tbuckley/cabot-search huggingface dataset:
Abstract 5977: Identification and characterization of an allosteric and mutant-selective PI3Kα inhibitor
Authors: Chengshan Niu, Shengli Dong, Shaoqing Chen, Kaige Ji, Maolin Zheng, Mingtao Chen, Yuanjie Li, Meihua Li, Zhengfei Guo, Hongqiang Li, Yu Yu, Xinlong Yang, Chao Zhou, Apeng Liang, Yin Zhou, Wei Wu, Mingyu Jiang, Jun Li, Yusheng Wu
Journal: Cancer Research (2025)

Abstract Introduction: The PI3K-AKT-mTOR signaling pathway is pivotal in tumorigenesis. PIK3CA, a PI3K isoform, is one of the most frequently mutated genes, occurring in approximately 14% of cancers and in up to 40% of breast cancers. PIK3CA mutations are highly enriched at “hotspot” amino acid sites in the helical domain (E542K, E545K) and kinase domain (H1047R/L). PI3Kα mutations are often oncogenic drivers of other refractory cancers, including gastric cancer, colon cancer, uterine cancer, and head and neck squamous cell carcinoma. Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib have been approved for the treatment of patients with advanced HR+/HER2− breast cancer. However, alpelisib and inavolisib lack mutant selectivity and inhibit WT PI3Kα, which plays a critical role in cellular glucose homeostasis, resulting in dose-limiting toxicity such as hyperglycemia and hyperinsulinemia. Selective targeting of mutant PI3Kα is anticipated to enhance antitumor efficacy and mitigate the toxicity associated with wild-type PI3Kα inhibition in normal tissues. Multiple allosteric and mutant-selective PI3Kα inhibitors have been successfully developed into clinical stage, including LOXO-783 (NCT05307705), RLY-2608 (NCT05216432) and STX-478 (NCT05768139). TY-2291 is an allosteric and mutant-selective PI3Kα inhibitor developed by TYK Medicines Inc. Results: TY-2291 is a potent kinase inhibitor of mutant PI3Kα with high selectivity over WT PI3Kα. In in vitro antiproliferative test, TY-2291 showed better antiproliferative activity against multiple PI3Kα mutant cells than LOXO-783, STX-478, and RLY-2608. In the mouse HCC1954 CDX model, TY-2291 showed potent tumor-inhibitory activity and excellent tolerance. TY-2291 also demonstrated excellent DMPK properties and desirable drug-like properties. In the insulin tolerance test, TY-2291 had no effect on fasting plasma glucose levels after four days of treatment. In conclusion, we have identified a potent allosteric and mutant-selective PI3Kα inhibitor. Our findings indicate that TY-2291 may significantly enhance the therapeutic index of PI3Kα-mutant cancers in the absence of PI3Kα WT-related toxicities. Citation Format: Chengshan Niu, Shengli Dong, Shaoqing Chen, Kaige Ji, Maolin Zheng, Mingtao Chen, Yuanjie Li, Meihua Li, Zhengfei Guo, Hongqiang Li, Yu Yu, Xinlong Yang, Chao Zhou, Apeng Liang, Yin Zhou, Wei Wu, Mingyu Jiang, Jun Li, Yusheng Wu. Identification and characterization of an allosteric and mutant-selective PI3Kα inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5977.
Abstract 4523: Personalized risk prediction for treatment intolerance in operable HPV-negative head and neck cancer: Beyond the eyeball test
Authors: Marco Antonio Mascarella, Keith Richardson, Nader Sadeghi, Alex Mlynarek, Michael Hier, Khalil Sultanem, Christina Tsien, Khashayar Esfahani, Marie-Jeanne Kergoat
Journal: Cancer Research (2025)

Abstract Introduction: Head and neck cancer (HNC) treatment is highly complex, with substantial toxicity risks from curative therapies, often including surgery, radiation, and chemotherapy. Poor treatment tolerance can hinder optimal recovery, impacting patient outcomes. Current predictive tools lack precision in forecasting treatment intolerance for HNC patients undergoing curative surgery. Frailty and sarcopenia, especially muscle quantity biomarkers, are increasingly recognized as crucial predictive factors. This study aims to develop a comprehensive risk index incorporating sarcopenia, frailty, and patient-specific factors to better predict intolerance. Methods: An ambispective observational study was conducted with 542 patients undergoing curative-intent HNC surgery from 2015 to 2024. Patient data on demographics, frailty, sarcopenia (via cervical paraspinal muscle index or CPSMI), tumor staging, and planned adjuvant therapy were collected. Using logistic regression, we evaluated predictive factors for treatment intolerance, defined as major adverse events (MAEs) or incomplete treatment. Risk model performance was validated internally and externally and compared against ASA, mFI, and RAI. Results: In 542 patients, lower CPSMI (first tertile) correlated significantly with intolerance (OR 1.85, 95% CI 1.10-3.13). High-density muscle was protective, while low-density muscle predicted intolerance (OR 1.88, 95% CI 1.18-2.99). Sarcopenia and frailty were independently predictive, with the mFI also strongly correlating with intolerance (OR 4.92, 95% CI 1.88-12.9). The new risk index demonstrated superior predictive accuracy, showing a 0.04 increase in the C-statistic compared to existing indices (p=0.02). Conclusion: The multimodal risk index effectively predicts treatment intolerance in HNC surgery patients. By integrating sarcopenia, frailty, and patient-specific factors, the tool enables better preoperative counseling and intervention planning, with particular utility for high-risk individuals. Further research on prehabilitation strategies may enhance treatment tolerance in vulnerable patients, supporting a proactive approach to HNC care. Citation Format: Marco Antonio Mascarella, Keith Richardson, Nader Sadeghi, Alex Mlynarek, Michael Hier, Khalil Sultanem, Christina Tsien, Khashayar Esfahani, Marie-Jeanne Kergoat. Personalized risk prediction for treatment intolerance in operable HPV-negative head and neck cancer: Beyond the eyeball test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4523.
Abstract 4253: Turning pro-tumor inflammation into target opportunity: Development of an IL1RAP ADC for solid tumor treatment
Authors: Yufei Chen, Marlena Gray, Piper Meigs Treuting, Craig Miller, Sara Carbonetti, Katie Snead, Kaleb Smith, Robert Lawrence, Alyson J. Smith
Journal: Cancer Research (2025)

Abstract Chronic and dysregulated inflammation caused by activation of interleukin-1 (IL-1) signaling supports tumor growth and helps establish an immunosuppressive microenvironment. Interleukin 1 receptor accessory protein (IL1RAP, IL-1RAcP, IL1R3) serves as a co-receptor for interleukin 1 receptor type 1 (IL1R1) at the cell membrane and plays a key role in mediating IL-1 signaling. By combining multi-omics and immunohistochemistry analysis, we identified the upregulation of IL1RAP on many solid tumor indications, including melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and esophageal cancer, while normal tissue expression is mainly restricted to the bone marrow. This expression pattern and tumor-supporting biological function makes IL1RAP an attractive target for an antibody-drug conjugate (ADC) therapy approach. Through a hybridoma antibody campaign, we generated a pool of candidate anti-IL1RAP monoclonal antibodies (mAbs) to evaluate as ADC candidates. The candidates all exhibited ability to disrupt the IL-1 signaling cascade but demonstrated variable potency to do so. All of the clones had similar ability to drive drug delivery and direct cytotoxicity to tumor cells as ADCs. These in vitro activities translated into strong in vivo anti-tumor activity in several CDX and PDX human tumor models, with clonal separation only apparent in low expressing models. While strong activity was seen in all CDX models with various IL1RAP expression levels, primary human sample PDX models demonstrated a much stronger expression:response correlation. To evaluate any potential normal tissue liabilities of an IL1RAP ADC, and assess how clone selection may impact this, a primary human bone marrow colony formation unit assay was employed. While several of the anti-IL1RAP antibodies demonstrated on-target myeloid progenitor cell lethality, not all clones were equipotent, despite all driving similar in vivo anti-tumor activity. Collectively this data demonstrates the potential to leverage IL1RAP as an effective and well tolerated ADC and how appropriate antibody selection could potentially aid in increasing the therapeutic index. Citation Format: Yufei Chen, Marlena Gray, Piper Meigs Treuting, Craig Miller, Sara Carbonetti, Katie Snead, Kaleb Smith, Robert Lawrence, Alyson J. Smith. Turning pro-tumor inflammation into target opportunity: Development of an IL1RAP ADC for solid tumor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4253.
Abstract 5125: Low-density lipoprotein receptor-related protein 1 as a negative regulator in epithelial-mesenchymal transition and metastasis of colorectal cancer: Targeting the Wnt/β-Catenin signaling pathway
Authors: Zhihong Zhang, Dingwen Zhong, Tanxing Cai, Ze Li, Yufeng Chen, Xiaojian Wu, Xiaobin Zheng
Journal: Cancer Research (2025)

Abstract Background and aim: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in various cellular processes, including cancer progression. Its role and the underlying mechanisms in the metastasis of colorectal cancer (CRC) remain to be fully elucidated. Methods: LRP1 expression in CRC was assessed by immunohistochemistry in a cohort of 400 tissue samples, with subsequent Kaplan-Meier survival analysis. In vitro studies included real-time PCR, western blot, colony formation assays, immunofluorescence assays, wound healing assays, and migration and invasion experiments to explore LRP1's impact on epithelial-mesenchymal transition (EMT), cell migration, and invasion. In vivo, mouse xenograft and metastasis models were employed to assess tumorigenicity and metastatic potential, with immunohistochemistry, real-time PCR, and western blot used to evaluate protein expression levels. Luciferase reporter assays were conducted to investigate LRP1's influence on the Wnt/β-catenin signaling pathway. Results: LRP1 was found to be highly expressed in 68.2% of the CRC specimens and was significantly associated with membranous E-cadherin expression and cytoplasmic β-catenin localization. Elevated LRP1 levels, in conjunction with reduced Wnt/β-catenin signaling activity, correlated with decreased nuclear accumulation of β-catenin and predicted better prognosis. LRP1 suppressed cell proliferation, migration, and invasion both in vitro and in vivo, and hindered the nuclear translocation of β-catenin. Wnt/β-catenin signaling could counteract LRP1's effects on EMT and enhance the expression of vimentin, a mesenchymal marker. Restoring vimentin expression mimicked the effects of LRP1 knockdown without altering Wnt/β-catenin activity. Conclusions: LRP1 appears to be a significant negative regulator in the EMT, invasion, and metastasis of CRC, potentially acting upstream of the Wnt/β-catenin signaling pathway. Therefore, the combined targeting of LRP1 and the Wnt/β-catenin pathway may offer a novel and promising therapeutic strategy for CRC patients. Citation Format: Zhihong Zhang, Dingwen Zhong, Tanxing Cai, Ze Li, Yufeng Chen, Xiaojian Wu, Xiaobin Zheng. Low-density lipoprotein receptor-related protein 1 as a negative regulator in epithelial-mesenchymal transition and metastasis of colorectal cancer: Targeting the Wnt/β-Catenin signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5125.
Abstract 5053: Targeted sequencing panel for comprehensive MTAP deletion detection in diverse cancer types
Authors: Hua Bao, Haimeng Tang, Rui Liu, Ningyou Li, Min Wu, Xunbiao Liu, Zhili Chang, Xue Wu
Journal: Cancer Research (2025)

Objective: Methylthioadenosine phosphorylase (MTAP) deletion is a prevalent genomic alteration across various malignancies, often correlated with unfavorable clinical outcomes. The detection of MTAP deletions offers opportunities for personalized therapeutic strategies aimed at exploiting specific metabolic vulnerabilities. However, existing detection methodologies are frequently costly and labor-intensive, highlighting the necessity for an efficient and economical detection panel. Developing such a tool is essential for the timely identification of MTAP deletions, facilitating prompt initiation of targeted therapies and improving patient prognoses. Methods: We retrospectively analyzed 5,787 tissue samples from patients diagnosed with 11 distinct cancer types, including colorectal, lung, liver, gastric, bladder, pancreatic, and esophageal cancers. A targeted sequencing approach (approximately 1,000X coverage) was employed using the GeneseeqPrime™ panel, which encompasses 437 cancer-related genes. Additionally, an independent cohort of 29 cancer samples was analyzed to assess the concordance of our sequencing panel with Fluorescence In Situ Hybridization (FISH) and Immunohistochemistry (IHC). Results: The evaluation of MTAP deletions across a spectrum of cancer types revealed significant variations in both total and homozygous deletion rates. Bladder cancer exhibited a total deletion rate of 43.43%, with homozygous deletions accounting for 11.11%. Esophageal squamous cell carcinoma indicated a total deletion rate of 46.15%, with homozygous deletions at 15.73%. Glioblastomas displayed the highest prevalence of total deletions at 58.33%, including 30.21% homozygous deletions. Furthermore, non-small cell lung cancer (NSCLC) and pancreatic cancer had total deletion rates of 35.84% and 42.55%, respectively, with homozygous deletions at approximately 8.21% and 15.55%. Our panel demonstrated perfect concordance with both FISH and IHC (100% agreement). Conclusion: This study establishes the variable prevalence of MTAP deletions across multiple cancer types, underscoring its significance as a prognostic biomarker associated with poor outcomes. The GeneseeqPrime™ panel provides a rapid and cost-effective means for identifying MTAP deletions, facilitating timely diagnosis and personalized therapeutic strategies. Further validation in larger cohorts and clinical settings is warranted to enhance its applicability in routine oncological practice. Citation Format: Hua Bao, Haimeng Tang, Rui Liu, Ningyou Li, Min Wu, Xunbiao Liu, Zhili Chang, Xue Wu. Targeted sequencing panel for comprehensive MTAP deletion detection in diverse cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5053.
Abstract 1292: Innovative 3D ecm platforms for tumoroid development, drug screening, and personalized treatment
Authors: Navneet Kaur, Dazhi Yang, Jamel Ali
Journal: Cancer Research (2025)

Abstract New advances in cancer research require robust in vitro and in vivo models that mimic the complexity of human tumors. Traditional 2D cell cultures lack the complexity of the tumor microenvironment (TME), leading to unreliable prediction of drug efficacy. Animal models are costly, time-intensive, and fail to fully replicate human tumor biology due to interspecies differences. To overcome these limitations, we present an innovative approach that involves TME-mimetic extracellular matrix (ECM)-based 3D platforms and co-culture systems for the development of tumoroids, circulating tumor cell (CTC) expansion, and PDX models. These 3D systems provide a physiologically relevant TME by mimicking the native cellular and extracellular interactions that drive tumor growth and progression. Tumoroids established through co-culturing a pool of primary cells dissociated from human solid tumors using a solid micro extracellular matrix (smECM) exhibited pathohistological properties, biomarker expression, and tissue architecture closely resembling the original tumors. Incorporating human foreskin fibroblasts (HFFs) in co-culture further enhanced tumor growth and stromal support, making these 3D models highly effective for drug screening and functional studies. Additionally, the use of smECM provided an innovative solution for expanding rare CTCs ex vivo. Unlike traditional methods, the 3D smECM platform supported the sustained viability and proliferation of CTCs, preserving their heterogeneity and allowing for rapid generation of CTC-seeded PDX models. These models demonstrated a high degree of clinical relevance by maintaining genomic profiles and chemoresistance characteristics of the original patient tumors. By integrating these advanced 3D platforms, we offer a powerful tool to develop versatile models for cancer research. Citation Format: Navneet Kaur, Dazhi Yang, Jamel Ali. Innovative 3D ecm platforms for tumoroid development, drug screening, and personalized treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1292.
Abstract 6157: PAR2 inhibitors reduce resistance to immunotherapy against cancer
Authors: Thibaut Brugat, Maleck Kadiri, Samya Aouad, David Allard, Camille Fuselier, Emma Skora, Antoine Mousson, Aurélie Janvier, Luc Baron, Christel Franchet, Anne-Laure Blayo, Stephan Schann, John Stagg
Journal: Cancer Research (2025)

Abstract A pan-cancer meta-analysis showed that Protease-activated receptor 2 (PAR2) is one of the genes most significantly associated with resistance to immune checkpoint blockade (ICB) and T cells dysfunction in cancer patients. PAR2 is also upregulated and associated with poor prognosis in several cancer types which makes it a promising therapeutic target in the fight against cancer. However, the potential of PAR2 inhibitors and their mechanism of action in immuno-oncology has not been determined yet. The efficacy of PAR2 knock out and a biased negative allosteric modulator (NAM) of PAR2, RD35-11, in monotherapy or in combination with an anti-PD1 was assessed in the MC38 model. Strikingly, the combination therapy significantly increased the number of complete responses compared with mice treated with immunotherapy alone. As MC38 cells do not express PAR2, this result indicated that RD35-11 promote tumor regression by changing the tumor microenvironment. To investigate this hypothesis, the effect of PAR2 inhibition alone or in combination with an anti-PD1 on tumor-infiltrating immune cells was assessed in vivo by flow cytometry, cytokine measurement, bulk and single cell RNA sequencing. Results obtained showed that a PAR2 NAM reduced the level of immune-regulatory cells (M2 macrophages) and cytokines (e.g. IL10) while promoting antigen presenting cells and pathways. Ex-vivo experiments further demonstrated that PAR2 inhibition reduces IL10 secretion by macrophages while enhancing antigen cross-presentation by dendritic cells. Taken together, our data clearly demonstrate that PAR2 NAM can alleviate resistance to immune checkpoint blockade by reducing macrophage-induced immunosuppression and promoting antigen presentation. Domain Therapeutics has identified a novel PAR2 biased NAM, DT-9045, orally available and with clear competitive advantages. IND-enabling studies are currently ongoing to bring this new hope for cancer patients to the clinic. Citation Format: Thibaut Brugat, Maleck Kadiri, Samya Aouad, David Allard, Camille Fuselier, Emma Skora, Antoine Mousson, Aurélie Janvier, Luc Baron, Christel Franchet, Anne-Laure Blayo, Stephan Schann, John Stagg. PAR2 inhibitors reduce resistance to immunotherapy against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6157.
Abstract 4857: The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy
Authors: Alyssa Kim, Wonkyung Oh, Deepika Dhawan, Deborah W. Knapp, Seung-Oe Lim
Journal: Cancer Research (2025)

Abstract Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. However, despite its recent success, such impact has been shown to be limited to tumors encompassing specific tumor microenvironment characteristics. Furthermore, a significant proportion of initial responders eventually develop resistance. Combining PD-1/PD-L1 blockade with chemotherapy, radiotherapy, or targeted therapy have been suggested to overcome resistance, yet have been shown to be insufficient in fully accounting for resistance. Unlike normal, differentiated cells, most cancer cells produce large amounts of lactic acid. This metabolic property is often referred to as “aerobic glycolysis, ” a well-known metabolic reprogramming of cancer cells to sustain cell proliferation and a hallmark of cancer. Such property as well as others of the altered metabolism of cancer cells and its byproducts affect the anti-tumor immune response. Notably, glycolytic metabolites, such as lactate, regulate T cell proliferation and function. However, the mechanism behind how such metabolic alterations impact the cancer cells’ resistance to PD-1/PD-L1 blockade therapy remains unclear. Thus, we sought to decipher the role of tumor-cell derived lactic acid in PD-1/PD-L1 therapy resistance and propose new immunotherapeutic strategies to improve the efficacy of PD-1/PD-L1 blockade therapies. Here, we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. Altogether, the findings in this study uncover a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment strategy to overcome the tumor resistance to PD-1/PD-L1 blockade therapy and improve clinical outcomes. Citation Format: Alyssa Kim, Wonkyung Oh, Deepika Dhawan, Deborah W. Knapp, Seung-Oe Lim. The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4857.