughlin, Warner K. Huh, Sejong Bae. Surgical approach and five year survival in early stage cervical cancer: A national cancer database analysis [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 871.

Background Diabetes mellitus is associated with dyslipidemia, elevated blood pressure, and increased risk for incident cardiovascular disease (CVD). Objectives This study examined whether diagnosed diabetes before age 40 years is associated with incident CVD risk independent of other measured risk factors. It also evaluated whether cumulative glucose exposure from young adulthood to age 40 years is associated with subsequent CVD risk and explored the relative contribution of diabetes compared with other CVD risk factors. Methods Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we created a sequential propensity-score-matched sample at age 40 years: Each participant with diabetes was matched to one prediabetes participant and up to 2 without diabetes. Cox proportional hazards regression models were used to assess associations of diabetes and cumulative glucose exposure with incident CVD and its components: coronary heart disease, stroke, and congestive heart failure. Results Of 4,931 individuals, 766 propensity-score-matched participants experienced 103 incident CVD events during a median 22-year follow-up after age 40 years. Diagnosed diabetes was independently associated with incident CVD after adjustment for other known risk factors (HR: 2.13; 95% CI: 1.33-3.41 for diabetes vs nondiabetes, P = 0.002); CVD risk rose as cumulative glucose exposure increased. Among matched participants, the excess CVD rate associated with diabetes was greater than the rate difference associated with other cardiovascular risk factors commonly elevated in diabetes. Conclusions Diabetes by age 40 years was associated with higher subsequent CVD risk beyond established risk factors, with CVD risk increasing as cumulative glucose exposure rose.

Background:Residents in persistent poverty areas experience higher cancer mortality due to social determinants of health that negatively affect multiple factors, including health behaviors. Objective:This study aimed to characterize demographic, clinical, and social determinant of health factors among survivors of cancer in persistent poverty areas using electronic health record (EHR) data-including an embedded social risk screener and natural language processing (NLP) of social work notes-to inform community-engaged adaptation of lifestyle interventions. Methods:EHR data from a large multispecialty group practice were extracted for patients with cancer residing in zip codes inclusive of persistent poverty areas targeted for a health behavior intervention and receiving care between January 2018 and November 2023. Self-reported social determinant of health data were obtained using the Protocol for Responding to and Assessing Patients' Assets, Risks, and Experiences (PRAPARE) and through NLP of social histories from a social work visit. Results:We identified 2672 unique patients with cancer, of whom 578 (21.6%) had PRAPARE data and 1597 (59.8%) had social history data available for analysis. The most common cancers among survivors (n=1420, 53.1% female; n=1299, 48.6% Black individuals; mean age 65.2, SD 13.7 years) included breast (n=536, 20.1%), prostate (n=400, 15%), and lymphoid or hematopoietic (n=323, 12.1%) cancer. Among survivors in persistent poverty areas (n=509, 19%; all with a high Social Vulnerability Index), 34.6% (176/509) were single, 55.4% (282/509) had Medicare coverage (with only 73/509, 14.3% having private insurance), 36.5% (186/509) had obesity, 63.9% (325/509) had hypertension, and 31.2% (159/509) had diabetes. Of survivors in persistent poverty areas with PRAPARE data, 15.8% (19/120) lacked transportation, 4.2% (5/120) lived with housing insecurity, and 6.7% (8/120) felt unsafe where they lived. Conclusions:Innovative EHR and NLP approaches identified several socioeconomic and safety-related challenges along with opportunities for health behavior interventions to leverage Medicare coverage and target multiple comorbidities when adapting interventions for survivors of cancer living in persistent poverty areas.

Background:Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, hypoxic and immune-suppressive tumor microenvironment (TME). Integrin αvβ3-expressing cells, including endothelial and cancer-associated fibroblasts (CAFs), contribute to the development of this TME. ProAgio is a novel cytotoxin that targets integrin αvβ3-expressing cells. ProAgio is currently in clinical trials. We have previously shown that the combination of GPH (gemcitabine, paricalcitol, and hydroxychloroquine) influences PDAC TME. Based on the overlapping mechanisms of action, we hypothesized that ProAgio could potentiate effects of GPH and enhance its anti-tumor immunity. Methods:Patient-derived xenograft (PDX) and orthotopic models of PDAC were used to assess the therapeutic activity and mechanism of action of ProAgio in combination with GPH. Immunohistochemistry was used to evaluate hypoxia, EMT and angiogenesis. Changes in the immune cells were measured with multi-parameter flow cytometry. Dynamic contrast-enhanced MRI (DCE-MRI) was used to study tumor perfusion in mice and patients (NCT06182072). Findings:ProAgio potentiated the growth inhibitory effects of GPH in PDX and orthotopic models by depleting integrin β3 expressing cells, leading to ECM remodeling, reduced vascular leakage, improved hypoxia, and reversed EMT. DCE-MRI showed a significant increase in tumor perfusion following ProAgio treatment in mice and patients (NCT06182072). Immune profiling revealed that the combination treatment significantly increased the infiltration of γδ T cells, natural killer T (NKT) cells, CD4+ effector T cells, and M1-like macrophages. Furthermore, the combination treatment reduced the expression of myofibroblastic CAFs (myCAFs), further supporting the immunomodulatory and stromal normalizing effects of GPH and ProAgio. Conclusion:Targeting integrin αvβ3 using ProAgio modulates the PDAC TME by improving perfusion, reducing hypoxia, reversing EMT, and alleviating immune suppression. ProAgio potentiates the effects of GPH therapy, which should be evaluated in future trials.

Abstract Background: Lung cancer exhibits disparities in incidence, disease prevalence, and treatment outcomes. Chemokines and their corresponding receptors have been shown to be associated with these observed disparities within different ethnic groups. In this study, we have demonstrated that the differential signaling of chemokine receptor CCR6 and its natural ligand is associated with the observed disparity, and this differential CCR6 signaling is primarily due to the diversity in CCL20. Methods: Bulk RNA-seq data (BioProject ID: PRJNA1039495) from lung cancer cell lines derived from African American (AA) and European American (EA) individuals were analyzed to identify and quantify different isoforms of CCL20. MD simulations were performed to evaluate the binding affinity of CCL20, hydrogen-bond stability, and conformational behavior upon interaction with the CCR6 receptor. Downstream pathway activation potential was inferred by comparing the expression of signaling molecules that support oncogenic pathways and are associated with poor therapeutic outcomes. Furthermore, smoking habits, including higher nicotine intake, distinct metabolite patterns, and alterations in basic cytokine levels, were incorporated into the model as external factors that may influence CCL20 isoforms and CCR6 signaling. Results: Out of 5 CCL20 isoforms, Isoform-1 (24 TPM) and Isoform-2 (36 TPM) showed stronger interactions with CCR6 compared to EA cells (Isoform-1: 7.5 TPM; Isoform-2: 11.2 TPM). Across smoking groups, AA cells showed higher Isoform-2 levels than EA cells, increasing from non-smokers (Isoform-1: 18 TPM; Isoform-2: 18 TPM) to smokers (Isoform-1: 24 TPM; Isoform-2: 40 TPM), while EA cells showed lower increases from non-smokers (Isoform-1: 18 TPM; Isoform-2: 19 TPM) to smokers (Isoform-1: 24 TPM; Isoform-2: 30 TPM). MD simulations revealed that lung-cancer-cell CCR6 binds both CCL20 Isoform-1 & 2 from AA-derived cell lines with significantly stronger affinity compared to EA-derived cells, reflected by lower binding free energies, more stable hydrogen-bonds, and longer ligand-receptor contact durations. Isoform-2 showed the strongest overall binding affinity, indicating that it may be the dominant activator of CCR6 signaling. Population-level behavioral data, including All of Us cohort metrics, showed that AA smokers tend to use cigarettes with higher nicotine content, inhale more deeply, and exhibit slower nicotine and cotinine clearance, which corresponded with increased Isoform-2 expression. Conclusion: Lung cancer cells derived from AA exhibit a ligand-rich and affinity-enhanced CCL20-CCR6 signaling axis driven primarily by Isoform-2. Isoform-specific expression, receptor affinity, and smoking-associated inflammation together highlight the significance of Isoform-2 in disparity observation in Lung cancer, as a key player in contributing to disparity. Citation Format: Murugesh Eswaran, Briana Alicia Brock, Hina Mir, Sejong Bae, Gabriella M. Oprea-Ilies, Eric L. Flenaugh, Sanjay R. Jain, Brian M. Rivers, Rick A. Kittles, James W. Lillard, Rajesh Singh, Shailesh Singh. Health behavior associated CCL20 ligand variation contributes to the disparity in non-small cell lung cancer [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 1507.

Patient Characteristics by Treatment Time Inclusion

Characteristics of patients with EOCRC by timeliness of treatment.

Association between sex, race, and timeliness of treatment on survival.

Association between sex and race on survival by timeliness of treatment.

Survival by Sex, Race/Ethnicity, and Timely Treatment

Conventional chemotherapeutics for colon cancer often fail to achieve optimal clinical outcomes, as many patients develop resistance and experience significant toxicity, thereby increasing the overall health burden. Understanding the mechanisms conferring resilience to cancer cells is essential for developing more effective therapies. 5-Flourouracil (5FU) is the standard of care used for colon cancer. 5FU-associated inflammation, characterized by a change in cytokine profile, enables the colon cancer cells to evade cell death, thereby undermining the cytotoxic effects of the drug. Current study underscores the significance of CCL20 signaling, which is linked to inflammatory conditions and is elevated during colon carcinogenesis, in tempering the cytotoxic effects of 5FU. The presented data demonstrate an inverse correlation between CCL20 concentrations in colon cancer and sensitivity to 5FU. Moreover, treatment with 5FU further stimulates CCL20 signaling in colon cancer cells, likely via increased fatty acid efflux. Notably, the findings reveal that IL10 signaling is under negative regulation of CCL20. Additionally, exposure to 5FU elevates IL10 levels, thus creating a complex interplay of pro-inflammatory and anti-inflammatory pathways. Such dual activation of contrasting mechanisms undermines the therapeutic efficacy of 5FU. Therefore, the insights gained from this study emphasize the significance of addressing immune signatures characterized by CCL20 and IL10 to enhance the effectiveness of 5FU in colon cancer treatment.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have improved outcomes in metastatic non-small cell lung cancer (NSCLC), but benefit in tumors lacking PD-L1 expression remains limited. Dual checkpoint blockade may enhance antitumor immunity by overcoming an immunologically "cold" tumor microenvironment. Circulating tumor DNA (ctDNA) is an emerging early response biomarker. PATIENTS AND METHODS:The DISCERN study (UAB 2432) is a single-center, randomized, open-label pilot trial comparing dual immune checkpoint blockade (nivolumab + ipilimumab) plus chemotherapy (Arm A) versus single ICI (pembrolizumab) plus chemotherapy (Arm B) in patients with PD-L1-negative, stage IV NSCLC. The study plans to enroll 24 patients. ctDNA positivity is required at baseline. ctDNA response is evaluated at Cycle 3 Day 1 using Guardant Infinity NGS platform. Primary endpoint is ctDNA molecular response. Secondary endpoints include RECIST-based response rates, progression-free survival (PFS), and overall survival (OS). CONCLUSION:DISCERN will provide novel insight into the comparative impact of dual versus single ICI regimens in PD-L1-negative NSCLC and the potential role of ctDNA clearance as an early marker of treatment efficacy in this subset of NSCLC.

Toxicity from IVT oHSV in the left lateral ventricle and third and fourth ventricles at different time points.

Disparities in breast and cervical cancer outcomes continue to affect Black women in the South, particularly in rural and underserved areas of Alabama and Georgia. Despite similar incidence rates, Black women experience disproportionately higher mortality due to systemic barriers, including limited access to early detection, timely follow-up, and high-quality care. The Project Health Equity (PHE) Initiative, is a community-academic-government-industry partnership between the Black Women’s Health Imperative (BWHI) and Hologic, with the University of Alabama at Birmingham (UAB), Morehouse School of Medicine (MSM), and their respective state breast and cervical cancer programs. The study centers on identifying and addressing these multi-level barriers to breast and cervical cancer screening (BCCS) through a collaborative approach. The PHE builds on long-standing, established community-academic research and service delivery models of navigation to access care, and transdisciplinary collaboration with the aims to: (1) identify barriers to breast and cervical cancer screening and detection among Black women; (2) evaluate the outcomes of the navigation component of the project; and (3) develop a research strategy to create policies to address multi-level barriers in BCCS, treatment, and follow-up care among Black women. UAB and MSM lead site-based implementation, including outreach, recruitment, enrollment, navigation to screening, and data collection and analysis. Hologic and state programs provide resources, support, and services. BWHI provides scientific leadership and ensures translation of research findings into actionable strategies. Cross-site coordination ensures that implementation efforts are grounded in community priorities and informed by diverse perspectives. The added-value of this partnership results in the ability to pool data and conduct multi-state/site comparisons that support advocacy efforts and will help to establish greater impact across the South. At each site, institutional and community partnerships, across departments and clinics, have played a critical role in driving project success. This partnership brings together complementary strengths in community engagement, scientific research, and culturally responsive care, creating a powerful model for addressing cancer disparities in the South. The PHE illustrates how a community-academic-government-industry partnership can meaningfully address structural and individual barriers to cancer prevention and care among Black women in the South. The collaboration between BWHI, Hologic, UAB, MSM and BCCS programs demonstrates the power of aligning research and service delivery expertise with community priorities and the advocacy and resources of government and industry to reduce health disparities. As findings continue to emerge, the project will aim to inform institutional practices, shape policy, and guide the development of a research agenda focused on eliminating inequities in breast and cervical cancer outcomes. DeBran Tarver, Ifeoma Udoh, Samantha Whitfield, Catanya Stager, Maya Zeigler, Linda Goler Blount, Mia Keeys, Silvia Gisiger Camata, Cynthia Y. Johnson, Alison M. Caddell, Sejong Bae, Vishruti Pandya, Melissa Ryan, Elabrar Ebrahim, Pooja Mishra, Sophia Stein, Christopher Ervin, Amirah Burton-Obanla, Desiree Rivers, Timiya Nolan, Lori Bateman. Bridging gaps through partnership: A community-academic-government-industry approach to advancing cancer equity for Black women in the South [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C158.

Activated RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS-mutant cancer cells irrespective of the RAS mutation or isozyme. Wild-type RAS (RASWT) cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, whereas insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS-mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immunocompetent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancers. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors.Significance: ADT-007, a first-in-class pan-RAS inhibitor, has unique selectivity for cancer cells with mutant RAS or activated RAS protein and the capability to circumvent resistance to suppress tumor growth, supporting further development of ADT-007 analogs.