Citations

Abstract Background: The BRAF(V600E) mutation in colorectal cancer (CRC) is associated with treatment resistance and a poor prognosis. CDK2/9 is frequently activated in human cancers, and we have previously shown that BRAFV600E can upregulate MCL-1, which can be suppressed by the selective CDK2/9 inhibitor fadraciclib. Herein, we determined whether targeting CDK2/9 by fadraciclib can be enhanced by concurrent Bcl-2/Bcl-xL inhibition using LP-118, which minimizes platelet toxicity in patients, compared to the Bcl-2 inhibitor venetoclax. Effects of the drugs on apoptosis, colony formation and tumor growth were studied in a zebrafish model. Methods: We utilized isogenic human RKO (BRAFV600E/V600E/WT) and T29 (BRAFWT/−/−) CRC cell lines in addition to HCT-116 (BRAFWT) and Bax knockout (HCT-116Bax-/-) CRC cells. Cells were treated for 24h with fadraciclib (500nM) plus encorafenib (500nM) in the presence or absence of LP-118 (1µM) or venetoclax (1µM). Apoptosis and cell growth inhibition were assessed using annexin V/PI staining and colony formation assays, respectively. Expression of MCL-1, Bcl-xL, Bcl-2, PARP, and cleaved caspase-3 (Asp175) proteins was analyzed. In a zebrafish tumor xenograft model, the effects of the drugs on caspase-3 cleavage and tumor growth were then evaluated. Results: Fadraciclib suppressed MCL-1 expression, induced apoptosis and significantly inhibited colony formation in all CRC cell lines. However, this effect was enhanced by encorafenib only in RKO (BRAFV600E/V600E/WT) cells. The addition of LP-118 to fadraciclib plus encorafenib potently enhanced apoptosis induction, shown by annexin V and cleavage of PARP, caspase-3, in RKO and HCT-116 cell lines, which was synergistic and Bax dependent. Treatment with LP-118 combined with fadraciclib and encorafenib suppressed both Bcl-xL and MCL-1 expression in RKO cells. The addition of LP-118 to fadraciclib plus encorafenib enhanced apoptosis (annexin V) to a greater extent than did venetoclax. In a zebrafish tumor xenograft model, the addition of LP-118 to fadraciclib plus encorafenib significantly enhanced caspase-3 activation and reduced the tumor xenograft size. Conclusion: LP-118 synergistically enhanced the antitumor activity of fadraciclib plus encorafenib in BRAFV600E human CRC cells, and to a greater extent than did venetoclax. Mechanistically, targeting Bcl-2/Bcl-xL concurrent with inhibition of MCL-1 and CDK2/9 by fadraciclib potently induced apoptosis and suppressed tumor cell growth. These findings suggest a novel and effective therapeutic strategy for BRAFV600E human CRCs. Citation Format: Md Mohiuddin, Vanda Póvoa, Beatriz Sebo, Rita Fior, Frank A. Sinicrope. Novel Bcl-2/Bcl-xL inhibitor, LP-118, enhances apoptosis induction by the CDK2/9 inhibitor, fadraciclib, in BRAF(V600E) human colorectal cancer cells [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 4658.

Abstract Introduction: COE has become the gold standard in addressing health disparities. COE’s value is emphasized by NIH and leading cancer-related organizations e.g., AACR. The Alliance for COE (The Alliance) mission is to advance the art, science, and impact of COE; promote community health and wellness; and reduce cancer burden and disparities. Methods: This abstract builds on the Alliance’s Science of Community Outreach and Engagement (SoCOE) Conference a NCI R13 funded series. SoCOE Conference is organized by 10 NCI-designated Cancer Centers to provide a platform for COE academic-clinical-policy-community stakeholders to share best practices for solution-focused community responsive cancer prevention, diagnostics, therapeutics and survivorship research and practice. Results: > 500 researchers, clinicians, policymakers, healthcare administrators, with >12% being survivors and/or advocates, participated in our SoCOE Conferences. The delegates’ recommendations are: Decentralize who/entities that hold all the power in science and clinical research (trials). Communities hold valuable, necessary wisdom and resources to inform and guide science Include multisectoral partners early and always Community capacity building and compensation with gratitude Mentoring of junior COE researchers, clinicians, policymakers, healthcare administrators, survivors and advocates with humility is a must Develop virtual communities to share best practices across cancer centers and within regions Develop working groups to identify and explore commonalities across COE work in rural/urban, diverse/homogenous spaces Publish Science of COE papers on various topics related to COE Frameworks and evidenced-solutions Provide community reports on best practice guide that can be widely available to be shared locally and in-person, and digitally Partner and learn from COE teams working with other cultural/ethnic groups Attend to, measure and remedy societal/social drivers of health disparities that mirror barriers to care, and research engagement and participation. Discussion: Informed by our community advisory boards and the findings for our SoCOE Conferences, we present the pillars of the Alliance to tackle population cancer burden and disparities: Training future COE leaders/advocates, Advocating for public health policies/guidelines, Increasing access to cancer prevention and care that will also increase access to studies, Engaging and partnering with multisectoral stakeholders and communities, Building community capacity, Advancing COE science through catchment-relevant research, and Leading bi-directional communication and information and resource sharing between catchment area communities and cancer centers. The expectation and impact of COE can only be achieved if COE teams are valued, supported cancer center members with community advisory boards and community as cancer centers’ priority population. Citation Format: Kimlin Ashing, CHARNITA ZEIGLER-JOHNSON, Hayley S. Thompson, Kim Rhoads, Nadine Barrett, Lisa Carter Bawa, Timiya S. Nolan, Monica Baskin, Vanessa B. Sheppard, Marvella E. Ford, Erica Phillips, Lorna H. McNeill, Folakemi T. Odedina. Advancing the science, practice and impact of COE [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 7577.

Abstract Background: Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, develops through multiple pathways; however, the extent to which HBV, HCV, and non-viral etiologies shape tumor biology and influence treatment responses remain incompletely understood. The availability of viral detection methods from sequencing data and multiomics workflows give us a new opportunities to study how etiology influences the molecular landscape of HCC. Here, we analyze TCGA's LIHC samples categorized into HBV-, HCV-, and non-viral tumors to compare genomic, transcriptomic and methylation profile of these HCC tumors to identify biological pathways specific to each group. Methods: Whole-exome, RNA-seq, and clinical data from TCGA-LIHC (n=325) were analyzed. Viral status was assigned using Exogene (≥5 HBV/HCV reads; mixed infections excluded; non-viral = 0 reads). Mutation and clinical comparisons were performed using cBioPortal. RNA-seq data were processed with edgeR for 3-way differential expression (median count ≥25; |log2FC|>2; FDR<0.05). Pathway enrichment used ShinyGO. Findings were validated using the GSE62232 microarray cohort analyzed with limma. Results: Demographic patterns reflected known risk profiles: HBV patients presented younger (mean 53.9 years) and were predominantly male (78.8%) and Asian (92.9%), while HCV and non-viral groups were older and primarily White. Non-viral HCC showed the highest proportion of females (42.7%) and nearly half lacked significant fibrosis, consistent with metabolic disease. In contrast, HCV had the highest cirrhosis burden (47.2%), and HBV tumors showed the greatest proportion of poorly differentiated histology (52.2%).The comparison of the expressed genes between the 3 tumor subtypes revealed distinct etiology-associated pathways. Metabolic and mitochondrial including fatty acid β-oxidation differential expressed in Non-viral HCC. Activation of antiviral and interferon signaling, including type I IFN response and OAS-mediated defense pathways are observed in HCV-HCC. Finally, Cell-cycle and proliferation pathways are differentially expressed in HBV-positive, a finding consistent with effects of viral integration. Clustering analysis separated HBV and non-viral tumors into distinct groups. These signatures were reproduced in a validation cohort. Conclusion: Our analyses highlight that HBV-, HCV-, and non-viral HCC harbor distinct transcriptional and signaling pathways. These etiology-specific signatures provide a framework for developing more precise biomarkers and for tailoring therapeutic strategies to the molecular biology of each etiology. Acknowledgement: We acknowledge the late Dr. Sean Cleary, MD, for his invaluable contributions to this project. Disclosure: AI has been used to trim sentences in order to fit in the word limit. Citation Format: Amerti Guta, Daniel O'Brien, Aditya V. Bhagwate, Jean-Pierre A. Kocher, Lewis R. Roberts. Multiomic dissection of HBV-, HCV-, and non-viral HCC reveals distinct proliferation, interferon, and metabolic signatures [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 2682.

Abstract Background: Digital access, health literacy, and confidence in obtaining cancer information are well-known factors that influence cancer beliefs and behaviors. However, less is understood about whether these information-related factors vary across regions within a cancer center's catchment area and how they collectively relate to cancer beliefs in large community samples. This study investigated regional differences in digital access, health literacy, and confidence in seeking information, and examined the connections between these factors and cancer risk perceptions, fatalistic beliefs, prevention confusion, and willingness to participate in cancer clinical trials. Methods: Data (N=2,334) from the 2023 Mayo Clinic Comprehensive Cancer Center’s Cancer-Focused Needs Assessment, conducted across catchment areas in Arizona, Florida, and the Midwest (Minnesota, Wisconsin, Iowa). Regional differences in digital access (Internet use and device ownership), health literacy, and confidence in obtaining cancer information were analyzed using multivariable ANCOVAs and logistic regressions, adjusting for sociodemographic covariates. Follow-up models examined whether these information precursors are associated with perceived cancer risk, fatalistic beliefs, confusion about recommendations, and willingness to participate in cancer clinical trials, adjusting for the same covariates. Results: Regions showed minimal differences in digital access and health literacy. Health literacy was instead associated with ethnicity, age, gender, and education (all p<.001). Confidence in obtaining cancer information followed similar trends, with significant influences of ethnicity and gender (p<.01). Internet use was strongly associated with sociodemographic factors (all p<.01). Additionally, the information precursors consistently correlated with cancer beliefs across the full sample: Higher health literacy and greater confidence in obtaining cancer information were associated with increased perceived cancer risk, reduced cancer fatalism, and less confusion regarding prevention guidelines (ps < .001). Internet use and device access were significantly related to a greater willingness to participate in clinical trials (ps < .01). These relationships persisted even after controlling for sociodemographic covariates. Conclusions: Regional differences in digital access and health literacy were minimal, indicating a consistent information environment. Within this context, individual sociodemographic and information-related factors played a larger role, strongly shaping cancer beliefs. These findings underscore technology access and information empowerment as key targets for enhancing cancer prevention knowledge and research engagement, and indicate that the effects of information empowerment are primarily driven at the individual rather than the geographic level. Citation Format: Tingyu Zou, Monica L. Albertie, Emelina Asto-Flores, Manisha Salinas, Farhia Omar, Adeline Abbenyi, Noreen Stephenson, Nuwanthi Heendeniya, James R. Cerhan, Kathleen J. Yost, Folakemi T. Odedina. Digital access, health literacy, and cancer beliefs: Findings from a multi-region community survey [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 7553.

Abstract Background: Combination immune checkpoint inhibitor (ICI) therapy represents a standard-of-care for patients with metastatic melanoma. However, >40% of patients do not respond to treatment and severe immune-related toxicity affects up to 60% of patients. Accordingly, we need more precise ways to select patients for combination ICIs. To address this, we developed LiquidTME, a liquid biopsy method based on Spatial EcoTyper (Cancer Res (2025) 85 (8_Supplement_1): 153) that leverages a deep learning approach to noninvasively assess the tumor microenvironment from cell-free DNA (cfDNA) methylation data. LiquidTME was previously trained to predict ICI response using 78 patients with advanced melanoma treated at Yale University. Here we performed a blinded validation of LiquidTME in coordination with clinicians at Washington University (WashU). Methods: The WashU cohort consisted of pre-ICI plasma from 34 patients with advanced melanoma, each treated with ipilimumab and nivolumab (n=27) or relatlimab and nivolumab (n=7). ICI response was classified as durable clinical benefit (DCB) or no durable benefit (NDB) by a board-certified oncologist. Tumor mutational burden (TMB) was determined for 27 patients using commercial CLIA assays and analyzed as nonsynonymous mutations (mt) per megabase (Mb), using the FDA-approved 10 mt/Mb cutpoint for TMB-high and -low groups. The WashU cohort was sent to a scientific team that was blinded to all clinical and TMB data. Cell-free DNA was extracted from 2 mL plasma per patient and subjected to enzymatic methyl-seq (EM-seq) at a median depth of 15x. LiquidTME was performed on the resulting profiles, yielding a binary response prediction and a continuous response score for each sample. Test results were locked down and returned. Both assays were compared by AUC and two-sided Wilcoxon rank-sum tests for response classification, and Kaplan-Meier analysis for progression-free survival (PFS). Results: Median follow-up time of the cohort was 21.6 months. LiquidTME performed on cycle 1 day 1 pre-ICI plasma significantly stratified PFS with a hazard ratio (HR) of 0.27 (P = 0.005), with LiquidTME(+) patients achieving a median PFS of 1.7 years longer than LiquidTME(-) patients. LiquidTME distinguished DCB from NDB with an AUC of 0.77 (P = 0.007). Similar performance was seen across distinct combination ICI regimens. In patients with TMB data, LiquidTME maintained whole-cohort performance with a PFS HR of 0.30 (P < 0.03; AUC = 0.77). In contrast, TMB high vs. low subsets failed to stratify PFS (HR = 0.49; P = 0.17) or response (AUC = 0.53; P = 0.8). Conclusion: LiquidTME identified durable responders to combination ICI from pretreatment plasma in this blinded validation cohort of melanoma patients. Given its favorable performance, LiquidTME shows promise as a clinical tool to guide personalized immunotherapy decision-making. Citation Format: Aadel A. Chaudhuri, David Y. Chen, Tucker Hansen, Mirna Jarosz, Vincent A. Miller, Aaron M. Newman. Blinded clinical validation of LiquidTME, a cell-free DNA assay for predicting response to immunotherapy by noninvasively profiling the tumor microenvironment [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 1040.

Abstract Background: Multidisciplinary research networks often face challenges in harmonizing metrics and measures across participating sites, limiting the ability to aggregate data and generate generalizable insights. To address this barrier within the Connecting Patient Populations to Clinical Trials (CP2CT) Network, the Data, Evaluation, and Coordinating Center (DECC) coordinated the establishment of a unified framework that supports comparable evaluation and enhances the scientific impact of network-wide activities. Methods: Consensus was developed through a structured, iterative, and collaborative process: (1) drafting initial constructs, metrics, measures, and benchmarks informed by Network site materials and relevant literature; (2) soliciting qualitative and quantitative feedback from Network sites via Basecamp, an innovative online collaborative workspace for construct development; (3) conducting open dialogue sessions followed by systematic review and integration of site feedback; and (4) refining all elements through repeated feedback cycles until no further modifications were requested. Each iteration strengthened the clarity, coherence, and scientific precision of the final constructs. Results: A total of seven constructs were incorporated into the consensus-development process: clinical trials referral, clinical trials accrual, participants’ awareness of clinical trials, participants’ knowledge of clinical trials, providers’ awareness of NCI-supported clinical trials, providers’ engagement with NCI-supported clinical trials, and providers’ referral to NCI-supported clinical trials. For each construct, the Network established a conceptual definition (broad description of the construct), an operational definition (specification of how the construct is measured or observed), benchmarks (standards for assessing performance), metrics (quantitative indicators of performance), and measures (tools used to quantify inputs, processes, or outcomes). Common measures were developed for two constructs—clinical trials accrual and participants’ knowledge of clinical trials. Although full consensus was not achieved across all four Network sites for every construct, at least three sites reached consensus for the remaining five constructs. Conclusion: This consensus-building initiative resulted in the development of a unified, scientifically grounded framework. By harmonizing key elements related to clinical trial referral, accrual, awareness, knowledge, and provider engagement, the Network has established foundational tools that enable cross-site data comparability and facilitate more rigorous assessment of efforts to connect diverse patient populations to clinical trials. This framework positions the Network to inform strategies that improve equitable clinical trial participation. Citation Format: Folakemi T. Odedina, Jennifer Le-Rademacher, Robert Freimuth, Cristina Orozco, Laura Lectora, Timethia Bonner, Holly Thorson, Connecting Patient Populations to Clinical Trials(CP2CT) Program Evaluation Work Group, Connecting Patient Populations to Clinical Trials(CP2CT) Steering Committee. Development of and consensus building towards shared metrics, measures and benchmarks for the connecting patient populations to clinical trials (CP2CT) [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 860.

Abstract Introduction Detecting and estimating blood volume loss are important for the diagnosis and management of life-threatening hemorrhage. There is a direct relationship between percent blood volume loss (BVL%) and falling in stroke volume (SV); furthermore, there is a direct relationship between diminishing SV and the corrected flow time of the carotid artery (ccFT). Therefore, we hypothesized that change in ccFT (ccFTΔ) would directly relate with BVL% in a phlebotomy paradigm. Materials and Methods A prospective, convenience sample of healthy volunteers was studied. Volunteers underwent blood donation protocol in a physiology lab. A wireless, wearable Doppler ultrasound system monitored ccFT during blood donation. Traditional vital signs were also measured throughout. The relationship between traditional vital signs as well as ccFTΔ were compared to BVL% using 2 mixed linear regression models. Results Data from 20 subjects and blood donations comprising 46,123 cardiac cycles are included. On average 413.5 ± 39 mL of blood were drawn representing 8.6 ± 1.6% BVL%. There was a significant and strong linear relationship between BVL% and ccFTΔ during blood draw with the regression slope demonstrating that for every 1 ms reduction in ccFT there was a 0.4% reduction in blood volume. Conclusions In healthy subjects and when blood loss is the sole mechanism for falling SV, we estimate that for every 1 ms reduction in ccFT, there is an approximate 0.4 BVL%. Validation of these results in patients with traumatic hemorrhage is underway.

ABSTRACT Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by antibody‐mediated platelet destruction, often driven by long‐lived plasma cells (LLPCs) resistant to conventional therapies. While most patients respond to corticosteroids and intravenous immunoglobulin (IVIG), a subset develops life‐threatening refractory disease. In this case series, we describe three patients aged 39, 85, and 58 with life‐threatening, multi‐agent refractory ITP and platelet nadirs < 2 × 10 9 /L who failed corticosteroids, IVIG, and thrombopoietin receptor agonists (TPO‐RAs). Following salvage therapy with daratumumab, a monoclonal antibody targeting CD38, all three patients achieved rapid hematologic recovery, with platelet count normalization within 1 week. This accelerated response allowed for urgent clinical stabilization, including safe anticoagulation and surgical intervention. The efficacy of daratumumab likely stems from a dual mechanism: the depletion of CD38+ LLPCs and the immediate modulation of Fc‐receptor‐mediated platelet clearance. These observations suggest that CD38‐targeted therapy can bypass traditional treatment resistance to achieve near‐immediate remission in high‐complexity, high‐risk clinical settings. While these results are compelling, prospective clinical trials are warranted to define the long‐term safety, durability, and optimal dosing of anti‐CD38 therapies in refractory ITP populations.

Importance The management of infectious and inflammatory lesions of the breast remains controversial. The expert panel focused on management recommendations for 3 of the most common infectious breast conditions, as very few evidence-based guidelines for the management of these conditions exist. Observations Clinicians should distinguish between infectious and noninfectious lactational mastitis (LM) because the former often requires interventions whereas the latter requires supportive care only. Patients with infectious LM often have thick fluid collections that are not amenable to aspiration and usually require a stab incision with drain placement (but no packing) to resolve the infection. Operative drainage is only required if the patient cannot tolerate an office procedure. If a phlegmon is present, antibiotics should be prescribed for at least 10 days. The diagnosis of granulomatous mastitis (GM) requires pathology confirmation with characteristic findings on core biopsy. Cystic neutrophilic granulomatous mastitis (CNGM) is a specific form of GM associated with a granulomatous reaction to Corynebacterium infection and should be empirically treated with doxycycline. For patients without findings characteristic of CNGM and no other associated bacterium identified, there is no role for empiric antibiotic use. Granulomatous mastitis cases often recur and can take up to 18 months to resolve. Patients who have GM cases with worsening symptoms should be treated with repeated intralesional steroid injections; surgical excision or repeated aspirations should be avoided. Cases refractory to intralesional steroid injection may require oral steroids or even advanced biologic agents such as methotrexate or azathioprine. Periductal mastitis with squamous metaplasia of lactiferous ducts (PDM-SMOLD) is a distinct entity from other periductal mastitis cases that can present with recurrent abscesses and should be treated with antibiotics and aspiration for fluid collections. Operative excision for PDM-SMOLD is required for those patients who present with a fistula or recurrent episodes typically using a radial incision to remove the diseased ducts within and below the nipple. Conclusions and Relevance Evidence-informed, consensus-, and expert opinion–based guidelines for the management of infectious and inflammatory conditions of the breast were developed. Clinicians can use these guidelines to appropriately manage these conditions for which clinical care often varied in the past.

Background: Statins have been associated with a reduced risk of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC). However, the optimal use for effective protection and whether benefits vary by patient characteristics remain unclear. We evaluated the association between statin use and PLC risk in metabolic-dysfunction-associated steatotic liver disease (MASLD), considering cumulative exposure and potential effect modifiers. Methods: We conducted a retrospective cohort study using the Veteran Affairs electronic health records. Patients with chronically elevated liver enzymes and metabolic dysfunction, without other chronic liver diseases, were identified between 2007 and 2009 and followed through 2019 for incident PLC. Statin exposure was assessed at baseline and during the follow-up, with dose standardization by LDL-lowering potency (simvastatin-equivalent units). Time to PLC was analyzed using Cox models adjusted for covariates, considering potential interactions. Results: Among 329,577 patients (92% male; median age 62 years), 0.82% developed PLC (median follow-up of 9.7 years). Baseline statin use showed a significantly lower PLC risk (adjusted hazard ratio 0.64; 95% CI, 0.57–0.71; p < 0.0001). No significant interaction was observed with age, sex, metabolic syndrome, or cirrhosis. Higher cumulative statin exposure demonstrated a dose-dependent risk reduction, remaining significant at simvastatin-equivalent doses > 15,561 mg annually after accounting for incident cirrhosis. Atorvastatin/rosuvastatin use provided comparable protection, despite different lipophilicity, and demonstrated stronger effects than others. Conclusions: In MASLD, statin therapy was associated with a dose-dependent PLC risk reduction. High-intensity therapy (simvastatin-equivalent > 40 mg daily) conferred substantial protection regardless of age, sex, insulin resistance, or cirrhosis, supporting a potential statin-based PLC chemoprevention in MASLD.