Abstract RAS mutations are the most prevalent oncogenic mutations responsible for about one-third of all human malignancies. Despite decades of research, direct targeting of RAS remains a major clinical challenge. RAS inhibitors recently approved by the FDA or in clinical trials appear to have limited efficacy due to the emergence of acquired resistance. We recently described a mechanistically distinct pan-RAS inhibitor, ADT-007, that selectively kills cancer cells harboring activated RAS, whether driven by oncogenic mutations or activation by upstream receptor tyrosine kinase signaling. ADT-007 potently inhibited the growth of an array of cancer cell lines harboring various RAS mutations or activated RAS with low nM IC50 values. In contrast, cancer cells with downstream RAF mutations or cells of normal tissues were essentially insensitive. Cellular, biochemical, and biophysical studies demonstrated that ADT-007 binds nucleotide-free RAS to block GTP loading and activation of the MAPK/AKT signaling pathway, resulting in mitotic arrest and apoptosis. ADT-007’s unique selectivity was attributed to metabolic detoxification by glucuronidation from UDP-glucuronosyltransferases (UGTs), which we found to be enriched in normal cells compared with RAS-mutant cancer cells. Notably, ADT-007 induced apoptosis and caused nearly complete inhibition of colony formation in the Mia-PaCa-2 human pancreatic cell line, whereas a pan-KRAS inhibitor, BI-2865, and a pan-RAS inhibitor, RMC-6236, did not induce apoptosis but only suppressed proliferation and marginally inhibited colony formation under the same conditions. BI-2865 and RMC-6236 inhibited MAPK signaling in the sensitive lines but did not inhibit signaling in the resistant lines. Furthermore, RAS mutant colon and pancreatic cancer cells did not develop resistance to ADT-007 under chronic exposure, in contrast to sotorasib, BI-2865, and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor to which they were exposed. Moreover, the resistant cell lines also exhibited cross-resistance to mechanistically distinct classes of RAS inhibitors, including pan-KRAS, pan-RAS, and allele-specific KRAS inhibitors, but not to ADT-007 or a second-generation inhibitor, ADT-030. These observations suggest a shared mechanism of acquired resistance that may limit the efficacy of currently known RAS inhibitors (approved or in development). An orally bioavailable prodrug of ADT-007, ADT-1004, demonstrated favorable tolerability and suppressed tumor growth in orthotopic and patient-derived xenograft models of pancreatic cancer, accompanied by reductions in activated RAS and p-ERK levels. Consistent with in vitro experiments, ADT-1004 displayed superior efficacy to sotorasib or adagrasib in a xenograft model using a resistant MIA-PaCa-2 tumor model. These results support further development of ADT-1004 for a broad range of RAS-mutant cancers. Citation Format: Junwei Wang, Xi Chen, Sindhu Ramesh, Jeremy B. Foote, Chung-Hui Huang, Kristy L. Berry, Khalda Fadlalla, Bandi D. S. Reddy, Ganji P. Nagaraju, Elmar Nurmemmedov, Ivan Babic, Donald J. Buchsbaum, Asfar S. Azmi, Yulia Y. Maxuitenko, Adam B. Keeton, Bassel F. El-Rayes, Gary A. Piazza. A mechanistically distinct pan-RAS inhibitor, ADT-007, with robust antitumor activity evades resistance common to mutant-specific and pan-RAS Inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B014.

BackgroundGastric adenocarcinoma, or gastric cancer, typically has a poor prognosis. The objective of this study was to assess the quality, understandability, actionability, and comprehensiveness of online resources for patients diagnosed with gastric adenocarcinoma, or gastric cancer as patients increasingly rely on online health information.MethodsA systematic search using the term “stomach cancer” was conducted across three search engines (Google, Yahoo, and Bing) on three different browsers (Safari, Google Chrome, and Microsoft Edge) on 12/13/2024, with the top fifty websites recorded for each combination. Duplicates were removed and inclusion/exclusion criteria were applied. Quality was evaluated using the DISCERN instrument. The PEMAT-P was used to evaluate understandability and actionability. Readability was evaluated with the Flesch-Kincaid Reading Ease algorithm. Comprehensiveness was evaluated with author generated criteria based on national guidelines. Scores for each assessed metric were determined by two independent reviewers for each website and recorded, with any inter-reviewer discrepancies resolved by consensus. Statistical analysis was performed to compare results by website affiliation (academic, foundation or government) and search rank.ResultsThirty-seven websites evaluated (N = 17 academic, N = 13foundation and N = 7 government). The mean quality score (DISCERN) was 3.62 (SD 1.21), with no significant differences across affiliations or search positions. Thirty-five out of the 37 evaluated websites achieved an understandability (PEMAT-P) score above the recommended threshold of 70% (Mean 78.38%, SD 11.86%) and 14 websites exceeded the threshold for actionability (Mean 57.66%, SD 37.69%) with no significant differences across affiliations or search positions. Readability (Flesch-Kincaid) averaged a 10th–12th grade level, with a mean score of 51.88 (SD 8.93). Mean comprehensiveness was scored at 62.98% (SD 23.23%) across all websites without significant differences across affiliations or search positions, with over 85% of websites addressing epidemiology, risk factors, and symptomatology, but under 30% of websites including content on post-treatment complications or surveillance.ConclusionsWhile most online resources for gastric cancer provided understandable information, they lacked actionability, were written above recommended reading levels, and offered limited content on long-term management. These shortcomings reflect broader trends seen across other patient resources and highlight the need for more actionable, readable, and comprehensive online patient education materials.

Abstract Gain-of-function mutations in RAS genes are the most prevalent oncogenic mutations responsible for about one-third of all human malignancies. Despite decades of research, direct targeting of RAS remains a major clinical challenge as RAS inhibitors recently FDA-approved or in clinical trials appear to have limited efficacy due to the emergence of acquired resistance. We recently described a mechanistically distinct pan-RAS inhibitor, ADT-007, that selectively kills cancer cells harboring activated RAS, whether driven by oncogenic mutations or activation by upstream receptor tyrosine kinase signaling. ADT-007 potently inhibited the growth of an array of cancer cell lines harboring various RAS mutations or activated RAS with low nM IC50 values. In contrast, cancer cells with downstream RAF mutations or cells of normal tissues were essentially insensitive. Cellular, biochemical, and biophysical studies demonstrated that ADT-007 binds nucleotide-free RAS to block GTP loading and activation of the MAPK/AKT signaling pathway, resulting in mitotic arrest and apoptosis. ADT-007’s unique selectivity was attributed to metabolic detoxification by glucuronidation from UDP-glucuronosyltransferases (UGTs), which we found to be enriched in normal cells compared with RAS-mutant cancer cells. Notably, ADT-007 induced apoptosis and caused nearly complete inhibition of colony formation of Mia-PaCa-2 human pancreatic cell line, while the pan-KRAS inhibitor, BI-2865, and the pan-RAS inhibitor, RMC-6236, did not induce apoptosis, but only suppressed proliferation and marginally inhibited colony formation under the same conditions. Furthermore, RAS mutant colon and pancreatic cancer cells did not develop resistance to ADT-007 under chronic exposure, in contrast to sotorasib, BI-2865, and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor they were exposed to. Moreover, the resistant cell lines exhibited cross-resistance to mechanistically distinct classes of RAS inhibitors, including pan-KRAS, pan-RAS, and allele-specific KRAS inhibitors, but not to ADT-007 or a second-generation inhibitor, ADT-030. These observations suggest a shared mechanism of acquired resistance that may limit the efficacy of currently known RAS inhibitors (approved or in development). An orally bioavailable prodrug of ADT-007, ADT-1004, demonstrated favorable tolerability and suppressed tumor growth in orthotopic and patient-derived xenograft models of pancreatic cancer, accompanied by reductions in activated RAS and p-ERK levels. Consistent with resistance experiments, ADT-1004 displayed superior efficacy than sotorasib or adagrasib in a xenograft model using a resistant MIA-PaCa-2. These findings support further development of ADT-1004 that holds promise for broad and durable efficacy against RAS-driven cancers. Citation Format: Junwei Wang, Xi Chen, Sindhu Ramesh, Jeremy B. Foote, Chung-Hui Huang, Kristy L. Berry, Khalda Fadlalla, Dhana Sekhar Reddy Bandi, Purnachandra Ganji, Elmar Nurmemmedov, Ivan Babic, Donald Buchsbaum, Asfar S. Azmi, Yulia Y. Maxuitenko, Adam B Keeton, Bassel El-Rayes, Gary A. Piazza. ADT-007: A mechanistically distinct Pan-RAS inhibitor with capacity to escape acquired resistance common to other RAS inhibitors [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 413.

Abstract Background and Objective: Advanced pancreatic neuroendocrine tumors (pNETs) respond poorly to current FDA-approved therapies, emphasizing the urgent need to find new and effective treatment targets. Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD biosynthesis pathway, has emerged as a crucial therapeutic target in pNETs. Despite its importance, specific inhibitors directly targeting NAMPT for pNET treatment are currently lacking. This study aimed to evaluate the efficacy of RPT-E-037, a novel NAMPT inhibitor, in preclinical models of pNETs. Methods: Growth inhibition was determined by MTT, colony formation and apoptosis assays. We also measured growth arrest using cell cycle analysis. Expression of gene or protein was determined using quantitative PCR, and western blotting techniques. The impact of NAMPT inhibitor RPT-E-037 was evaluated in pNET in vitro cultures and in in vivo. Results: RPT-E-037 demonstrated its growth inhibitory effect in BON-1 and QGP-1 pNET cell lines at pharmacologically relevant concentrations. The inhibitory concentration-50 (IC50) were determined as 0.3 and 1.2 micromolar (µM) in BON-1 and QGP-1 cells respectively. Importantly, RPT-E-037 demonstrated selectivity, showing no adverse effects on normal islet cells (ABC-TC4286, AcceGen) at concentrations effective against tumor cells (reflected by its 40-folds higher IC50). In addition, growth inhibitory effect of RPT-E-037 significantly rescued by nicotinic acid (niacin) treatment in BON-1 cells. Niacin also diminishes its colony reduction and apoptotic ability of RPT-E-037 in this cell line. The novel NAMPT inhibitor RPT-E-037 was shown to induce “DNA synthesis (S) phase” cell cycle arrest. However, niacin treatment switches “S phase” cell cycle arrest to “G0/G1 phase” cell cycle arrest. RPT-E-037 synergized with pNETs standard of care mTOR targeted agent everolimus in both BON-1 and QGP-1 cell lines leading to superior cell deaths (CI<1). The in vivo efficacy of RPT-E-037 in BON-1 and QGP-1 cell line derived xenografts (CDxs) are under way. Conclusion: For the first time, this study reveals the therapeutic potential of RPT-E-037, a new NAMPT inhibitor, for pNETs in preclinical models. RPT-E-037 shows promise as a novel NAMPT inhibitor and deserves further clinical investigation for pNETs.Generative AI was used for improving the language of the abstract. Citation Format: Md Hafiz Uddin, Husain Yar Khan, Amro Aboukameel, Sahar F. Bannoura, Irfana Muqbil, Hugo Jimenez, Filza Khan, Rafic Beydoun, Gregory Dyson, Yang Shi, Mohammed N. Al Hallack, Nitin Vaishampayan, Ibrahim Azar, Steve Kim, Eliza W. Bael, Miguel Tobon, Khalil Choucair, Walid Sukkari, Hafsa Imtiaz, Herbert Chen, Muhammad W. Saif, Anthony Frank Shields, Ramzi M. Mohammad, Philip Philip, Bassel F. El Rayes, Min Wu, Michael Schelle, Boris Pasche, Asfar S. Azmi. Targeting NAMPT using Novel Inhibitor RPT-E-037 in Pancreatic Neuroendocrine Tumor [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 419.

Pancreatic neuroendocrine tumors (PNETs) represent a biologically heterogeneous group of neoplasms shaped by both intrinsic genomic alterations and dynamic interactions with the tumor microenvironment (TME). Conventional analytical approaches offered limited insight into these complex mechanisms. However, the emergence of multi-omics technologies including genomics, transcriptomics, proteomics and spatial single-cell platforms dramatically expanded current understanding of tumor evolution, immune-stromal crosstalk and phenotypic plasticity. In the present review, findings from novel multi-omics studies were integrated to reframe PNET biology through the perspective of TME co-evolution. The present review highlighted how genomic instability serves as a key driver, promoting transcriptomic reprogramming and clonal evolution that subsequently remodels the TME into an immunosuppressive niche rich in cancer-associated fibroblasts and characterized by immune exclusion. The present review further emphasized the novel role of spatial multi-omics in deciphering the spatial heterogeneity of the PNET ecosystem. These insights accelerated the identification of novel biomarkers and revealed novel therapeutic susceptibilities, potentially paving the way for rational combination strategies that target both tumor-intrinsic pathways and microenvironmental constraints. Therefore, the present review proposed that multi-omics profiling provides not only a descriptive landscape but a mechanistic framework for precision oncology, enabling improved patient stratification and biomarker-driven therapeutic interventions in PNETs.

KPT-9274, a potentially first-in-class, dual NAMPT/PAK4 inhibitor, has shown single-agent anticancer activity in hematologic and solid tumor cell lines and xenografts. KPT-9274 has shown anti-tumor activity in combination with nivolumab in nonclinical models. KCP-9274-901 was a first-in-human, multi-center, open-label clinical study to assess preliminary safety, tolerability, and efficacy of KPT-9274 in patients with advanced solid tumors. This study was conducted in three parts. A two-part (A, B) dose escalation phase to determine the recommended phase II dose and maximum tolerated dose (MTD) of KPT-9274 alone and with niacin. Part 3 (C) was a dose-finding and expansion phase in patients with melanoma treated with KPT-9274 plus nivolumab. A total of 60 patients were enrolled (part A and B n = 50; part C n = 10). Three dose-limiting toxicities (DLTs) were observed in the 40-mg (n = 1) and 80-mg plus niacin (n = 2) cohorts. MTD was not reached in parts A and B and was 60 mg plus nivolumab in part C. The most frequently reported TEAEs (≥30 www.clinicaltrials.gov , NCT02702492.

Menin scaffolds the oncogenic histone-lysine-N-methyltransferase (KMT2A)-fusion protein (FP) complex in KMT2A-r and wild-type KMT2A complex in NPM1-m acute myeloid leukemia (AML). Menin inhibitors (MIs) are effective in KMT2A-r AML and NPM1-m AML. However, not all patients respond to MIs as monotherapy. In this preclinical study, we demonstrate that the MI ziftomenib, in combination with the XPO1 inhibitor selinexor, synergistically inhibited the growth of multiple KMT2A-r and NPM1-m AML cell lines (CI<1). The combination suppressed colony formation in primary CD34+ KMT2A-r progenitor cells without affecting normal stem cells. Robust apoptosis and decreased G2/M populations were also evident. The combination downregulated HOXA9 and MEIS1 while upregulating monocytic differentiation marker CD11b in both the AML molecular signatures. RNA sequencing and proteomic analysis in KMT2A-r revealed suppression of multiple bona fide menin-KMT2A target genes. Our mechanistic studies also identified a novel role of XPO1 in stabilizing menin's binding to chromatin and its interactions with KMT2A and KMT2A/MLLT3. XPO1 inhibitor-mediated disruption of these interactions, particularly in combination with ziftomenib, synergistically impairs oncogenic transcriptional programs. In vivo, combination therapy improved survival in both MV4;11 and OCI-AML3 cell line and primary patient-derived KMT2A-r and NPM1-m AML xenograft models in NSG mice, effective even at reduced drug doses. These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and XPO1 can be a more effective translational strategy for treating KMT2A-r and NPM1-m AML than MI monotherapy to deepen responses and delay/prevent relapses.

Sporadic pancreatic neuroendocrine tumors (pNETs) with wild type MEN1 represent a major yet largely ignored subset whose biology and metastatic potential remain poorly understood. Because metastasis can occur despite low histologic grade and modest mutational burden, we hypothesized that metastatic competence in MEN1-wild-type pNETs reflects quantitative reinforcement of shared oncogenic pathways rather than distinct mutational processes. We profiled 75 primary low-grade pNETs by whole-exome and RNA sequencing, including 25 percent with lymph node and/or liver metastasis, and integrated genomic and transcriptomic data to connect pathway lesions with expression state. Metastatic tumors showed a slight increase in mutation frequency but conserved base-substitution spectra relative to non-metastatic cases, and adverse clinicopathologic features were enriched in Grade 2 disease. Aggregating alterations to pathways revealed broad convergence on canonical networks, with transcriptomic analyses demonstrating cohort-wide enrichment of Calcium, WNT, and KRAS/PI3K-AKT programs in metastasis. Intersection of significantly mutated genes with differentially expressed genes identified a focused 29-gene overlap, including RYR1 and ZNF273, that marks these convergent axes and distinguishes metastatic from non-metastatic tumors. Gene set enrichment confirmed preferential activation of Calcium, WNT, and PI3K-AKT signaling in metastatic tumors, consistent with a network-intensity model of progression. Finally, upstream-regulator analysis (iPathwayGuide) and gene-centric perturbation mapping (Gene2Drug) nominated candidate targeted and repurposable agents predicted to reverse the metastatic expression phenotype and flagged drugs unlikely to provide benefit, yielding a prioritized, testable therapeutic shortlist which includes fasudil and spaglumic acid. Convergent, domain-specific mutational patterns in highly mutated genes such as ZNF273 and CLCA1 define a molecular signature that could stratify metastatic risk in low-grade pNETs. Collectively, our data reframe metastasis in MEN1-wild-type low-grade pNETs as a property of pathway state rather than mutation quantity and provide a translational blueprint for biomarker-guided therapy development focused on Calcium, WNT, and KRAS/PI3K hubs.

Abstract Kirsten rat sarcoma virus (KRAS) gene, a member of the well-known RAS oncogene family, has been identified in a wide variety of malignant diseases and plays a crucial role in oncogenesis and progression. KRAS mutations have been strongly associated with shorter overall and progression-free survival in many different malignant diseases, including multiple myeloma (MM). Multiple myeloma (MM) is a malignant plasma cell disorder ranked as the second most common blood cell malignancy. Clinically, it manifests as anemia, renal damage, skeletal lesions, and a high frequency of infections, often resulting in death. Despite significant progress in treatment such as immunotherapeutic drugs, proteasome inhibitors, and apoptosis inhibitors, MM remains incurable due to the development of drug resistance in patients. The overall survival rate is approximately 60% at 5 years, highlighting the urgent need for new and affective agents. At least 20% of MM patients have been reported to carry KRAS point mutations. Therefore, targeting the KRAS oncoprotein provides a potential therapeutic strategy in MM. Early evidence revealed that down-regulation of KRAS using siRNA inhibited MM tumor growth both in vitro and in vivo. Daraxonrasib (RMC6236), an FDA-approved small molecule pan-Ras (ON) state inhibitor, has shown anti-tumor activity in U.S. clinical trials. In this study, we evaluated the anti-myeloma activity of RMC6236 in MM cells. Our results showed that RMC6236 inhibited cell growth in a dose response manner across different MM cell subtypes, including both KRAS mutant and wild-type (WT) cells. Depending on the KRAS genotype mutational status, the IC50 of RMC6236 was estimated to range from 20 to 800 nM, Also, cell cycle assays revealed that RMC6236 treatment significantly decreased the number of cells in S phase (DNA synthesis), suggesting an inhibition of cell cycle progression in MM cells. Moreover, combining RMC6236 with anti-myeloma agent venetoclax or a novel anti-PCNA agent AOH1996 significantly reduced cell growth in KRAS mutant and WT MM cells. RT-qPCR assays revealed that RMC6236 treatment led to decreased gene expression of KRAS, CSC signature markers, anti-apoptotic markers, IL-6, STAT3, and mTOR in MM cells, along with the down-regulation of EZH2 and MEK/ERK signal pathways. These findings suggest that the inhibition of MM cell growth by RMC6236 may be linked to the down-regulation of these tumor-associated genes. Ongoing studies aim to further evaluate the anti-myeloma potential of RMC6236. Citation Format: Jeffreay Zonder, Bin Bao, Amro AbouKameel, Sahar Bannoura, Husain Y. Khan, Hafiz Uddin, MD, Walid M. Sukkari, Ramzi Mohammad, Long Gu, Pouya Haratipour, Robert J. Hickey, Linda Malkas, Asfar S. Azmi. Kirsten rat sarcoma virus (KRAS) oncoprotein as a new therapeutic target in multiple myeloma [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 421.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy driven predominantly by oncogenic KRAS mutations. Proliferating cell nuclear antigen (PCNA) is a ring-shaped clamp protein that encircles DNA and regulates replication, repair, and resolution of transcription-replication conflicts; processes hyperactivated in PDAC. AOH1996 is a first-in-class, selective PCNA inhibitor currently in Phase I clinical trials. PCNA has predicted synthetic lethal interactions with KRAS, suggesting combination potential with emerging KRAS inhibitors. This study evaluated AOH1996 alone and in combination with KRAS-targeted agents in PDAC models. Methods: In this study, we investigated the use of AOH1996 in preclinical models of KRAS-mutant PDAC. We determined cell viability and growth inhibition by MTT, colony formation and spheroid assays. Apoptosis and the cell cycle were analyzed by flow cytometry. RNA-seq, RT-qPCR and western blot were performed for mechanistic evaluations. Drug combination synergy modeling was performed using SynergyFinder. In vivo efficacy was assessed in PDAC xenograft models treated with AOH1996, KRAS inhibitors (MRTX1133, sotorasib, and RMC-6236), or combinations. Residual tumors were analyzed for pERK and pAKT signaling changes. Results: AOH1996 showed potent, dose-dependent cytotoxicity in multiple PDAC cell lines and 3D spheroids (IC50: 0.5-1.5 μM). RNA-seq revealed broad transcriptional alterations, with enrichment of MAPK, PI3K-Akt and Hippo signaling pathways. Across KRAS G12C and G12D models, AOH1996 exhibited strong synergy with KRAS inhibitors, including MRTX1133, sotorasib, adagrasib, and RMC-6236. Combination therapy caused marked G1 and G2/M phase arrest, increased Annexin V-positive apoptosis, and dual suppression of pERK and pAKT. In patient-derived tumoroids, AOH1996 plus RMC-6236 significantly reduced viability compared to single agents. In vivo, AOH1996 combined with MRTX1133 or with sotorasib produced robust tumor regressions with no significant weight loss, supporting tolerability. Conclusions: AOH1996 is a promising therapeutic candidate for PDAC, demonstrating potent single-agent activity and strong synergy with clinically relevant KRAS inhibitors across in vitro, ex vivo, and in vivo models. The combination induces profound apoptotic and cell-cycle effects and disrupts key KRAS effector pathways. These results support further translational development of AOH1996-based combination regimens for patients with KRAS-mutant PDAC. Citation Format: Sahar F. Bannoura, Husain Y. Khan, Md Hafiz Uddin, Amro Aboukameel, Yin Wan, Bin Bao, Adeeb Aboukameel, Rafic Beydoun, Pouya Haratipour, Long Gu, Muhammad Wasif Saif, Robert J. Hickey, Linda H. Malkas, Yang Shi, Mohammed Najeeb Al Hallak, Ramzi M. Mohammad, Boris C. Pasche, Asfar S. Azmi. Novel PCNA inhibitor AOH1996 synergizes with KRAS-targeted therapies in pancreatic ductal adenocarcinoma [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 4580.

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are a heterogeneous group of rare tumors with poor clinical outcomes. These patients have limited treatment options after progressing on first-line platinum-based chemotherapy. Although dual immune checkpoint inhibitors (ICIs) with anti-CTLA-4 and anti-PD-1 blockade have significantly improved outcomes for several solid tumors, they demonstrated modest activity for EP-NECs with 9–26% response rates and low survival rates. Preliminary data demonstrated that NP-101 (Nigella sativa formulation) enhances T-cell infiltration and is synergistic with dual ICPIs in NECs’ cellular models. This pilot study evaluated the tolerability and efficacy of NP-101 plus nivolumab and ipilimumab in patients with metastatic EP-NECs refractory to first-line platinum-based chemotherapy. This is a single-arm pilot study (NCTNCT05262556) in which patients with metastatic EP-NECs received NP-101 (oral capsules), 3,000 mg daily, plus ICPIs (intravenous nivolumab 3 mg/kg and ipilimumab 1 mg/kg) every 3 weeks for four cycles. Nonprogressors received NP-101 (3,000 mg daily), plus biweekly maintenance of nivolumab (240 mg), and then completed 24 weeks of treatment. Treatment-related adverse events (TR-AEs) were characterized according to CTCAE v4.03. The response rate was estimated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The Kaplan–Meir method was used to estimate median PFS and OS. Twelve patients received ≥1 dose of NP-101 and nivolumab plus ipilimumab. There were no dose-limiting toxicities (DLTs). Grade 1/2 TR-AEs occurred in 100% (12/12) of patients. The most common G1/2 TR-AEs included the following: fatigue (75%), nausea (41.7%), pruritus (41.7%), muscle weakness (33.3%), vomiting (25%), rash (25%), and abdominal pain (25%). Eight patients (66%) experienced grade 3/4 TR-AEs, including rash (33.3%), nausea (16.7%), vomiting (16.7%), and transaminitis (16.7%). No treatment-related grade 5 toxicities or deaths were recorded. The objective response rate was 41.7% (2/12 (16%) complete response (CR) + 3/12 (25%) partial response (PR); 95% CI: 15.2–72.3%) for all patients and 50% (2/8 CR + 2/8 PR, 95% CI: 0.16–0.84) for patients with NEC of gastrointestinal origin. The median duration of response was 7.5 months. As for the median progression-free survival, it was 5.7 months, and the median overall survival (OS) was 10.5 months with a median follow-up of 10.4 months. The combination of NP-101 plus dual ICPIs (nivolumab and ipilimumab) was safe and well tolerated with preliminary evidence of antineoplastic activity. Currently, a randomized phase II clinical trial evaluating the combination is under development.

e23407 Background: Arab Americans are frequently misclassified as White in U.S. cancer registries, limiting the study of cancer presentation, treatment patterns, and outcomes in this understudied population. Michigan hosts the largest Arab American community in the U.S., providing an opportunity to characterize cancer epidemiology in this group. We aimed to describe clinicopathologic features, treatment patterns, and outcomes across solid tumors in an institutional Arab American cohort to support future disparities-focused investigations. Methods: We created a database by identifying patients with Arabic or Arab-appearing surnames and confirming Arab ethnicity through chart review based on self-reported language and/or country of origin. Patients with any solid tumor at any stage were included; those with unconfirmed or non-Arab origin were excluded. Demographics, tumor characteristics, treatments, and outcomes were collected. Treatment patterns were analyzed by cancer type and stage. Survival was assessed using Kaplan–Meier methods, with multivariable Cox regression performed to evaluate prognostic factors for overall survival. Results: A total of 96 patients were included (2004-2024): breast (n = 40), colorectal (n = 20), prostate (n = 20), and lung (n = 16) cancers. The median age was 56 years and 64.6% presented with early-stage disease (AJCC 8 th Edition, I–II). Surgery was performed in 68.8%, chemotherapy in 40.6%, radiation in 44.8%, hormone therapy in 40.6%, immunotherapy in 3.1%, and targeted therapy in 4.2%. There was significant overlap reflecting multimodality therapy in stage I–III disease, whereas stage IV patients were predominantly treated with systemic therapy alone (73.3%). At a median follow-up of 56 months, median OS was not reached (95% CI: 129 months to NR), with 5-year OS of 80.2% (95% CI: 71.8%–89.6%). Cancer-specific 5-year OS varied: breast 91.9%, prostate 93.3%, lung 59.6%, and colorectal 58.2%. Median PFS for all stages was 80 months (95% CI: 50-NR), with stage III–IV patients having median PFS of 13 months (95% CI: 9–45). In multivariable analysis, age < 65 years was associated with improved survival (HR 0.163, 95% CI: 0.038–0.705, p = 0.015), while advanced stage (III–IV) showed a trend toward worse outcomes (HR 3.374, 95% CI: 0.910–12.517, p = 0.069). Indirect comparison to SEER-published 5-year relative survival estimates revealed lower 5-year OS for colorectal cancer (58.2% vs ~65%) in our cohort, while breast, prostate, and lung cancer survival were similar or higher than population benchmarks. Conclusions: This is the first descriptive study to characterize treatment patterns and oncologic outcomes among Arab American patients. This preliminary analysis highlights the need for expanded comparative and molecular studies of site-specific cancers to better understand racial disparities in outcomes.

KRASG12D-selective and pan-RAS inhibitors have shown promise in pancreatic ductal adenocarcinoma (PDAC), yet adaptive resistance is anticipated to limit durability of response. Exportin 1 (XPO1), a nuclear export protein frequently overexpressed in PDAC, represents a potential vulnerability in KRAS-mutant cancers. We evaluated whether pharmacologic inhibition of XPO1 enhances therapeutic efficacy and durability of KRAS pathway inhibition. KRASG12D inhibitor- and pan-RAS inhibitor-resistant PDAC cellular models were generated and assessed for sensitivity to the second-generation XPO1 inhibitor Eltanexor. Antiproliferative synergistic effects of Eltanexor combined with MRTX1133, Zoldonrasib (RMC9805), or Daraxonrasib (RMC6236) were evaluated in PDAC 2D cultures, 3D spheroids, patient-derived organoids, and tumor-fibroblast co-culture models. Eltanexor sensitized KRAS inhibitor-resistant PDAC cells and synergistically enhanced growth suppression across multiple KRASG12D-mutant models. Combination treatment reduced clonogenic survival, disrupted 3D spheroid integrity, and significantly inhibited viability of patient-derived organoids. The in vivo efficacy of the combination was tested in PDAC cell-derived xenograft/allograft and patient-derived xenograft models. Combining sub-therapeutic doses of Eltanexor with allele-specific inhibitors or pan-RASi resulted in significant tumor regression, prevention of metastatic spread and prolonged survival in vivo. Notably, Eltanexor maintenance therapy suppressed tumor regrowth following RAS inhibitor withdrawal and preserved responsiveness upon re-challenge. Mechanistically, molecular and phosphokinome profiling showed that the combination broadened suppression of MAPK- and mTOR-associated signaling and reduced activity of multiple oncogenic kinases. In conclusion, XPO1 inhibitor Eltanexor enhances the efficacy and durability of KRAS and pan-RAS inhibition in PDAC models. These findings provide a preclinical rationale for clinically evaluating Eltanexor in combination with RAS-targeted therapies to delay or overcome adaptive resistance in KRAS-mutant PDAC.

742 Background: KRAS, TP53, CDKN2, and SMAD4 mutations are implicated in PDAC development and progression. Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway, and its loss may be associated with a shorter overall survival (OS). Early clinical trials in patients with MTAP-deficient malignancies are currently underway with encouraging results. However, there are only few studies characterizing patients with MTAP-deficient PDAC. Our study is a retrospective case series interrogating the molecular profiles, demographics, and clinical courses of patients diagnosed with MTAP-deficient PDAC in 3 institutions. Methods: This is a multi-center retrospective cohort study of patients with metastatic PDAC from January 2019 to August 2025. MTAP gene loss and associated genomic changes were determined by next generation sequencing (NGS) of tumor tissue. Patient demographics, tumor characteristics, treatment history, and survival data were collected. Plasma ctDNA based NGS was done for select patients. Results: 21 patients were identified. 85% of patients were white, 10% African American, 5% Asian. 57% of patients were female. The median age at diagnosis was 63 years, with a range of 49 to 81 years of age. Liver metastasis was present in 80% of patients. TP53 and SMAD4 mutations were present in 95%, and 25% of patients, respectively. CDKN2A and B mutations were present in 80% and 85% of patients, respectively. 10% of patients had neither CDKN2A nor B mutation. All patients had KRAS mutations; G12D and Q61H/R mutations were each present in 29% of patients, while G12V and G12R mutations were seen in 20% and 15% of patients, respectively. MTAP deletion was not detected by plasma ctDNA analysis undergone by 9 patients. Five patients (25%) were initially diagnosed with localized disease and underwent surgical resection prior to developing metastatic disease. Three patients (15%) had rapidly progressive disease and died before starting treatment. Two patients recently began treatment and are yet to be assessed for response. Of the 16 patients with an evaluable treatment response, 25% experienced disease progression on first-line therapy and 75% experienced disease stability or partial response by RECIST criteria. Mean response duration was 8.5 months. Median survival of the entire cohort was 15.5 months. Conclusions: Patient demographics and clinical courses did not vary significantly from the general metastatic PDAC population. KRAS mutation subtype frequency is different than expected, with the higher frequency of Q61H/R mutations. Further study of the relationship between MTAP deletion and specific KRAS mutation subtypes may influence treatment decision-making and future clinical trial designs. Lack of detection in liquid biopsy may relate to type of assay used.

e16387 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcomes and limited benefit from systemic therapy. Non-invasive biomarkers capable of dynamically capturing treatment response are needed to improve therapeutic monitoring. Circulating plasma microRNAs (miRNAs) represent a promising class of longitudinal biomarkers. We evaluated on-treatment changes in plasma miRNA profiles in PDAC patients receiving gemcitabine plus nab-paclitaxel (GnP). Methods: Patients with histologically confirmed PDAC were enrolled in a prospective clinical study of GnP. Plasma samples were collected longitudinally at baseline and during treatment. Total RNA was isolated from plasma and subjected to miRNA sequencing, with differential expression analysis performed between pre- and on-treatment samples. Selected miRNAs were validated by RT-qPCR. Exploratory functional studies were conducted in PDAC cell lines. Results: Twenty-eight patients were enrolled, 13 of them had a paired microRNA blood samples (before and on treatment) to be evaluable for longitudinal biomarker analyses. Longitudinal plasma miRNA profiling revealed reproducible on-treatment modulation of circulating miRNAs, including upregulation of miR-296-3p, miR-127-3p, miR-766-5p, miR-202-3p, miR-449c-5p, miR-993, and miR-625-3p, and downregulation of miR-15b-5p, miR-3150a, miR-3158-3p, and miR-4669, which were confirmed by RT-qPCR. The forced expression of miR-3158-3p inhibited cell growth and increased the drug sensitivity to GnP in MiaPaCa2 cells. Correlation of selected miRNAs with therapeutic response and resistance is ongoing using gain- and loss-of-function approaches with miRNA mimics and inhibitors in PDAC models. The correlation of clinical outcomes with the microRNA panel changes is ongoing. Conclusions: Longitudinal on-treatment plasma miRNA profiling identifies dynamic biomarker signatures associated with GnP therapy in PDAC. These circulating miRNAs may serve as minimally invasive biomarkers for treatment monitoring and provide biologic insight into therapy-associated tumor responses. Continued enrollment and longitudinal follow-up are ongoing to further assess clinical relevance.

Phosphodiesterase 10 (PDE10) was previously reported to be overexpressed in various cancers and essential for cancer cell proliferation and survival. Here, we studied a novel PDE10 inhibitor, ADT-030, and found it to potently and selectively inhibit KRAS mutant PDAC cell proliferation and clonogenicity by inducing G2/M arrest and apoptosis. ADT-030 also inhibited motility of PDAC cells in vitro. These effects were mediated by increased cAMP/cGMP levels and activation of PKA/PKG. The growth inhibitory activity of ADT-030 was associated with reduced β-catenin and RAS signaling. Notably, ADT-030 also inhibited the growth of KRASG12D and KRASG12C mutant PDAC cells resistant to allele-specific KRAS inhibitors. Oral administration of ADT-030 significantly suppressed tumor growth, reduced lung and liver metastasis, and increased survival without systemic toxicity in syngeneic and patient-derived xenograft (PDX) PDAC models. ADT-030 also increased chemotherapy response in orthotopic PDAC models. Immune phenotyping and single-cell RNA sequencing revealed remodeling of the tumor microenvironment by ADT-030 with a more favorable immune suppressive profile to activate anti-tumor immunity. These results show that ADT-030 is a promising drug development candidate for the treatment of KRAS-mutant PDAC capable of simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that remains largely refractory to immune checkpoint blockade, owing to a profoundly immunosuppressive and immune excluded tumor microenvironment (TME). Nuclear cytoplasmic transport is essential for immune signaling in tumor and stroma. Exportin 1 (XPO1), the dominant nuclear export receptor, is overexpressed in PDAC and has been linked to therapeutic resistance, yet its role in PDAC immunopathogenesis has not been defined. Methods: In this study, we have utilized syngeneic and genetically engineered mouse models (GEMMs; KPC (Kras/p53/Cre)), digital spatial profiling (DSP; transcriptomics/proteomics), and single-nucleus RNA sequencing (snRNAseq). PDAC cells were treated with the selective XPO1 inhibitor Selinexor and Gemcitabine-nab-paclitaxel and profiled by bulk RNA sequencing. KPC tumors receiving Selinexor and Gemcitabine-nab-paclitaxel underwent snRNAseq, DSP, immunohistochemistry (IHC), and immune phenotyping. In Pan02 syngeneic model, Selinexor was combined with anti PD-1 antibody and tumor growth, and tumor and splenic immune subsets were quantified by flow cytometry. Results: Treatment of PDAC with Selinexor and Gemcitabine-nab-paclitaxel induced profound immune reprogramming characterized by broad remodeling of innate and adaptive immune responses. Our transcriptomics and flow cytometry analyses revealed enrichment of immune cells with anti-tumor immune function, antigen presentation and cytotoxic T cell activation. In line with these data, snRNAseq and IHC analysis of KPC tumors demonstrated increased intratumoral CD4+ and CD8+ T cell infiltration and elevated expression of T and B cell-associated transcripts (CD3d, CD3e, CD4, CD8a, CD8b1, CD19) together with upregulation of inflammatory monocyte marker Ly6C1, indicating coordinated expansion of effector lymphoid populations and anti-tumorigenic monocytes within a dense desmoplastic stroma. Furthermore, DSP showed that Selinexor and Gemcitabine-nab-paclitaxel enhanced pathways related to MHC class II-mediated antigen processing and leukocyte activation across both tumor and stromal compartments. Selinexor and Gemcitabine-nab-paclitaxel treatment suppressed the expression of the immunosuppressive chitinase-like protein Chil3, as this was validated by IHC, western blot and qPCR suggesting attenuation of pro-tumor myeloid signaling in PDAC TME. Consistently, Selinexor combined with anti-PD-1 therapy in Pan02 models significantly reduced tumor growth without much toxicity and reprogrammed myeloid cell populations toward Ly6ChiCd11b+ phenotype. Conclusions: Together, these data identify XPO1 driven nuclear export as a central upstream regulator of PDAC immune evasion and support clinical testing of XPO1 inhibitor immune checkpoint blockade combinations in pancreatic cancer. Ongoing validation in diverse preclinical models is informing planned clinical trials. Citation Format: Md Hafiz Uddin, Mohammed Najeeb Al Hallack, Misako Nagasaka, Sahar F. Bannoura, Husain Y. Khan, Amro Aboukameel, Fulya K. Alkan, Hilmi K. Alkan, Khalil Choucair, M Wasif Saif, Bin Bao, Ibrahim Azar, Eliza W. Beal, Miguel Tobon, Steve Kim, Amr Mohamed, Gregory Dyson, Rafic Beydoun, Ramzi M. Mohammad, Herbert Chen, Bassel El-Rayes F. El-Rayes, Philip A. Philip, Boris C. Pasche, Hasan Korkaya, Asfar S. Azmi. Targeting XPO1 reprograms immune microenvironment and confers sensitivity to immune checkpoint blockade in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB416.