tbuckley/cabot-search huggingface dataset:
Abstract SY22-02: Cell cycle plasticity drives tumor progression and drug resistance
Authors: Yian Yang, Thu Pham, Janet McLaughlin, Steffi Oesterreich, Adrian Lee, Katarzyna Kedziora, Wayne Stallaert
Journal: Cancer Research (2025)

Abstract The cancer cell cycle possesses an incredible capacity to adapt or change in response to oncogenic mutations or drug treatment (cell cycle “plasticity”) to generate a diversity of solutions to the cell cycle (distinct cell cycle “programs”) that differ in key regulatory effectors and mechanisms. To study the extent and role of cell cycle plasticity in tumor progression and drug resistance, we developed cell cycle mapping - a single-cell proteomic imaging platform that combines highly multiplexed immunofluorescence with manifold learning to visualize cell cycle plasticity among and within tumors. Applying cell cycle mapping to a large library of hormone receptor (HR)+ breast tumors, we observed 4 distinct cell cycle programs driving tumor growth. These programs differed in the expression/activity of key cyclins and CDKs. In many cases, we observed multiple cell cycle programs within a single tumor correlating with differences in the cellular composition of the local tumor environment. These results also highlight the challenge of targeting the cancer cell cycle (e.g. with CDK4/6 inhibitors), given the heterogeneity of cell cycle programs actin within a single tumor. To further explore the role of cell cycle plasticity in targeted therapy, we used a combination of cell cycle mapping and time-lapse imaging to reveal how the breast cancer cell cycle responds to a panel of FDA-approved drugs targeting a range of cell cycle effectors, including multiple CDK inhibitors. We observed clear heterogeneity in the mechanisms of cell cycle adaptation executed across a panel of cell lines modeling distinct molecular (HR+, HER2+, basal) and histological subtypes (invasive ductal carcinoma, invasive lobular carcinoma) of breast cancer. Altered expression/activity of key cell cycle regulators provides a new “path” through the cell cycle, a molecular detour that allows cells to continue proliferating in the presence of drug to drive therapeutic resistance. Citation Format: Yian Yang, Thu Pham, Janet McLaughlin, Steffi Oesterreich, Adrian Lee, Katarzyna Kedziora, Wayne Stallaert. Cell cycle plasticity drives tumor progression and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY22-02.
Abstract CT243: Phase 2 study of Ivonescimab in patients with cutaneous squamous cell carcinoma
Authors: Neal Akhave, Ashley Holder, Michael Davies, Omar Pacha, Roi Weiser, Funda Meric-Bernstam, Aung Naing
Journal: Cancer Research (2025)

Abstract Background: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer. In the setting of unresectable locally advanced or metastatic disease, checkpoint inhibitors are standard of care and are associated with robust response rates and durable disease control. However, in those who do not respond or progress on immunotherapy, there are limited available standard therapies. Ivonescimab is a tetravalent bispecific antibody targeting programmed cell death protein 1 (PD-1) and vascular endothelial growth factor A (VEGF-A) that has shown promising activity in multiple tumor types. VEGF-mediated activities include driving angiogenesis creating a tortuous tumor vasculature and decreasing effector T-cells within the tumor microenvironment. Herein, we hypothesize that dual targeting of PD-1 and VEGF-A may overcome resistance to checkpoint inhibitors and extend the benefit of immunotherapy in CSCC. Methods: This phase 2, single-arm study will enroll up to 24 patients and will be conducted using a Bayesian optimal phase 2 (BOP2) design. Patients will receive Ivonescimab 20mg/kg intravenously every 3 weeks until progression, death, or intolerance. The main inclusion criteria include unresectable locally advanced or metastatic CSCC that is refractory to prior checkpoint inhibitors, Eastern Cooperative Oncology group performance score of 0-1, and measurable disease by RECIST version 1.1. Primary exclusion criteria comprise prior severe immunotherapy-associated toxicities, prior organ transplant, or major blood vessel invasion. There are no limits on lines of therapy. Primary objective and endpoint is objective response rate in CSCC. Key secondary endpoints include duration of response, disease control rate, progression free survival, and safety. Additional exploratory objectives include evaluating predictive biomarkers of treatment response or resistance utilizing a mandatory biopsy performed both pre-and on-treatment, with correlatives including whole exome sequencing, RNA sequencing, multiplex IHC. Active recruitment and enrollment are ongoing at The University of Texas MD Anderson Cancer Center, Houston, Texas. ClinicalTrials.gov (NCT06567314) Citation Format: Neal Akhave, Ashley Holder, Michael Davies, Omar Pacha, Roi Weiser, Funda Meric-Bernstam, Aung Naing. Phase 2 study of Ivonescimab in patients with cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT243.
Abstract LB061: Cell polarity proteins as novel regulators of macropinocytosis
Authors: Guillem Lambies Barjau, Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, Cheska M. Galapate, Anagha Deshpande, Aniruddha J Deshpande, David A. Scott, David W. Dawson, Cosimo Commisso
Journal: Cancer Research (2025)

Abstract Macropinocytosis has emerged as a nutrient-scavenging pathway that cancer cells exploit to survive the nutrient-deprived conditions of the tumor microenvironment. Cancer cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis, allowing the cells to escape metabolic stress through the production of extracellular-protein-derived amino acids. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι, as novel regulators of macropinocytosis. In normal epithelial cells, aPKCs are known to regulate cell polarity in association with the scaffold proteins Par3 and Par6, controlling the function of several targets, including the microtubule-associated Par1 kinases. In PDAC cells, we identify that each of these cell polarity proteins are required for glutamine stress-induced macropinocytosis. Mechanistically, we find that the aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the relocation of Par3 to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, we determine that cell fitness impairment caused by aPKC depletion in glutamine stress is rescued by the restoration of macropinocytosis and that aPKCs support PDAC growth in vivo. These results identify a previously unappreciated role for the cell polarity protein network in the regulation of macropinocytosis and provide a better understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress. Citation Format: Guillem Lambies Barjau, Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, Cheska M. Galapate, Anagha Deshpande, Aniruddha J Deshpande, David A. Scott, David W. Dawson, Cosimo Commisso. Cell polarity proteins as novel regulators of macropinocytosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB061.
Abstract SY14-01: AI inferred spatial transcriptomics unlocks cancer biomarker discovery from histopathology
Authors: Eytan Ruppin
Journal: Cancer Research (2025)

Abstract Path2Space: AI histopathology-inferred spatial transcriptomics as a driver of next-generation fast and cost effective precision oncology. I will start briefly reviewing my lab’s decade long work on developing a synthetic lethality approach for predicting patients’ response to therapy from tumor transcriptomics and whole slide pathology images [Cell 2021, MED 2023, Nature Cancer 2024]. The main part of my talk will focus on Path2Space, a new generic unpublished deep learning approach that predicts spatial gene expression directly from histopathology slides. Applied to study breast cancer as an example, Path2Space robustly predicts the spatial gene expression of more than 4000 genes and accurately infers cell-type abundances in the tumor microenvironment (TME) based on the inferred ST data. Path2Space characterizes thee TME of more than a 1000 breast cancer TCGA samples on an unprecedented scale and identifies three new spatially-grounded breast cancer patients subgroups with distinct survival rates. Closing a decade long circle, Path2Space- enables more accurate predictions of patients’ response to chemotherapy and trastuzumab directly from H&amp;E slides than those obtained by existing established sequencing-based transcriptomics biomarkers. Path2Space thus offers a transformative approach to robustly delineate the tumors microenvironment directly from their histopathology slides. It facilitates the development of a new type of spatially-grounded biomarkers and lays the basis for a new generation of fast and low cost precision oncology biomarkers. Citation Format: Eytan Ruppin. AI inferred spatial transcriptomics unlocks cancer biomarker discovery from histopathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY14-01.
Abstract SY06-01: Neuronal regulation of brain cancers
Authors: Michelle Monje
Journal: Cancer Research (2025)

Abstract In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Concordantly, neuronal activity robustly promotes progression of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes synapse formation between neurons and glioma cells. Glioma cells integrate into neural circuits through neuron-to-glioma synapses that exhibit mechanisms of malignant synaptic plasticity and a diversity of synapse types. This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. Thus, both paracrine and synaptic neuron-glioma interactions play important roles in the pathogenesis of glial cancers, highlighting a number of potential therapeutic opportunities. The subversion of mechanisms of neurodevelopment and plasticity by malignant gliomas underscores the importance of understanding the neuroscience of brain cancer. Similar mechanisms of neuron-cancer interactions are increasingly appreciated in brain metastases and in cancers outside of the CNS; nervous system-cancer interactions are now emerging a new hallmark of cancer. Citation Format: Michelle Monje. Neuronal regulation of brain cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY06-01.
Abstract LB446: Development of drug candidate for metastatic cancer by targeting pathogenic mitochondrial DNA
Authors: Hiroki Nagase
Journal: Cancer Research (2025)

Abstract The 5-year survival rate for stage 4 advanced cancer is 5.8% for stomach cancer, 17% for colon cancer, 8.4% for lung cancer (NSCLC), 4.4% for liver cancer and 38.6% for breast cancer, 5.1% for cervical cancer and 27.1% for ovarian cancer in Japan (Cancer Statistics 2024). So, development of new modalities for the treatment of metastatic cancer is essential. Mitochondria-targeted cancer drugs may have the potential to become Pan-Cancer Drugs for advanced cancers, and is recently focused on induction of ferroptosis by promoting oxidative stress in cancer cells. However, there are no drugs that can induce cancer-specific apoptosis by specifically removing abnormal mitochondria by mitophagy (mitochondria-specific autophagy) and promote cell membrane destruction by super-excess of reactive oxygen species (ROS) released from mitochondria during the mitophagic process. We have synthesized a pyrrole imidazole polyamide that can bind sequence-specifically to the minor-groove of double-stranded DNA conjugated with the mitochondria-localized lipophilic cation triphenylphosphonium (TPP). Metastatic cancers are near homoplasmy of the mutant mtDNA and mitophagy was induced in almost all mitochondria. In advanced cancer cells, ROS was generally over-presented and endogenous antioxidant, which reactively express and inhibit against ROS excess and cell death as seen in normal cells, were exhausted and apoptosis or cell destruction were induced instead of ferroptosis. We further developed a compound, CCCh-560-TPP, targeting the ATP6 gene variant m.8860A&amp;gt;G, which does not affect mitochondrial membrane potential and is almost always coexisted with any mtDNA mutations in various cancer types, as a passenger variant. Thus, CCCh-560-TPP may overcome the irrationality of drug development for each cancer mutation and be used as a pan-cancer drug candidate especially for metastatic cancers. We confirmed its induction of cancer cell death and safety in a mouse toxicity study. This lead compound CCCh-560-TPP is applicable to highly malignant pan-cancer, in which ROS-producing mitochondrial mutations exist, and is considered a promising new compound and is currently being prepared for the Phase I clinical trial. Citation Format: Hiroki Nagase. Development of drug candidate for metastatic cancer by targeting pathogenic mitochondrial DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB446.
Abstract LB053: Targeting macrophage metabolism in pancreatic cancer
Authors: Austin D. Silva, Sabrina E. Calderon, Rima Singh, Cecily Anaraki, Taryn Morningstar, Anai C. Contreras, Natalie Yousefian, Avary S. Baker, Christopher Halbrook
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the leading causes of cancer-related mortality in the United States, despite its relatively low incidence rate. A significant challenge in treating PDA lies in its densely fibrotic tumor microenvironment, which is heavily infiltrated by immune cells. This environment is characterized by limited functional vasculature, restricting nutrient availability, and facilitating complex interactions between tumor cells and immune populations, such as tumor-associated macrophages (TAMs). These conditions drive cancer cells to adopt diverse metabolic adaptations. One notable example is the metabolic enzyme Arginase 1 (ARG1), which catalyzes the breakdown of the amino acid L-arginine into urea and ornithine. Previous studies have shown a connection between arginine metabolism and macrophage effector function along the M1/M2 axis. In macrophages, arginine can be broken down in two ways: via inducible nitric oxide synthase (iNOS) into nitric oxide, which aids in effector function, or via Arginase 1 (ARG1) into ornithine and later proline, which is an essential component of the extracellular matrix (ECM). Additionally, it has been demonstrated that ARG1 is highly expressed in tumor-associated macrophages (TAMs), where it fosters an immune-suppressive phenotype, positioning it as a compelling therapeutic target. Thus, building on this foundation we have developed mouse models with a macrophage-specific knockout of Arg1. Utilizing this model, we are investigating the phenotypic effects of disrupting this metabolic pathway within macrophages in the contexts of both PDA and its major predisposing factor, pancreatitis. Citation Format: Austin D. Silva, Sabrina E. Calderon, Rima Singh, Cecily Anaraki, Taryn Morningstar, Anai C. Contreras, Natalie Yousefian, Avary S. Baker, Christopher Halbrook. Targeting macrophage metabolism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB053.
Abstract LB116: Real-world implementation of AI in target discovery: CURE AI predicts IL-15 as a therapeutic target in renal cancer
Authors: Neil Thomas Pfister, Amit Weiss, Vitalay Fomin
Journal: Cancer Research (2025)

Abstract We developed a machine learning platform that learns and measures the individualized benefit of a therapeutic intervention over standard of care, which we named CURE AI (Clinical trials Uncovering Real Efficacy Artificial Intelligence). To build CURE AI, we trained a foundation model with clinical and multi-omics data from hundreds of thousands of oncology patients using a proprietary deep learning architecture and training schema. CURE AI is designed to understand the interplay between all baseline clinicogenomic information to predict the magnitude of benefit of therapy for each patient enrolled on a clinical trial. The foundation model allows CURE AI to predict a counterfactual outcome for every patient - a predicted outcome for the trial therapy they did not receive - based on finetuning our foundation model with conditional average treatment effect modeling. The result is a continuous benefit prediction ranking of patients (the CURE Index) based on the most important and predictive clinical and genomic factors, which can be utilized to informbiomarker and target discovery. For the phase 3 JAVELIN Renal 101 trial, which compared avelumab/axitinib to sunitinib in advanced renal cell carcinoma patients, CURE AI identified a population of patients who had superior response to axitinib/avelumab. We show that if this CURE AI-selected patient group was utilized for trial enrollment, the JAVELIN Renal 101 trial could have been significant with 25% of the patients who were enrolled on the completed trial (n=886 to n=222). Using our novel Accelerated Approval Modeling method, we show that the trial could have sought FDA approval at least 6 months earlier (while enrolling one-fourth of the patient population) with the use of CURE AI. Target discovery analysis of the CURE AI-selected patient groups revealed that IL-15 was predictive of patient response, and we predict success of IL-15 agonists in patients with renal cell cancer. In summary, we developed and validated a causal clinicogenomic deep learning platform that calculates individualized patient benefit of investigational therapy compared to an existing standard of care. CURE AI is available to implement on completed or actively enrolling clinical trials to identify the patients who receive a true benefit from investigational therapy as well as to perform biomarker and target discovery. Citation Format: Neil Thomas Pfister, Amit Weiss, Vitalay Fomin. Real-world implementation of AI in target discovery: CURE AI predicts IL-15 as a therapeutic target in renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB116.
Abstract LB172: Chemoradiation-induced tissue toxicity in oral cancer using 3D Epithelioids
Authors: George Morcos, Erini Terpsi Vitti, Ines Ferreira, Philippa Samella, David Fernandez-Antoran
Journal: Cancer Research (2025)

Abstract Background: Oral mucositis is among the most prevalent side effects of head and neck cancer (HNC) therapy, impacting over 40% of patients treated with chemotherapy and 90% of those treated with chemoradiation. This widespread inflammation of the oral mucosa represents a major obstacle to the treatment and quality of life of HNC patients and is often a precursor of subsequent oral complications like dysphagia and infections. Although progress has been made in deciphering the mechanisms of oral mucositis, models to study this chemoradiotoxicity have been largely limited to tumor-bearing in vivo models which are both time and cost intensive. To overcome this, the Antoran lab has developed epithelioids, a novel in vitro system that recapitulates 3D epithelial structures from mouse and human tissues and can be extended to cancer epithelioids which recapitulate interactions between healthy and tumor cells along with the tumor microenvironment. Methods: The tongue and oral mucosa were excised from euthanized mice and the muscle layers were removed with forceps. Epithelium from both tissues was cut into small explants, plated on transparent six-well pored membrane trans wells, and incubated with keratinocyte typical media. Squamous cell carcinoma cells of varying aggressiveness were added in the center of each insert. Once confluent, the oral cancer epithelioids were treated with cisplatin, x-ray radiation, or both. Normal and tumor cell viability, proliferation, and recovery was observed using spinning disk confocal live imaging and immunofluorescent staining. Results &amp; Discussion: Real-time live-cell imaging confirmed epithelial cell growth to confluency followed by tumor invasion. Following cisplatin, x-ray irradiation, or combination therapy, epithelioids showed increased markers of DNA-damage and repair such as yH2AX and 53BP1 respectively, apoptosis, and decreased epithelial barrier function as measured by dextran-FITC permeability assays. Relative to normal tissue in the cancer epithelioids, cancer tissue showed greater double-stranded DNA damage in response to chemoradiation. Conclusion: Our results suggest that cancer epithelioids are a promising in vitro alternative to more complex in vivo models and may be used for studying mechanisms of oral mucositis and potential therapeutic interventions of this side effect. Citation Format: George Morcos, Erini Terpsi Vitti, Ines Ferreira, Philippa Samella, David Fernandez-Antoran. Chemoradiation-induced tissue toxicity in oral cancer using 3D Epithelioids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB172.