tbuckley/cabot-search huggingface dataset:
Abstract 1222: Integrating i<i>n vitro</i> and <i>in vivo</i> data with algorithm-driven PK/PD modeling: a fast and efficient tool for evaluating cancer therapies in preclinical models
Authors: Karina Adamowicz, David Cebrian, Fabio dell' Aquila, Leanne Doyle, Agnieszka Drzał, Simone Esposito, Bartosz Płóciennik, Katarzyna Urbańska, Martyna Sniegocka
Journal: Cancer Research (2025)

Preclinical in vivo PK/PD studies of cancer therapies are invaluable for cancer drug discovery and the translation of therapies from bench to bedside. However, conventional in vivo experimentation are often time-intensive, resource-demanding, and may require redesign due to inefficient and/or toxic range of concentrations, or suboptimal study parameters. To address these challenges, we developed an integrated approach combining in vitro and in vivo data to generate in silico PK/PD models of anti-cancer compounds. Our algorithm was verified using standard chemotherapies, including Cisplatin and Dacarbazine, against tumoral cell lines for e.g. B16F10 and LLC. The algorithm was trained with the cells doubling time in vitro and with the tumor growth rate in mice. We then conducted an in vitro time-course experiment using a range of concentrations to assess cellular growth inhibition. This data was integrated into the algorithm thus it can calculate the IC50, the drug plasma concentration, and the efficacy over-time of each drug against the engrafted cell lines in mice. Finally, we validated our model in vivo using selected doses from the calculated efficacy ranges, achieving tumor volume reductions comparable to the model’s projections for the tested drugs. In conclusion, we generated a fast and resource-efficient method for PK/PD studies, broadly applicable to cancer drug candidates with minimal prior in vivo efficacy data. Citation Format: Karina Adamowicz, David Cebrian, Fabio dell' Aquila, Leanne Doyle, Agnieszka Drzał, Simone Esposito, Bartosz Płóciennik, Katarzyna Urbańska, Martyna Sniegocka. Integrating in vitro and in vivo data with algorithm-driven PK/PD modeling: a fast and efficient tool for evaluating cancer therapies in preclinical models [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 1222.
Abstract 139: The nutrient-dictated ECM regulates cancer cell growth via the itga2-FAK-YAP axis
Authors: Kristof Turan, Julien Guillard, Simon Schwoerer
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. PDAC tumors are characterized by a dense desmoplastic stroma and altered nutrient availability that promote aggressive cancer cell behavior. A collagen-rich extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) is a key feature of PDAC’s stroma and associated with tumor progression and therapy resistance. How altered nutrient availability and ECM production are integrated to modulate PDAC cell biology is not well understood. To address this gap, we develop a spheroid outgrowth assay on ECM produced by CAFs under altered availability of glutamine, an amino acid shown to be depleted in PDAC. We find that glutamine availability dictates the composition of CAF-derived ECM. The glutamine-dictated ECM differentially modulates PDAC cell behavior, with ECM produced under high glutamine (HQ) availability restraining PDAC cell growth but promoting PDAC cell migration. We link these phenotypes to collagen I abundance, which is depleted in ECM produced under low glutamine (LQ) availability. Mechanistically, we find that increased stiffness of HQ ECM underlies its growth restraining properties, while its activation of focal adhesion kinase (FAK) signaling in PDAC cells supports migration. Specifically, collagen I in HQ ECM binds to integrin α2 (Itga2), activating FAK and downstream YAP/TAZ signaling, both of which are required for PDAC cell migration. In contrast, LQ ECM fails to activate YAP/TAZ signaling in PDAC cells. Activation of YAP/TAZ signaling alone was sufficient to rescue PDAC cell migration on LQ ECM. These findings demonstrate that tumor nutrient availability alters ECM composition, which modulates PDAC biology via Itga2-FAK-YAP signaling. Citation Format: Kristof Turan, Julien Guillard, Simon Schwoerer. The nutrient-dictated ECM regulates cancer cell growth via the itga2-FAK-YAP axis [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 139.
Abstract 816: Aurora kinase A inhibition overcomes tolerance to panHER inhibitors in HPV positive HNSCC
Authors: Sebastian Cruz-Gomez, Jong Woo Lee, Julian Barrantes, Richard Ivey, Sara Savage, Pratima Chaurasia, Gunner Dickson, Dickson Adah, Bing Zhang, Amanda Paulovich, Barbara Burtness
Journal: Cancer Research (2025)

Abstract The incidence of HPV-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) has been increasing in recent decades. The EGFR inhibitor cetuximab (CTX) is less active in HPV+ than HPV- HNSCC. HPV oncoproteins E6 and E7 induce HER3 overexpression, and EGFR-HER3 heterodimer-driven survival signaling via PIK3, AKT and ERK1-2 contributes to resistance to cetuximab and the EGFR inhibitor erlotinib. We demonstrate that although panHER inhibitors afatinib and dacomitinib more effectively inhibit growth of HPV+ HNSCC cells than do erlotinib or cetuximab, adaptive signaling through the AURKA/PLK1 axis mediates resistance to panHER inhibitors. We hypothesized that combined panHER and AURKA inhibition would synergize to overcome persistence of HPV+ HNSCC. We find that HPV+ HSNCC cells UM-SCC47 and UPCI:SCC154 express both EGFR and HER3. Indeed, cell viability experiments and clonogenic survival assays demonstrate strong synergy between panHER and AURKA inhibitors, confirmed in xenografted tumor models treated with the second generation AURKA inhibitor VIC-1911 and dacomitinib. We then performed RNAseq and shotgun proteomics to understand the cellular mechanisms behind our combination. Dacomitinib had expected effects downregulating Hallmark G2M and EGFR phosphorylation targets, upregulating EMT markers and cell death markers. In contrast, addition of AURKA inhibition upregulated PLK1 and pPLK1 and cell death markers. These findings indicate that combination therapy with AURKA inhibition will mitigate the adaptability to EGFR and panHER inhibitors previously described for HPV+ HNSCC. Citation Format: Sebastian Cruz-Gomez,Jong Woo Lee,Julian Barrantes,Richard Ivey,Sara Savage,Pratima Chaurasia,Gunner Dickson,Dickson Adah,Bing Zhang,Amanda Paulovich,Barbara Burtness. Aurora kinase A inhibition overcomes tolerance to panHER inhibitors in HPV positive HNSCC [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 816.
Abstract 2571: Effects of patient-derived ovarian cancer-associated fibroblasts and tumor progression and metastasis
Authors: Ji-Young Lee, Sung Wan Kang, Min-Seo Lee, Ok-Ju Kang, Yong-Man Kim, Shin-Wha Lee
Journal: Cancer Research (2025)

Abstract Background: Ovarian cancer (OC) is a highly treatment-resistant malignancy, often diagnosed late due to minimal symptoms and extensive metastasis. Despite platinum-based chemotherapy, recurrence and chemoresistance highlight the need for new therapies. This study focuses on cancer-associated fibroblasts (CAFs), key TME components, to explore their impact on OC progression and identify novel CAF subtypes. Methods: CAFs were isolated from OC patient tumors via enzymatic dissociation and flow cytometry. Their markers, FAP and α-SMA, were analyzed using immunofluorescence and flow cytometry. Conditioned media from CAF cultures were tested on OC cell lines (A2780, A2780-cp, SKOV3, OVCAR3) to assess proliferation and migration via cell viability and scratch assays. Cytokines in CAF-conditioned media were quantified using ELISA. Results: CAFs were identified within OC tumors, with their expression of FAP validated in high-grade serous ovarian cancer (HGSOC) samples via immunohistochemistry and flow cytometry. CAFs were successfully isolated and cultured from patient-derived OC tumors. Flow cytometry revealed that CAFs represent a minor subset of the total tumor cell population. Morphologically, CAFs exhibited plump spindle or stellate forms. CAFs derived from HGSOC displayed elevated levels of FAP and α-SMA expression compared to those derived from non-HGSOC tumors. Exposure of four OC cell lines (A2780, A2780-cp, SKOV3, OVCAR3) to CAF-conditioned media significantly promoted their growth. Scratch assays revealed enhanced motility in two OC cell lines (SKOV3 and OVCAR3) following treatment with CAF-conditioned media. Notably, the HGSOC-derived CAF subtype, W-OVCAF7, exhibited significantly greater growth- and motility-enhancing effects compared to non-HGSOC-derived CAFs. Scratch assays further confirmed that W-OVCAF7 markedly increased the migratory capacity of both SKOV3 and OVCAR3 cells, suggesting that CAF activity may vary depending on the tumor cell type. These findings underscore the pivotal role of CAFs in modulating the proliferation and migration of OC cells. Conclusion: Tumor-derived CAFs significantly enhance OC cell proliferation and migration, underscoring their critical role in the TME. This study highlights the importance of patient-derived CAFs for precise analysis of OC dynamics and lays a foundation for therapeutic strategies targeting the CAF-TME interplay. Citation Format: Ji-Young Lee, Sung Wan Kang, Min-Seo Lee, Ok-Ju Kang, Yong-Man Kim, Shin-Wha Lee. Effects of patient-derived ovarian cancer-associated fibroblasts and tumor progression and metastasis [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 2571.
Abstract 2905: Combination of the ATR inhibitor, ART0380, with irinotecan for treating ATM-negative tumors
Authors: Helen M. Robinson, Desiree Piscitello, Elias Elinati, Lucy Armstrong, Emily Graham, Silvia Peripolli, Giorgia Lillo, Joana F. B. P. Neves, Jayesh Majithiya, Eeson Rajendra, Marina Roy-Luzarraga, Lerin Geo, Vera Grinkevich, Ian C. Smith, Alessandro Galbiati, Arya Ashok Nair, Graeme C. Smith
Journal: Cancer Research (2025)

Abstract Ataxia telangiectasia mutated (ATM) and Ataxia telangiectasia and Rad3-related (ATR) proteins function in concert to regulate the cellular response to both intrinsic and extrinsic factors that induce replication stress such as oncogene activation and DNA damaging agents. Loss or inhibition of ATR has been well documented to be synthetic lethal with ATM deficiency in cancers and this concept is being explored in clinical trials, however, the efficacy of monotherapy with ATR inhibitors has been limited with objective response rates of ∼10%. Here, using a novel ATR kinase inhibitor, ART0380, we provide mechanistic preclinical evidence that exacerbating replication stress with a low dose of the TOPO1 inhibitor, irinotecan, further sensitizes ATM negative tumors to ATR inhibition. This enhanced cancer cell killing by the combination of ART0380 and irinotecan in ATM negative cells is linked to loss of cell cycle control and entry of ATM negative cancer cells into mitosis with DNA damage, leading to mitotic catastrophe. In a range of CDX and PDX mouse models we show that the combination of ART0380 with irinotecan leads to robust tumor growth inhibition and, in some instances, regressions across diverse ATM negative tumor types and is well tolerated. These findings highlight ART0380 in combination with low-dose irinotecan as a promising therapeutic strategy for ATM negative cancers, which supports the ongoing clinical investigation NCT04657068. Citation Format: Helen M. Robinson, Desiree Piscitello, Elias Elinati, Lucy Armstrong, Emily Graham, Silvia Peripolli, Giorgia Lillo, Joana F. B. P. Neves, Jayesh Majithiya, Eeson Rajendra, Marina Roy-Luzarraga, Lerin Geo, Vera Grinkevich, Ian C. Smith, Alessandro Galbiati, Arya Ashok Nair, Graeme C. Smith. Combination of the ATR inhibitor, ART0380, with irinotecan for treating ATM-negative 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 2905.
Abstract 79: Pax6 regulates stemness and enhances brain metastases in breast cancer
Authors: Laiba Anwar
Journal: Cancer Research (2025)

Abstract Brain metastasis (BrM) remains the most severe complication of breast cancer (BC), the most diagnosed cancer in females, associated with an abysmal prognosis. Our poor understanding of the molecular mechanisms driving the disease is one of the major reasons for the dearth of specific therapies. This highlights an urgent clinical need to decipher how BC cells form BrM. BCBrM is preceded by a period of dormancy, during which stem cell-like features of cancer cells may play a role in reactivating them to form metastatic lesions. Cancer stem cells, known as “brain tumor-initiating cells” contribute to tumor formation in the brain and could also lead to radio and chemoresistance in the treatment of brain metastases. We, therefore, conducted a bioinformatic analysis on publicly available transcriptomic datasets of matched primary and brain metastatic patient samples and found that Pax6, a transcription factor, was upregulated in the metastatic samples compared to the primary tumors. In tissue microarray (TMA) belonging to BrM patients, Pax6 expression was evident in the BrM lesions and nearly absent in normal brain tissue. Pax6 was found to be upregulated in BCBrM cell lines compared to primary BC cell lines. Pax6, a master regulator of transcription, essential for normal development of the eyes and central nervous system, has been implicated in cancer progression. Pax6 can promote proliferation, migration, and resistance to apoptosis. To delineate the essentiality of Pax6 in BCBrM, we performed CRISPR/Cas9-mediated Pax6 knockout (KO) in the BCBrM cell lines, which decreased proliferation, wound healing, and migration properties. Intracardiac injection of these Pax6 KO BCBrM cells into immunocompromised mice resulted in a significant reduction of brain metastatic tumor lesions compared to controls. Conversely, overexpression of Pax6 in primary BC cells induced a BrM-like phenotype, enhancing proliferation, migration, and wound healing. Since Pax6 regulates stem cell features we also found that Pax6 KO reduced the expression of stemness-promoting factors such as OCT4, NANOG, and KLF4. Further, to confirm the stemness features we found that in serum-free conditions, Pax6 KO cells significantly lacked mammosphere-forming abilities and side populations. These findings suggest that Pax6 mediates stemness in cancer cells and enhances the metastatic potential of BCBrM cells. Unraveling the role of Pax6 in BCBrM could potentially open new therapeutic avenues for the treatment of BCBrM patients which eventually will improve outcomes of these patients. Citation Format: Laiba Anwar. Pax6 regulates stemness and enhances brain metastases in 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 79.
Abstract 2917: Utilizing artificial intelligence for the discovery of a novel CNS-penetrating ATR inhibitor
Authors: Sarah Truong, Beibei Zhai, Louise Ramos, Mona Marzban, Fariba Ghaidi, Peter Guzzo, Mehran Khodabandeh, Ahmad Issa, Seyed A. Saberali, Jason Rolfe, Sarah Omar, Marshall Drew-Brook, John Langlands, Dennis Brown, Jeffrey Bacha, Mads Daugaard
Journal: Cancer Research (2025)

Abstract Introduction: Ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR) plays a crucial role in regulating DNA damage repair. ATR inhibitors have shown promise against solid tumors, not only as monotherapies, but also in combination with chemotherapy, radiotherapy, and immunotherapy with several clinical trials ongoing. The ATR inhibitors currently in clinical development have low CNS-penetration and are therefore sub-optimal for the treatment of brain tumors and brain metastases. It has been proposed that ATR inhibitors could be used as a monotherapy or could be used to potentiate the cytotoxicity of radiotherapy, one of the mainstay treatments for brain tumors. Development of novel, potent, CNS-penetrating ATR inhibitors could provide a new treatment alternative for patients with few options. Traditional drug discovery methods are time-consuming and costly, necessitating innovative approaches. Here, we describe the application of the Enki™ platform, an artificial intelligence approach, in the discovery of a novel ATR inhibitor for use against brain tumors. Methods: The Enki™ platform utilizes generative AI and deep machine learning to search a broad chemical space to identify hits. It uses variational autoencoders to optimize many properties simultaneously within the search space, including maximal potency against the primary target, selectivity, ADMET, and physicochemical properties. This platform was used to generate de novo molecules with optimized properties to penetrate the blood-brain barrier and specifically target ATR. Results: We will present preliminary results from the de novo molecule generation by the Enki™ platform. Validation of in vitro data, including ATR inhibition and selectivity, BBB permeability and metabolic stability, will be described. Conclusion: The Enki™ platform is being leveraged for the development of a CNS-penetrant ATR inhibitor, significantly accelerating the drug discovery and development process. Use of this system enables a broader exploration of the vast chemical space and refinement of drug properties, both shortening the drug development process and increasing specificity and efficacy of potential therapeutics. Citation Format: Sarah Truong, Beibei Zhai, Louise Ramos, Mona Marzban, Fariba Ghaidi, Peter Guzzo, Mehran Khodabandeh, Ahmad Issa, Seyed A. Saberali, Jason Rolfe, Sarah Omar, Marshall Drew-Brook, John Langlands, Dennis Brown, Jeffrey Bacha, Mads Daugaard. Utilizing artificial intelligence for the discovery of a novel CNS-penetrating ATR 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 2917.
Abstract 2501: pyVIPER: Enabling scalable and rapid insights from single-cell RNASeq data in cancer research
Authors: Alexander L. Wang, Zizhao Lin, Luca Zanella, Lukas Vlahos, Miquel Anglada Girotto, Aziz Ur Rehman Zafar, Heeju Noh, Andrea Califano, Alessandro Vasciaveo
Journal: Cancer Research (2025)

Abstract Single-cell sequencing has transformed cancer research by enabling the study of tumor heterogeneity and the complex interactions within the tumor microenvironment at an unprecedented resolution. However, the low signal-to-noise ratio in single-cell RNA sequencing (scRNASeq) poses challenges for quantitatively deciphering key cancer processes. We have demonstrated that gene regulatory network (GRN) analysis can address this by identifying Master Regulator (MR) proteins, using the VIPER algorithm, to pinpoint critical drivers of cancer and its microenvironment. As scRNASeq datasets from patient-derived tumors grow in size and complexity, there is a pressing need for scalable tools capable of analyzing datasets with hundreds of thousands of cells. To meet this need, we introduce pyVIPER, a highly efficient and scalable Python toolkit designed to assess protein activity in large-scale scRNASeq datasets. pyVIPER facilitates tumor and microenvironment analysis by supporting multiple enrichment algorithms, advanced data transformations, and a novel data structure for GRN manipulation. With seamless integration into publicly available state-of-art scRNASeq tools, as well as machine learning libraries, pyVIPER provides the ideal platform for analyzing tumor-derived samples. Benchmarking shows that pyVIPER reduces runtime from hours to minutes for large datasets, compared to previous tools, enabling a fast and comprehensive analysis of cancer and tumor microenvironment dynamics at single-cell resolution. This advancement makes VIPER-based analysis accessible for virtually any large-scale single-cell dataset from patient tumors, offering new insights into cancer biology and therapeutic targets. Citation Format: Alexander L. Wang, Zizhao Lin, Luca Zanella, Lukas Vlahos, Miquel Anglada Girotto, Aziz Ur Rehman Zafar, Heeju Noh, Andrea Califano, Alessandro Vasciaveo. pyVIPER: Enabling scalable and rapid insights from single-cell RNASeq data in cancer research [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 2501.
Abstract 808: Healthy dietary patterns and cancer survival: A cohort study
Authors: Zilong Bian, Xiaohang Xu, Siyun Zhou, Xue Li, Xifeng Wu
Journal: Cancer Research (2025)

Abstract Introduction: Diet plays a crucial role in the management and recovery of cancer patients. Making appropriate dietary choices can help provide necessary nutrients, enhance the immune system, maintain energy levels, and promote recovery. To examine the associations of dietary scores for 9 healthy eating patterns with risk of all-cause and cancer mortality in cancer survivors. Methods: A prospective cohort of cancer survivors (n = 4001; weighted number, 17548466) from the US National Health and Nutrition Examination Survey from 1999 to 2018. Participants were linked to mortality data from their interview and physical examination date through December 31, 2019. The exposures were Alternative Healthy Eating Index-2010 (AHEI2010), Alternate Mediterranean Diet score (AMED), Dietary Approaches to Stop Hypertension score (DASH), Dietary inflammation index (DII), Healthy dietary score (HDS), Healthy eating index-2020 (HEI2020), Plant-based diet index (PDI), Healthful plant-based diet index (hPDI), and World Cancer Research Fund/American Institute for Cancer Research dietary score (WADS). Main Outcomes were All-cause and cancer mortality. Results: The final study sample included 4001 cancer survivors (mean [SD] baseline age, 61.86[14.79] years; 2408 (66.37%) females; 2519(82.33) white individuals). During a total of 33130 person-years of follow-up, 1385 Participants died. Of note, when comparing the highest with the lowest tertiles, only AMED (HR (95% CI): 0.80 (0.65-0.98), P = 0.03), HEI2020 (HR (95% CI): 0.81 (0.68-0.96), P = 0.02), and hPDI (HR (95% CI): 0.84 (0.71-0.98), P = 0.03) were significantly associated with all-cause mortality. Also, higher levels of HEI2020 were associated with a lower risk of cancer mortality in cancer survivors (HR (95% CI): 0.70 (0.55-0.88), P = 0.003). All dietary scores had no nonlinear association with all-cause mortality. The inverse associations between these scores and risk of mortality were consistent in subgroups. Conclusions: In this cohort study of a nationally representative sample of US cancer survivors, embracing a comprehensive and nutritionally balanced dietary pattern, as exemplified by HEI2020, holds tremendous value in promoting the well-being and recovery of cancer survivors. Citation Format: Zilong Bian, Xiaohang Xu, Siyun Zhou, Xue Li, Xifeng Wu. Healthy dietary patterns and cancer survival: A cohort study [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 808.