Babiker, H.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is driven predominantly by oncogenic KRAS signaling and characterized by an immunosuppressive, fibrotic tumor microenvironment that limits therapeutic responses. RMC-6236, a pan-KRAS inhibitor, and ONIOYID, an investigational anti-tumor agent, each demonstrate partial activity in KRAS-mutant cancers. However, their combined therapeutic potential in PDAC remains unexplored. Here, we evaluated the anti-tumor efficacy, survival benefit, and immunomodulatory effects of RMC-6236, ONIOYID and irinotecan alone and dual combinations multiple in vitro and in vivo PDAC models. Methods: In vitro cytotoxicity assays were performed using KPC, PANC-1, AsPC-1, and PANC-02 cell lines. In vivo therapeutic studies were conducted in orthotopic KPC and PANC-1 tumor models. RMC-6236 was administered orally at 10 mg/kg; ONIOYID and irinotecan was administered intravenously at 5 mg/kg. Tumor growth inhibition, survival, collagen deposition, and immune cell infiltration were analyzed. Tumor microenvironment remodeling was quantified via immunohistochemistry for CD8, CD4, collagen I, and fibronectin. Results: The combination of RMC-6236 and ONIOYID elicited potent anti-tumor effects across all evaluated PDAC cell lines, achieving greater than 90% growth inhibition in vitro. In vivo, co-treatment resulted in more than 90% tumor regression in both KPC and PANC-1 xenograft models, markedly surpassing the efficacy of individual monotherapies and other dual-agent controls. Combination therapy significantly extended overall survival and produced sustained suppression of tumor progression. Mechanistic analyses revealed a substantial reduction in collagen and fibronectin deposition within the tumor microenvironment, consistent with attenuation of desmoplasia. Immune profiling demonstrated a robust enhancement of intratumoral CD8+ and CD4+ T-cell infiltration, along with a pronounced decrease in survivin expression. Importantly, no observable systemic toxicity was detected in treated animals. Conclusions: RMC-6236 combined with ONIOYID yields synergistic anti-tumor effects, remodels the fibrotic PDAC microenvironment, enhances T-cell infiltration, and significantly improves survival in aggressive pancreatic tumor models. These findings provide strong rationale for clinical evaluation of RMC-6236-based combination therapies for KRAS driven PDAC. Citation Format: Hari Krishnareddy Rachamala, Fang Wei, Debabrata Mukhopadhyay, Hani M. Babiker. Combined KRAS pathway inhibition and ONIOYID treatment enhances tumor regression, attenuates desmoplasia, and augments T cell infiltration 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 5842.

Abstract Background: Early-onset gastrointestinal (GI) cancers are increasing globally, yet the genomic basis for age-related differences across multiple tumor types remains poorly defined. We leveraged AACR Project GENIE v18.0 (N≈34,000 GI tumors) to characterize molecular distinctions by age in colorectal, pancreatic, small bowel, and anal cancers with sufficient early-onset representation. Methods: Clinical and genomic data were extracted and tumors classified into early-onset (<50 years) and late-onset (≥50 years). Mutation frequencies were compared by cancer type and age group, focusing on recurrent drivers, DNA repair, Wnt signaling, RAS/MAPK, chromatin remodeling genes, and targetable alterations. Results: Early-onset colorectal cancer (N=5,724) showed increased Wnt/β-catenin pathway alterations: APC (+4.9%), TCF7L2 (+4.1%), and TP53 (+5.0%), while late-onset tumors (N=15,807) were enriched for BRAF (−5.4%), RNF43 (−1.9%), and GNAS (−1.1%), indicating divergent tumorigenic pathways. Early-onset pancreatic cancer (N=890) exhibited significantly lower frequencies of canonical drivers—KRAS (−24.7%), TP53 (−15.6%), CDKN2A (−6.9%), SMAD4 (−6.0%)—with enrichment of MEN1 (+3.5%), TSC2 (+3.0%), ATRX (+2.0%), DAXX (+1.9%), and CTNNB1 (+2.4%), consistent with fusion-driven, hereditary, and chromatin remodeling biology. Small bowel cancer (N=99) in early-onset patients demonstrated enrichment in DNA damage response and MAPK/RAS genes including BRCA2 (+7.2%), NF1 (+7.4%), FBXW7 (+8.8%), FLT4 (+6.5%), ARAF (+6.4%), and ALK (+5.1%), whereas late-onset tumors (N=538) were enriched for KDR (−5.1%) and MGA (−5.2%). Early-onset anal cancer (N=62) showed elevated MGA (+7.8%), WHSC1/NSD2 (+6.9%), PBRM1 (+6.2%), FANCA (+5.2%), ERCC5 (+6.2%), and MSH6 (+5.9%), highlighting chromatin remodeling and DNA repair pathways potentially related to HPV biology; late-onset tumors (N=464) had enrichment in ATM (−5.6%), PTEN (−5.5%), STK11 (−5.2%), APC (−5.2%), and KMT2C (−5.0%), reflecting age-associated genomic instability. Conclusions: This pan-GI age-stratified analysis reveals distinctive oncogenic programs in early-onset GI cancers characterized by Wnt/TP53-driven colorectal, fusion- and chromatin remodeling-driven pancreatic, DNA damage response/MAPK-driven small bowel, and chromatin-immune DDR signatures in anal cancers. These findings underscore the need for age-tailored precision oncology and support routine genomic profiling in early-onset GI malignancies to identify targetable alterations enriched in younger patients. Citation: AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through an International Consortium. Cancer Discov. 2017;7(8):818-831. (Data: GENIE Release 18.0-public)Acknowledgement: AACR and Project GENIE registry Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Mosalem M. Osama, Hani M. Babiker. Distinct age associated genomic landscapes in colorectal, pancreatic, small bowel, and anal cancers: A pan gastrointestinal analysis of 34,000 tumors from AACR Project GENIE v18.0 [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 4105.

Abstract Background: PARP inhibitors are restricted to a subset of BRCA-associated cancers, but homologous recombination repair (HRR) deficiency signifies a broader genomic vulnerability that may extend therapeutic opportunities across diverse malignancies. We utilized AACR Project GENIE v18.0-public to define the pan-cancer prevalence of HRR gene alterations. Methods: Somatic mutation and clinical sample data from GENIE v18.0-public were analyzed. HRR genes included BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51B/C/D, RAD51L1, BARD1, BRIP1, and core FANC genes. HRR alteration rates were calculated by tumor type using unique samples; only de-identified aggregate results are reported. Results: Among 101,240 tumors, HRR gene alterations were frequent in multiple non-BRCA-associated cancers. Highest rates were seen in sialoblastoma (100%), large cell medulloblastoma (50%), malignant glomus tumor (50%), lung cancer (46.0%), infantile fibrosarcoma (42.9%), liver (40%), kidney (40%), non-melanoma skin (36.9%), colorectal (36.6%), melanocytoma (34.2%), biliary tract (33.3%), bladder (31.5%), and ovarian/fallopian tube (30.2%). Notably, lung, bladder, hepatobiliary, renal, gastrointestinal, and some sarcoma subtypes showed HRR mutation prevalence equal or higher than current PARP indications, yet lack FDA approval. Conclusions: HRR alterations are widespread across solid tumors, often surpassing rates in cancers eligible for PARP treatment. These findings support expanding tumor-agnostic HRR genomic testing beyond BRCA-linked malignancies and warrant prospective trials of PARP inhibitors in HRR-enriched tumor types such as lung, bladder, hepatobiliary, renal, gastrointestinal, and pediatric/rare cancers. Impact: Large-scale genomic profiling from AACR Project GENIE demonstrates that HRR gene alterations are common across diverse solid tumors, with prevalence in multiple cancer types surpassing those currently eligible for PARP inhibitor therapy. These findings support broad implementation of HRR genomic testing in routine molecular diagnostics and provide a rationale for expanding PARP inhibitor use beyond BRCA-associated malignancies. The data justify prospective tumor-agnostic clinical trials of PARP inhibitors in HRR-enriched cancers such as lung, bladder, hepatobiliary, renal, gastrointestinal, and select pediatric and rare tumors; this could transform therapeutic decision-making and accelerate development of synthetic lethality-based targeted therapies Citation: AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831 Acknowledgement: AACR and Project GENIE Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Osama M. Mosalem, Hani M. Babiker. Pan cancer enrichment of homologous recombination repair (HRR) gene alterations in 101,240 tumor samples from AACR Project GENIE: Implications for tumor-agnostic PARP inhibitor expansion [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 4106.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to aggressive biology, stromal desmoplasia, and profound immunotherapy resistance. Tumor Treating Fields (TTFields) disrupt mitosis and induce immunogenic cell death (ICD), type I interferon signaling, and microenvironment remodeling, providing a rationale for combining TTFields with immune checkpoint inhibition. This is the first systematic review to comprehensively synthesize mechanistic and clinical evidence for TTFields immunotherapy combinations across solid tumors, with emphasis on their translation relevance to PDAC. Methods: A systematic search of PubMed, Scopus, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through October 26, 2025, following PRISMA 2020 guidelines. Eligible studies evaluated TTFields combined with immunotherapy. Two reviewers independently screened and extracted data using Covidence. Evidence was summarized narratively by tumor type, study design, and immunotherapeutic approach. Results: Thirty-seven studies met criteria, including preclinical and clinical investigations across glioblastoma, NSCLC, mesothelioma, PDAC, and other tumors. Preclinical models consistently showed that TTFields trigger ICD hallmarks such as calreticulin exposure, HMGB1 and ATP release, and activate STING/type I interferon pathways, enhancing dendritic-cell maturation and T-cell and NK-cell function. Across in vivo models, TTFields combined with PD-1 or CTLA-4 blockade, vaccines, or other immunotherapies reduced tumor growth and increased lymphocyte infiltration. Clinical evidence, although early-phase and heterogeneous, indicates the combination is feasible, with toxicity dominated by low-grade skin reactions and no excess immune-related adverse events. In glioblastoma, adding TTFields to pembrolizumab and temozolomide showed numerically improved survival. The LUNAR phase 3 trial in metastatic NSCLC demonstrated an overall survival advantage when TTFields were added to systemic therapy, including immunotherapy. Evidence in PDAC remains preliminary, but the ongoing PANOVA-4 study combining TTFields with atezolizumab and chemotherapy highlights emerging translational relevance. Conclusions: TTFields enhance antitumor immunity when combined with immunotherapy across solid tumors. In PDAC, these mechanisms may help counteract the immunosuppressive microenvironment. Ongoing gastrointestinal trials will clarify optimal combinations, biomarkers of response, and the clinical role of TTFields-based immunomodulation. Citation Format: Douaa Albelal, Hari Krishnareddy Rachamala, Hani Babiker. Synergistic immunomodulation by Tumor Treating Fields combined with immunotherapy across solid tumors: A systematic review with translational relevance to 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 3813.

Abstract RMC-6236 (daraxonrasib) is a novel multiselect RAS(ON) inhibitor under investigation for pancreatic ductal adenocarcinoma (PDAC) and other RAS-mutant cancers. This compound shares structural similarities with RMC-7977 and exhibits a conserved binding site and interaction pattern within the tri-complex formed between active RAS (RAS(ON)) proteins and cyclophilin A (CypA). Tumor Treating Fields (TTFields) are low-intensity, alternating electric fields that disrupt mitosis and have shown clinical benefit in solid tumors. The PANOVA-3 trial demonstrated that TTFields combined with gemcitabine plus nab-paclitaxel improved survival, pain control, and quality of life in locally advanced PDAC. Our previous work demonstrated that TTFields abrogate oncogenic KRAS pathway. We thus hypothesize a potential for increase in effectievness with the combination. In this study, the metastatic PDAC cell line AsPC-1 was treated with TTFields (150 kHz, 1.8 V/cm), RMC-6236 (15 nM; sub-IC50), or combination. A sub-IC50 concentration (15 nM) of RMC-6236 was selected based on MTS assay results, and subsequent experiments were performed at this dose. The MTS assay revealed that both TTFields and RMC-6236 independently reduced AsPC-1 cell viability, with a more pronounced reduction observed at 72 hours compared to 48 hours. RMC-6236 alone produced minimal effects at either 48 hours (85.82 ± 13.9%) or 72 hours (90.48 ± 15.4%) compared with control (100.0 ± 8.4%, 48 h; 100.0 ± 8.2%, 72 h). TTFields treatment significantly reduced viability to 74.42 ± 21.4% at 48 hours and 50.17 ± 26.5% at 72 hours. The combination treatment (TTFields + RMC-6236) further decreased viability to 63.8 ± 25.2% at 48 hours and 40.93 ± 18.1% at 72 hours, demonstrating synergistic cytotoxicity relative to monotherapy. Clonogenic assays were performed to evaluate cell survival fractions following treatment with RMC-6236, TTFields, and their combination. Cell migration was assessed using scratch assays, revealing that untreated cells exhibited a migration rate of 91.49 ± 0.85%, RMC-6236-treated cells showed 89.48 ± 1.3%, TTFields alone reduced migration to 61.33 ± 16.3%, and combination treatment markedly suppressed migration to 24.6 ± 22.13% . For every case we were compared with 72h cell migration rate with 0 h migration rate. These findings indicate that TTFields alone significantly impair cellular motility, while their combination with RMC-6236 results in a profound anti-migratory effect, substantially inhibiting wound closure. Additionally, western blot analysis was performed to assess changes in KRAS protein expression, a key PDAC biomarker. Overall, our results demonstrate that the combination of TTFields and RMC-6236 significantly inhibits PDAC cell growth, migration, and survival at sub-IC50 concentrations, suggesting a promising alternative therapeutic approach for PDAC management. Citation Format: Ishita Saha, Santanu Bhattacharya, Debabrata Mukhopadhyay, Hani M. Babiker. Synergistic antitumor activity of tumor-treating fields and multiselect-RAS (ON) inhibitor RMC-6236 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 4478.