tbuckley/cabot-search huggingface dataset:
Abstract 1529: Colon cancer cells activate CCL20 and IL10 signaling to combat effects of 5 fluorouracil
Authors: Janani Muralidharan, Shailesh Singh, Hina Mir
Journal: Cancer Research (2025)

Abstract Advances in screening and therapy have significantly decreased colon cancer mortality rates; however, predictions indicate that by 2030, approximately one million patients may still die from this disease each year. While chemotherapies are effective, cancer cells often develop resistance mechanisms that necessitate higher doses, which can lead to severe toxicities that hinder treatment effectiveness and pose additional health risks for patients. Depending on the stage of cancer, 5FU, an antimetabolite, is typically administered alone or in combination with oxaliplatin. Despite its cytotoxic properties, 5FU can induce inflammation in the colon, which may counteract its effectiveness against cancer. This inflammation, characterized by altered cytokine profile, contributes to the resilience of cancer cells. The focus of our study is on the proinflammatory chemokine CCL20, which is elevated during colon cancer, and plays a significant role in liver metastasis. CCL20 signaling is linked to epithelial to mesenchymal transition and can influence the efficacy of chemotherapy. Our research findings indicate that colon cancer cells treated with cytotoxic doses of 5FU show a notable increase in CCL20 secretion, as well as elevated levels of extracellular fatty acids compared to untreated cells. Furthermore, treatment with palmitic acid enhances CCL20 secretion. After 5FU treatment, there is also an increase in interleukin 10 (IL10). Interestingly, inhibiting CCL20 signaling, either by neutralizing CCL20 or blocking its receptor CCR6, further elevates IL10 levels. This suggests that colon cancer cells increase their tolerance to 5FU by raising CCL20 and IL10.Our study highlights the need for further investigation into these mechanisms to develop more effective treatment strategies that maintain or improve patients' quality of life. Citation Format: Janani Muralidharan, Shailesh Singh, Hina Mir. Colon cancer cells activate CCL20 and IL10 signaling to combat effects of 5 fluorouracil [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 1529.
Abstract 4496: Small molecule inhibition of previously “undrubbable” transcription factors with AI-guided functional proteomics
Authors: Alexander J. Federation, Daniele Canzani, Andrea Gutierrez, Julia Robbins, Brian McEllin, Anastasiya Prymolenna, Lillian Tatka, Bodhi Hueffmeier, Yang Gao, Tonibelle Gatbonton-Schwager, Erin Broderick, Gaelle Mercenne, William Fondrie, Lindsay Pino
Journal: Cancer Research (2025)

Abstract Transcription factors (TFs) are central regulators of gene expression and key drivers of diseases such as cancer, autoimmune disorders, neurological disease, and metabolic conditions. Despite their critical role, TFs have long been considered “undruggable” due to their intrinsic disorder outside of native cellular environments, complex multiprotein assemblies, and the absence of traditional binding pockets suitable for small molecule targeting. To address these challenges, Talus Bio has developed TF-Scan, a live-cell platform that provides a proteome-wide view of drug-induced changes in TF DNA-binding activity. This technology integrates high-resolution functional proteomics with advanced machine learning to measure TF:DNA engagement directly in unmodified human cells. Data from TF-Scan feeds into Strategian, a deep tensor factorization model trained on Talus Bio’s proprietary TF-Scan database, enabling AI-driven discovery of novel small molecule modulators. Strategian evaluates a chemical universe of billions of drug-like molecules to predict their effects on TF activity, prioritizing candidates by potency and selectivity. These predictions are validated experimentally using TF-Scan, which further refines lead selection. This approach has enabled the identification of novel scaffolds for TFs including TBXT, ARv7, and STAT3, demonstrating the ability to generate drug-like compounds tailored to specific TFs. By combining live-cell proteomics with AI-driven modeling, TF-Scan and Strategian create a powerful, scalable platform for targeting TFs and other challenging regulators within the regulome. This work establishes a new paradigm for drug discovery, transforming previously intractable targets into actionable opportunities to address critical unmet medical needs. Citation Format: Alexander J. Federation, Daniele Canzani, Andrea Gutierrez, Julia Robbins, Brian McEllin, Anastasiya Prymolenna, Lillian Tatka, Bodhi Hueffmeier, Yang Gao, Tonibelle Gatbonton-Schwager, Erin Broderick, Gaelle Mercenne, William Fondrie, Lindsay Pino. Small molecule inhibition of previously “undrubbable” transcription factors with AI-guided functional proteomics [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 4496.
Abstract 3733: Increased risk of EOCRC after multiple exposures to antibiotics in A/J mice
Authors: Niti Jani, Maredith Richardson, Kristen Hogan, Maria M. Pena
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer-related deaths in the United States and globally. When diagnosed in individuals under 55 years of age, it is referred to as early onset colorectal cancer (EOCRC). EOCRC has been increasing in incidence and mortality since the 1990’s with an 11% to 20% increase from 1995 to 2019 and projected to rise by 140% by 2030. Although EOCRC has been associated with known risk factors for CRC, the exact causes and mechanisms remain unclear. Based on current knowledge, we propose that EOCRC may be driven by exposure to internal and external factors (collectively known as exposomes) that have been on the rise over the past four decades, potentially affecting the microbiome and leading to dysbiosis and inflammation in the distal colon and rectum. One significant contributing factor may be the use of antibiotics (Abx), especially in infants and young children. In this study, we hypothesized that early life exposure to Abx could lead to dysbiosis and inflammation in the distal colon and rectum, which in turn may cause increased mutations and epigenetic changes that promote development of EOCRC. To test this hypothesis, we investigated the impact of commonly prescribed pediatric Abx on the gut microbiota and inflammatory environment in the colon, and their potential role in tumor development when exposed to a carcinogen. A/J mice were treated with several rounds of Abx and then exposed to azoxymethane (AOM), a known carcinogen, to assess their effect on tumor formation. The results revealed that Abx exposure induced dysbiosis and inflammation in the colon, along with systemic inflammation in the treated mice. When AOM was introduced in the presence of Abx-induced dysbiosis, this led to increased tumor burden in the distal colon. These findings suggest that Abx may play a role in elevating the risk of EOCRC. Future studies are aimed at examining age-dependent effects of Abx on EOCRC risk and in combination with other common exposomes. Citation Format: Niti Jani, Maredith Richardson, Kristen Hogan, Maria M. Pena. Increased risk of EOCRC after multiple exposures to antibiotics in A/J mice [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 3733.
Abstract 5825: SWA1211, a next generation HPK1 inhibitor exhibits superior anti tumor efficacy in preclinical studies
Authors: Guanglong Sun, Yuyang Ge, Huting Wang, Desheng Kong, Carrie Xiang
Journal: Cancer Research (2025)

Abstract Immune oncology is an important breakthrough for cancer therapy represented by immune checkpoints inhibitors like PD-1/L1, CTLA4 antibody drugs. Although this type of drug has become the standard treatment for many kinds of cancers, a large proportion of patients fail to respond to them or become resistant eventually. Therefore, new mechanisms or targets remain urgent to further improve the therapeutic outcomes or overcome the resistance of immunotherapy.Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, belongs to the MAP4K family of protein serine/threonine kinases. HPK1 is a negative regulator of T-cell signaling and has been identified as a promising target to combat cancers by eliciting robust anti-tumor immunity. Many HPK1 inhibitors are under active clinical development.SWA1211 is a best-in-class (BIC) HPK1 inhibitor designed using Stonewise’s proprietary 3D molecular generation model. To conquer the challenge of selective inhibition on HPK1, a steric group was designed to extend toward the small hydrophobic pocket formed by Leu23 and Val31 in HPK1, which does not exist in GLK due to the different residue, Ile22. This unique molecular structure design significantly improved potency and selectivity of our compounds, and excellent immune cell activation was achieved (biochemical assay IC50=0.9nM @ATP 1mM; human T-cell activation EC50=9nM). Selectivity study showed a unique kinases inhibition profile with no obvious off-kinase activity related risk.More importantly, when compared to other HPK1 inhibitors developed by leading developers, SWA1211 stimulates T cell activation efficiently in an ever-known broadest concentration range without any exhaustive effect (up to a concentration of 1000 folds of EC50). This unique non-bell-shaped immune cell activation curve translates to unmatched efficacy as no other HPK1 inhibitors have shown in preclinical settings. Single agent of SWA1211 induces tumor shrinkage in Hepa1-6 and EMT6 mouse syngeneic tumor models. GLP toxicity studies indicated ideal therapeutic index was obtained. We believe SWA1211 to be a promising next generation immune therapy for cancer patients.We have completed all IND enabling studies for SWA1211 and the results demonstrated a favorable drug-like profile. We expect to receive the green light for a clinical trial from the FDA and NMPA by March 2025; the clinical trial will be initiated immediately afterward. Citation Format: Guanglong Sun, Yuyang Ge, Huting Wang, Desheng Kong, Carrie Xiang. SWA1211, a next generation HPK1 inhibitor exhibits superior anti tumor efficacy in preclinical studies [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 5825.
Abstract 3769: Targeting TAK1 kinase triggers anti-tumor immunity and sensitizes pancreatic cancer to checkpoint blockade
Authors: Sapana P. Bansod, Vikas Somani, Hung-Po Chen, Lin Li, John Baer, David G. DeNardo, Kian-Huat Lim
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with limited effectiveness to immune checkpoint therapies, primarily due to its immunological “cold” tumor microenvironment (TME). We identified overactivation of phosphorylated Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1 a. k. a. MAP3K7) kinase during development of pancreatic cancer in Human and mouse PDAC models. We demonstrated that phospho-TAK1 activity was increased in human PDAC TMA tissues, and it’s correlated with high levels of TGFB and less CD8+ cytotoxic T cell abundance. The pharmacological inhibition of the TAK1 using selective TAK1 inhibitor Takinib significancy reduces tumor progression, prolong overall survival, enhances intratumoral CD4+ and CD8+ effector T cells, and decreases myeloid infiltration in the p48-Cre/TP53f/f/LSL-KRASG12D (KPC) mouse PDAC model. Further, genetic or pharmacologic inhibition of TAK1 enhances the sensitivity of PDAC to immune checkpoint blockade (anti-PD-1 and anti-CTLA4), leading to significant reduction in tumor desmoplasia and extended survival in KPC mice. Mechanistically, inhibition of TAK1 in PDAC cells triggers cGAS-STING signaling by inducing cytosolic DNA damage which facilitates cytotoxic CD8+ T cell-dependent cell death. Together, our data provide the rationale for combining TAK1 inhibition with immune checkpoint blockade (anti-PD-1 and anti-CTLA4) as a therapeutic strategy for PDAC patients. Citation Format: Sapana P. Bansod, Vikas Somani, Hung-Po Chen, Lin Li, John Baer, David G. DeNardo, Kian-Huat Lim. Targeting TAK1 kinase triggers anti-tumor immunity and sensitizes pancreatic cancer to checkpoint blockade [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 3769.
Abstract 1251: Decoding tumour evolution and relapse drivers in EGFR mutant NSCLC in never smokers
Authors: Komal Gupta, Dawn Lau Pingxi, Ngak Leng Sim, Kenneth Chow, Lan Ying Wang, Mengyuan Pang, Stephanie Saw, Wanjin Hong, Anders Martin Jacobsen Skanderup, Regina Hoo, Daniel Shao Weng Tan
Journal: Cancer Research (2025)

Abstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Unlike smoking-related NSCLC, the incidence of lung cancer among never-smokers in East Asia is rising, often driven by oncogenes such as EGFR. While Tyrosine Kinase Inhibitors (TKIs) have improved outcomes in EGFR-mutated NSCLC, resistance remains a significant challenge. Identifying the genomic and transcriptomic features that underpin tumour progression and relapse in early-stage EGFR-mutated NSCLC in non-smokers is crucial for developing novel therapeutic approaches to improve patient outcomes. Due to the diverse evolutionary trajectories of EGFR mutated NSCLC, our capacity to forecast disease trajectory is still limited. To address this, we performed 578 multi-region whole-exome and transcriptome sequencing from 180 treatment naïve early-stage EGFR-mutated resected NSCLC tumours. Among these, 56 (31%) patients eventually relapsed, while 124 (69%) did not, with a mean follow-up of 5.4 years. Our findings revealed that driver mutations in EGFR, TP53, and RBM10 were predominantly clonal, while a multitude of subclonal driver mutations contributed to increased tumour diversity. Interestingly, mutational signature SBS40a, of unknown origin, was prevalent as clonal alterations, suggesting early involvement in EGFR-mutated tumours. Notably, relapsed tumours exhibited distinct genomic features, including elevated subclonal APOBEC mutational signatures, higher rates of whole-genome doubling, and increased chromosomal aberrations, linking these features to greater mutational burden, intra-tumour heterogeneity and poorer outcomes. Overall, our results demonstrate the diversity of clonal and subclonal mutational processes that shape the clonal architecture of EGFR-mutated NSCLC in non-smokers and identify key features driving relapse. Ongoing efforts are focused on leveraging these features to identify potential prognostic markers for risk stratification and therapeutic targets for early-stage disease. Citation Format: Komal Gupta, Dawn Lau Pingxi, Ngak Leng Sim, Kenneth Chow, Lan Ying Wang, Mengyuan Pang, Stephanie Saw, Wanjin Hong, Anders Martin Jacobsen Skanderup, Regina Hoo, Daniel Shao Weng Tan. Decoding tumour evolution and relapse drivers in EGFR mutant NSCLC in never smokers [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 1251.
Abstract 4512: Impact of clinical response and treatment tolerability on HRQoL in patients treated with ponatinib or imatinib for newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL)
Authors: Ajibade Ashaye, Ling Shi, Ibrahim Aldoss, Pau Montesinos, Pankit Vachhani, Vanderson Rocha, Cristina Papayannidis, Jessica T. Leonard, Maria R. Baer, Jose-Maria Ribera, James McCloskey, Yanyu Wu, Meliessa Hennessy, Alexander Vorog, Shien Guo
Journal: Cancer Research (2025)

Abstract In the PhALLCON trial (NCT03589326), ponatinib demonstrated superior minimal residual disease (MRD)-negative complete remission (CR) rate, patient-reported treatment tolerability, and health-related quality of life (HRQoL) over imatinib in combination with reduced intensity chemotherapy in adults with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). To further substantiate the effect of treatment benefits on HRQoL, we assessed the effect of clinical response and treatment tolerability on changes in HRQoL over time in PhALLCON trial patients. HRQoL was assessed using prespecified primary domains from the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire and the EQ-5D-5L. Treatment tolerability was assessed using the FACT-GP5 item “bothered by treatment side effects”. Linear mixed-effects regression models were used to examine changes in HRQoL over time, with CR status and treatment tolerability as time-varying predictors, while controlling for significant covariates. The analysis included 238 patients (ponatinib 159, imatinib 79). Achieving CR was linked to significant HRQoL improvement in all FACT-Leu domains and the EQ-5D visual analogue scale (EQ-VAS), with clinically meaningful improvements in the FACT-Leu Trial Outcome Index, FACT-G Total Score, and FACT-Leu Total Score domains (Table). Treatment-related side effects led to significant and clinically meaningful deterioration in all scales. Higher levels of “bother” were associated with greater worsening in HRQoL. Given the 2-fold higher MRD-negative CR rate of ponatinib compared to imatinib, these analyses further support the HRQoL benefit of ponatinib over imatinib in patients with Ph+ ALL. Citation Format: Ajibade Ashaye, Ling Shi, Ibrahim Aldoss, Pau Montesinos, Pankit Vachhani, Vanderson Rocha, Cristina Papayannidis, Jessica T. Leonard, Maria R. Baer, Jose-Maria Ribera, James McCloskey, Yanyu Wu, Meliessa Hennessy, Alexander Vorog, Shien Guo. Impact of clinical response and treatment tolerability on HRQoL in patients treated with ponatinib or imatinib for newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) [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 4512.
Abstract 5777: A guidance platform for nanoparticle mediated photothermal therapy for solid tumors
Authors: Ivan Kosik, Robert Weersink, Margarete Akens, Fumi Yokote, Sangeet Ghai, Gang Zheng, Brian Wilson
Journal: Cancer Research (2025)

Introduction Nanoparticle-mediated Photothermal therapy (PTT) is an option for treating solid tumors with low cost and toxicity. Except for a limited set of cancers, PTT in general has not seen widespread clinical adoption, due in part to lack of effective treatment guidance technology. Recent clinical trials here and elsewhere investigating MRI-guided PTT have highlighted 3 critical requirements, including visualization of (1) tumor nanoparticle uptake, (2) temperature distribution during PTT and (3) treatment effect. These trials also highlighted shortcomings of MRI guidance, including high cost and limited access, complexity, speed and indirect functionality, so there is a need for novel direct, real-time PTT-guidance technology. Methods and Results We have designed and constructed a PTT-guidance platform based on hand-held multispectral photoacoustic (PA) tomography enabled by an in-house built frequency-optimized acoustic sensor array designed specifically to capture volumetric PA signals at depths of up to several cm. This is able to quantitatively image bulk-tissue endogenous and exogeneous contrast, including nanoparticle distribution in tumor (Requirement #1). In addition, this platform provides highly sensitive deep-tissue temperature mapping through the temperature dependence of the tissue Gruneisen parameter, matching or exceeding MRI-based thermometry but with direct, real-time precision in an ergonomic hand-held configuration (Requirement #2). Integration of a custom-built diffuse optical tomography (DOT) module into the PAI platform provides measures of the time-dependent tissue optical properties during PTT, particularly scattering that is known to increase 2 to 3-fold with coagulation above ∼55oC. Thereby, it provides immediate feedback on the size and location of the photocoagulated lesion (Requirement #3). Results of in vivo and pre-clinical validation studies are presented, showing nanoparticle injection and distribution in tissues, PA thermal mapping and DOT-based proof-of-principle monitoring of PTT treatments in patients with localized prostate cancer. Conclusions These studies indicate that we can provide the three needed functionalities for PTT guidance and that, for the first time, this can be done on a spatial scale relevant to clinical translation. This work is supported by the Terry Fox Research Institute and the Canadian Cancer Society. Citation Format: Ivan Kosik, Robert Weersink, Margarete Akens, Fumi Yokote, Sangeet Ghai, Gang Zheng, Brian Wilson. A guidance platform for nanoparticle mediated photothermal therapy for solid tumors [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 5777.