tbuckley/cabot-search huggingface dataset:
Abstract 815: AZD5335, a folate receptor alpha-targeted ADC, enhances ovarian cancer treatment with bevacizumab, paclitaxel and/or carboplatin
Authors: Jason J. Zoeller, Ravinder Tammali, Ana De Almeida, Shane Cronin, Nancy Lee, Alma Andoni, Claire Myers, Elaine Joseph, Michael Lehmann, Rebecca Sargeant, Ina Bisha, Simon Christ, Iris Dino, Xhenifer Guza, Jixin Wang, Lisa Godfrey, Roger Dodd, Neki Patel, Edward Rosfjord, Marco Gymnopoulos, Tim Brier, Sabina Cosulich, Elaine Hurt, Puja Sapra
Journal: Cancer Research (2025)

Abstract Elevated expression of folate receptor alpha (FRα) in various cancers, including epithelial ovarian cancer (EOC), highlights FRα as a potential target for the development of novel therapeutics to treat FRα-expressing tumor types. AZD5335, an FRα-targeting antibody conjugated to a topoisomerase 1 inhibitor (TOP1i) payload, is currently being investigated in the FONTANA Phase I/IIa clinical trial (NCT#05797168), either as a single agent or in combination with a PARP1-selective inhibitor (saruparib). Using an FRα-expressing EOC xenograft model (OV90), we evaluate additional AZD5335-relevant combined treatment strategies and report pre-clinical assessment of AZD5335 in combination with bevacizumab, paclitaxel and/or carboplatin. Compared to monotherapy treatment, we successfully demonstrate that combination treatments with AZD5335+bevacizumab, AZD5335+paclitaxel or AZD5335+carboplatin result in significant and durable anti-tumor responses. Using the same EOC xenograft model, we extended these studies to include AZD5335+bevacizumab plus either paclitaxel or carboplatin treatments and demonstrated that these triplet combos resulted in superior and durable anti-tumor activities. Combination data in a number of additional CDX/PDX will be presented. A series of in vitro studies will also define the ADC/SOC drug interactions and further delineate underlying mechanisms driving enhanced efficacy. These studies inform our ongoing clinical development of AZD5335 in ovarian cancer. Citation Format: Jason J. Zoeller, Ravinder Tammali, Ana De Almeida, Shane Cronin, Nancy Lee, Alma Andoni, Claire Myers, Elaine Joseph, Michael Lehmann, Rebecca Sargeant, Ina Bisha, Simon Christ, Iris Dino, Xhenifer Guza, Jixin Wang, Lisa Godfrey, Roger Dodd, Neki Patel, Edward Rosfjord, Marco Gymnopoulos, Tim Brier, Sabina Cosulich, Elaine Hurt, Puja Sapra. AZD5335, a folate receptor alpha-targeted ADC, enhances ovarian cancer treatment with bevacizumab, paclitaxel and/or carboplatin [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 815.
Abstract 2575: Tumor microenvironmental metabolites regulate cancer-associated fibroblast heterogeneity
Authors: Chufan Cai, Marta Storl-Desmond, Kristof Turan, Axel R. Concepcion, Jing Chen, Simon Schwoerer
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic response with a high abundance of cancer-associated fibroblasts (CAFs). CAFs are a functionally and transcriptionally heterogeneous population of cells and include inflammatory CAFs (iCAFs), thought to promote tumor growth via the secretion of cytokines and chemokines, as well as myofibroblasts CAFs (myCAFs), thought to restrain tumor growth via the secretion of extracellular matrix. The iCAF and myCAF states are highly plastic. Preventing the interconversion of CAF populations could have significant clinical benefits, but how this plasticity is regulated is largely unknown. Cytokines like IL1α and growth factors like TGFβ are required but not sufficient to induce changes in the CAF state. Instead, their effect is dependent on the presence of other environmental factors. We recently demonstrated that cancer cell-derived cytokines synergize with hypoxia to induce a transition from a myCAF- towards and an iCAF state, indicating that metabolic factors in the TME can modulate the CAF state in combination with signaling molecules. To identify other extracellular metabolic factors that synergize with cytokines in regulating CAF plasticity, we performed a high-content screen using a human blood chemical library in combination with our recently developed fibroblast reporter (FIRE) system incorporating iCAF (IL6-EGFP) and myCAF (Acta2-DsRed) transcriptional reporters. Out of hundreds of compounds, we identified and validated one metabolite that synergizes with the cytokines IL1α and TNFα to promote IL6 expression in a time- and dose-dependent manner. Intriguingly, previous studies have reported that this metabolite accumulates in the PDAC TME to a high micromolar range. Metabolite and cytokine treatment together induce pancreatic stellate cells (PSCs) to upregulate production and secretion of pro-inflammatory cytokines including IL6, CXCL1 and LIF. Pretreatment of PSCs with physiological concentrations of this metabolite is sufficient to alter the fibroblast state and to promote tumor growth when co-injected with PDAC cells in vivo. Mechanistically, we find that this metabolite acts in part through the JAK-STAT pathway, a major regulator of the iCAF state. These findings support the idea that TME metabolites can alter PDAC progression by regulating CAF heterogeneity through synergy with cancer cell-derived signaling molecules. Citation Format: Chufan Cai, Marta Storl-Desmond, Kristof Turan, Axel R. Concepcion, Jing Chen, Simon Schwoerer. Tumor microenvironmental metabolites regulate cancer-associated fibroblast heterogeneity [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 2575.
Abstract 2185: Advancing macrophage-directed therapies: bioluminescent assays for macrophage effector function
Authors: Jonathan Mitchell, Denise Garvin, Rich Moravec, Julia Gilden, Adityarup Chakravorty, Jim Hartnett, Pete Stecha, Mei Cong, Jamison Grailer
Journal: Cancer Research (2025)

Abstract Macrophages play a pivotal role in anti-cancer immunity through phagocytosis and presentation of tumor antigens to T cells. Antibody-dependent cellular phagocytosis (ADCP), mediated by macrophages and other myeloid cells, is a key mechanism-of-action (MoA) for antibody-based cancer immunotherapies. Strategies that enhance ADCP and other macrophage effector functions not only promote direct tumor destruction but also facilitate broader anti-tumor immunity. ADCP is initiated by the binding of antibody Fc domains to Fc gamma receptors (FcγRs), which triggers receptor crosslinking and signal transduction, leading to inflammatory cytokine production and phagocytosis. These effector functions are further regulated by immune checkpoints, and therapeutic interventions that block inhibitory checkpoints (e.g., SIRPα, ILT4, ILT2) or activate stimulatory pathways (e.g., TLR signaling) can enhance macrophage activity. However, current methods to measure macrophage functions are often low-throughput, labor-intensive, and highly variable. To address these challenges, we developed a suite of robust, cell-based bioluminescent bioassays to assess macrophage effector functions. These include: 1) ADCP: Using monocytic cells with endogenous FcγR expression and a FcγR-activation-dependent luminescent reporter. 2) Direct Phagocytosis Detection: Utilizing the HiBiT split luciferase system for sensitive and quantitative measurements. 3) Immune Checkpoint Modulation: Bioassays to measure SIRPα/CD47, ILT2/HLA-G, and ILT4/HLA-G interactions. 4) TLR Activation: Reporter bioassays for TLR activation. These assays are robust, easy-to-use, and pre-qualified according to ICH guidelines. Together, this comprehensive toolbox enables screening and the accelerated development of immunotherapies that target macrophage effector functions, paving the way for innovative cancer treatment strategies. Citation Format: Jonathan Mitchell, Denise Garvin, Rich Moravec, Julia Gilden, Adityarup Chakravorty, Jim Hartnett, Pete Stecha, Mei Cong, Jamison Grailer. Advancing macrophage-directed therapies: bioluminescent assays for macrophage effector function [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 2185.
Abstract 837: A highly potent and selective small molecule TY-4028 for the targeted therapy of non-small cell lung cancer with EGFR exon 20 or HER2 exon20 insertion mutations
Authors: Chengshan Niu, Shengli Dong, Shaoqing Chen, Zhongwei Guo, Huan Wang, Apeng Liang, Kaige Ji, Meihua Li, Bailu Zheng, Yanchao Zhao, Ming Wu, Mingyu Jiang, Xiugui Chen, Jun Li, Yusheng Wu
Journal: Cancer Research (2025)

Abstract Introduction: Following EGFR exon 19del and EGFR L858R mutations, EGFR exon20 insertion mutations are the third most common type of EGFR mutations, representing up to 12% of all EGFR mutations. Approximately 2% of NSCLC patients bear hotspot mutations in HER2, and over 90% of these HER2 mutations are exon 20 insertion mutations. The FDA-approved 1st to 3rd targeted EGFR inhibitors failed to effectively treat NSCLC harboring constantly active EGFR exon20ins mutations in the clinic. To date, no small molecule targeted therapy has been approved by the FDA for the treatment of EGFR exon20ins in NSCLC. Furthermore, Antibody such as Amivantamab has difficulty penetrating the BBB, brain metastases presents a significant clinical challenge in lung cancer with EGFR exon20ins mutations. There is an urgent unmet medical need to develop targeted therapeutics against EGFR and Her2 exon20ins mutations. Results: TY-4028 is a novel, potent, and orally available inhibitor targeting EGFR and Her2 exon20ins mutations. It is a highly potent covalent inhibitor with rapid absorption and clearance, which contributes to the decreased toxicity of covalent drugs. Preclinical studies have shown a good PK profile and manageable toxicity with TY-4028. TY-4028 showed remarkable efficacy in in vitro and in vivo models of EGFR exon20ins and HER2 exon20 Ins. The data showed that the efficacy of TY-4028 was similar to that of Mobocertinib(TAK-788)and better than that of Sunvozertinib (DZD9008), whereas the tolerance of TY-4028 was better than that of Mobocertinib in CDX mouse models. The B/P ratio (brain tissue AUClast/plasma AUClast) of SD rats was 1.63 and 1.04, respectively, suggesting that TY-4028 has good potential to cross the BBB. Taken together, TY-4028 was fully developed by TYK Medicines, Inc., and the compound has great potential to meet the unmet medical needs of NSCLC patients with EGFR exon20ins mutation or HER2 exon20ins mutation. IND clearances of TY-4028 from the US FDA and CN NMPA has received. Citation Format: Chengshan Niu*, Shengli Dong*, Shaoqing Chen, Zhongwei Guo, Huan Wang, Apeng Liang, Kaige Ji, Meihua Li, Bailu Zheng, Yanchao Zhao, Ming Wu, Mingyu Jiang, Xiugui Chen, Jun Li*, Yusheng Wu. A highly potent and selective small molecule TY-4028 for the targeted therapy of non-small cell lung cancer with EGFR exon 20 or HER2 exon20 insertion mutations [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 837.
Abstract 259: Germline p53 R181 mutants and DNA binding cooperativity in tumorigenesis
Authors: Renyta Moses, Alexandra Indeglia, Alison S. Levine, Ryan Hausler, Gregory Kelly, Sven A. Miller, Melissa Heller, Anh N. Le, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Sophie H. Cahill, Luke D. Maese, John Karanicolas, Judy E. Garber, Maureen E. Murphy, Kara N. Maxwell
Journal: Cancer Research (2025)

Abstract TP53 is the most frequently mutated gene in cancer, and its encoded protein p53 has many tumor-suppressive functions. There are several different classes of mutant p53 acquired in human cancer and inherited in cancer-prone families with Li-Fraumeni Syndrome, where individuals have an 80-90% increased risk of cancer. These include structural mutations that are generally misfolded (R175H), DNA contact mutations (R273H); and oligomerization mutations (A347D). A new class of variants called “cooperativity” mutations affect the binding of the p53 tetramer to DNA via disruption of a salt bridge formed by the negatively charged glutamic acid (E) 180 residue of one p53 monomer and the positively charged arginine (R) 181 residue of another. p53 cooperativity mutations at the R181 residue (R181H and R181C) have been increasingly identified in cancer-prone families undergoing genetic testing; however, the mechanism by which these variants disrupt p53 tumor suppression in humans is not understood. We show that R181H and R181C have significantly diminished ability to transactivate a curated set of ∼300 known p53 target genes in CRISPR knock-in colorectal and breast cancer cell lines. This loss of transactivation ability is not explained by defects in p53 structure or oligomerization, but through reduced cooperative binding to p53 target sites on DNA as determined by fluorescence polarization and chromatin-immunoprecipitation experiments. Interestingly, we observe residual apoptotic activity in R181H and R181C mutant cells upon DNA damage, despite the poor transcriptional activation of p53’s proapoptotic targets. We observe increased p53 at the mitochondria for transcription-independent apoptosis in R181-mutant cells. Understanding the tumor suppressive activities that are lost versus retained will guide the definition of the pathogenicity of R181 variants, which account for 5000 cancer cases per year in the United States. Citation Format: Renyta Moses, Alexandra Indeglia, Alison S. Levine, Ryan Hausler, Gregory Kelly, Sven A. Miller, Melissa Heller, Anh N. Le, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Sophie H. Cahill, Luke D. Maese, John Karanicolas, Judy E. Garber, Maureen E. Murphy, Kara N. Maxwell. Germline p53 R181 mutants and DNA binding cooperativity in tumorigenesis [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 259.
Abstract 1428: Dissecting a triple-negative breast cancer super enhancer: insights into oncogenic gene regulation
Authors: Natalia Maldonado Vázquez, Nicole Zaragoza Rodríguez, Hector Franco
Journal: Cancer Research (2025)

Abstract Triple Negative Breast Cancer (TNBC) is an aggressive and therapeutically challenging subtype of breast cancer, characterized by significant intra-tumoral heterogeneity and the absence of actionable molecular markers. This study addresses the urgent need for targeted therapies by investigating the role of non-coding regulatory elements, specifically super enhancers (SEs), in TNBC pathogenesis. SEs are large clusters of enhancers with high transcription factor occupancy and enhancer RNA (eRNA) production, regulating key genes involved in cell identity and cancer progression. Using Chromatin Immunoprecipitation sequencing (ChIP-seq) and Global Run-On sequencing (GRO-seq) across 13 cancer cell lines, we identified a novel TNBC-specific, transcriptionally active SE on chromosome 17, located upstream of the ITGA3 gene. To elucidate its functional role, we conducted CRISPR-interference (CRISPRi) assays coupled with RNA sequencing in TNBC cells, revealing genome-wide SE target genes. Integration with high-throughput chromosome conformation capture (Hi-C) data established direct chromatin interactions linking the SE to its target genes, which collectively form a gene signature predictive of poor clinical outcomes. Perturbation of this SE via CRISPR significantly impaired tumor cell proliferation, highlighting its role as a potential driver of oncogenic phenotypes. These findings provide new insights into enhancer-target gene interactions in TNBC and identify this SE and its associated gene network as promising therapeutic targets. Citation Format: Natalia Maldonado Vázquez, Nicole Zaragoza Rodríguez, Hector Franco. Dissecting a triple-negative breast cancer super enhancer: insights into oncogenic gene regulation [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 1428.
Abstract 2170: S100a6-Lars2 oncogenic signaling shaping immunosuppressive environment contributes to platinum-based resistance
Authors: Yuqing Wang, Chuxia Deng
Journal: Cancer Research (2025)

Abstract Chemotherapy-induced drug resistance is a very complex process. About 20% of cancer patients have received effective therapy with platinum (Pt) medicines, and drug resistance has since emerged through several mechanisms. To investigate the complicated heterotypic interactions between cancer cells and immune cells during the resistant tumor outgrowth processes under Pt treatment, we dissected the crosstalk signals with single-cell RNA sequencing and performed functional studies on Pt-induced drug resistance using overexpression, knockout, and DOX-inducible technologies. In this study, we have identified that: 1) S100a6-Lars2 oncogenic signaling could promote TGF-β production from tumor and immune cells and induce expressions of PD1, Tim3, and Selplg on T cells, which could contribute to resistant tumor outgrowth under Pt treatment; 2) Pt drugs could promote the survival of cancer stem cells (CSCs) with elevated hyaluronan-mediated motility receptor (Hmmr) and mTOR oncogenic pathway; 3) we validated Lars2 oncogenic action in resistant tumor outgrowth in FVB immunocompetent mice and the dynamic changes of the immune cell population; 4) combinatory treatment involving the inhibition of TGF-β signaling, the mTOR pathway, and Hmmr action, along with PD1 antibody, shows a significant effect in inhibiting tumor growth. This study advances the understanding of the mechanism of Pt drug-induced resistant tumor outgrowth, which may allow us to better manage the tumor immune microenvironment (TIME) and postpone the onset of resistance. Citation Format: Yuqing Wang, Chuxia Deng. S100a6-Lars2 oncogenic signaling shaping immunosuppressive environment contributes to platinum-based resistance [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 2170.
Abstract 2533: Image-guided surgery with a new optical probe for breast cancer
Authors: Sunam Mander, Duy Binh Tran, Goto Masahide, Konstantin Christov, Albert Green, Tapas K. Das Gupta, Tohru Yamada
Journal: Cancer Research (2025)

Abstract Accurate surgical removal of tumors significantly impacts patient outcomes. However, distinguishing between breast tumors and normal tissue during surgery is often challenging or even impossible. Given the lack of visual discrepancy between malignant and surrounding normal tissue, current breast-conserving surgery (BCS) is associated with a high re-excision rate. Due to this clinical challenge, a new method of complete tumor removal at the initial surgery is needed. To address this, we developed a new fluorescent imaging agent, ICG-p28, for intraoperative imaging guidance to better aid surgeons in achieving negative margins in BCS. ICG-p28 consists of the clinically nontoxic tumor-targeting peptide p28 and the FDA-approved near-infrared (NIR) dye indocyanine green. Here, we evaluated our imaging approach with ICG-p28 in vitro and in breast cancer animal models. First, we determined the detection limit of the objective size and depth using phantoms incorporating tumor-simulating inclusions. Even with the smallest objective (1 mm), NIR fluorescence imaging of ICG-p28 at nanomolar concentrations was able to detect the specific signals. We estimated the detection limit of the cell number in vitro. NIR-specific signals were detected from breast cancer cells as low as 200 cells in 1 mm size. Next, we evaluated ICG-p28 in multiple animal models. Athymic mice xenografted with MDA-MB-231 and IOWA-1T human breast cancer cells received a single injection of ICG-p28 i.v. at 0.5 mg/kg (=125 nmole/kg). Twenty-four hours after ICG-p28 injection, we observed the preferential uptake of ICG-p28 by tumors and a clear contrast between the tumor and the surrounding tissue. The histological analyses with H&amp;E and Ki-67 staining on the set of tumor margin samples revealed that image-guided surgery with ICG-p28 could result in a clear negative margin at the edges of mammary tissues. Moreover, our imaging approach can also visually detect LN metastases (metastatic breast cancer in lymph nodes) through the preferential uptake of ICG-p28 concentrated over a period of time in small (∼1 mm) LN metastases. Overall, this nontoxic, and cost-effective method can offer a new approach that enables surgeons to identify tumor margins intraoperatively and potentially improves overall outcomes for breast cancer patients. Citation Format: Sunam Mander, Duy Binh Tran, Goto Masahide, Konstantin Christov, Albert Green, Tapas K. Das Gupta, Tohru Yamada. Image-guided surgery with a new optical probe for breast 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 2533.