tbuckley/cabot-search huggingface dataset:
Abstract 2086: Multiplex spatial bioimaging and AI-based image analysis for precision cancer therapeutics
Authors: Arindam Bose, Emily Quann Alonzo, Sophie Struble, Jeremy Fisher, Richard A. Heil-Chapdelaine, Natasha F. Diaz Granados, Vasundhara Agrawal
Journal: Cancer Research (2025)

Abstract Breast cancer (BC) is a heterogeneous disease both at the molecular and clinical level. Worldwide, BC is the leading cause of cancer-related deaths in women. Besides conventional chemo/radio therapy, immunotherapy is one of the most promising choices for a small subset of responding individuals. However, these treatments often fail to prevent recurrence and metastasis. Disease heterogeneity in BC poses challenges for survival prediction, as patients with similar diagnoses often respond differently to treatment. In this study, we apply multiplexed spatial proteomics analysis on breast cancer tissue paired with normal tissue and observe multiple immune cell types and biomarkers that could provide insight into features of the tumor microenvironment (TME) that influence response to immunotherapy. Our findings show that systematic mapping of the TME by multiplexed spatial proteomics, could empower precision immuno-oncology. The Cell DIVE Multiplex Imaging Solution allows probing and imaging of dozens of biomarkers on a whole single tissue section with an iterative staining and dye inactivation workflow. At its core, Cell DIVE is a precise and adaptable open multiplexing solution that enables flexibility in antibody selection of biomarker panels used in a multiplexed imaging study. Cell Signaling Technology (CST) has a broad portfolio of IHC-validated antibodies to detect key proteins in the TME, enabling immune cell detection and phenotyping in tissue. CST offers off the shelf (OTS), ready-to-ship antibody conjugates that have been verified to work on Cell DIVE. CST employs a rigorous approach to IHC validation, followed by verification on the Cell DIVE platform to ensure successful detection of proteins. Here, we demonstrate multiplexed Cell DIVE imaging using a novel panel of dozens of CST biomarkers across human breast cancer tissue samples. In summary, multiplexed whole slide imaging using validated antibodies and Aivia, AI-based image processing software enables spatially resolved tissue analysis of the tumor microenvironment. Citation Format: Arindam Bose, Emily Quann Alonzo, Sophie Struble, Jeremy Fisher, Richard A. Heil-Chapdelaine, Natasha F. Diaz Granados, Vasundhara Agrawal. Multiplex spatial bioimaging and AI-based image analysis for precision cancer therapeutics [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 2086.
Abstract 1715: Novel patient-derived organoids (PDOs) models for studying HER2-positive endometrial cancer
Authors: Natalia Bednarek, Anh Q. Nguyen, Julieta Barroeta, Benedikt Nagele, Subin Myong, Katherine Kurnit, Diane Yamada, Gini Fleming, Sridevi Challa
Journal: Cancer Research (2025)

Abstract Endometrial carcinoma (EC) is the most common cancer of the reproductive organs in women with 66, 200 new cases and 13, 030 deaths in United States in 2023. Recent clinical trials are evaluating the use of antibody-drug conjugates (ADCs), such as trastuzumab-deruxtecan (T-Dxd) for the treatment of solid tumors, including EC. T-Dxd consists of anti-HER2 antibody (trastuzumab) and topoisomerase I inhibitor (deruxtecan). The mechanism of action of T-Dxd involves the HER2-directed cytotoxic effect induced by deruxtecan, as well as the bystander killing effect when deruxtecan is released into neighboring cells. This dual mode of action makes T-Dxd a suitable candidate for the treatment of both HER2-high and HER2-low cancers. Patient-derived organoids (PDOs) have emerged as models for studying tumor biology and screening for new drugs. As opposed to regular 2D cultures, organoids provide a more accurate representation of the key features and therapeutic response of patient tumors. The primary goal of our project is to generate endometrial cancer PDOs to test the efficacy of new combination treatments including T-DXd. We have successfully generated several organoid lines from endometrioid and clear cell cancer tissues using patient samples obtained from surgeries. Established organoids were submitted for pathological review and genetic testing which demonstrated that tissue morphology and genetic alterations of PDOs strongly correlate with patient tumors. Immunohistochemical analysis has shown that T-DXd treatment of the organoids causes a decrease in HER2 levels and an increase in pERK1/2 levels. We also treated the HER2-positive organoids with the combination of T-DXd and MEK inhibitors and monitored changes in growth. We observed decreased growth of organoids after combination treatment compared to untreated control. In conclusion, we successfully generated PDOs models of endometrial tumors and confirmed the response to single-agent and combination treatments. Obtained organoid lines can be further utilized to study tumor biology and test new combinations of drugs. Citation Format: Natalia Bednarek, Anh Q. Nguyen, Julieta Barroeta, Benedikt Nagele, Subin Myong, Katherine Kurnit, Diane Yamada, Gini Fleming, Sridevi Challa. Novel patient-derived organoids (PDOs) models for studying HER2-positive endometrial 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 1715.
Abstract 5153: Synergistic efficacy of PARP and DNMT inhibition in ATM and CHEK2 CRISP-engineered in vitro and in vivo models
Authors: Fateme Karimi Dermani, Sibapriya Chaudhuri, Luika Timmerman, Scott Thomas, Pamela Munster
Journal: Cancer Research (2025)

Introduction: More than a decade of work has demonstrated the benefit of using poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with BRCA1 and BRCA2 mutant tumors, based on their compromised ability to repair DNA damage by homologous recombination (HRD). While the benefits of PARPi monotherapy can be limited, our laboratory is working to identify co-therapeutics to improve therapeutic efficacy. Homologous recombination requires the function of many other proteins besides BRCA1 and BRCA2, and PARP sensitivity of tumors with these mutations has not been well explored. Of particular interest are tumors with mutations in the ATM and CHK2 proteins. Here in preclinical studies, we explore the sensitivity of these mutants to PARP directed therapeutics, and to our current therapeutic combination with a DNA methyltransferase inhibitor (DNMT1; decitabine) that we now have in Phase 1 clinical trials. We hypothesize that tumors with pathogenic ATM and CHK2 mutations may also show PARP inhibitor sensitivity, which might also be potentiated in combination with decitabine. Methods: To test this hypothesis, we generated inducible RNA knockdown variants of the HR proficient triple negative breast cancer cell line MDA-MB-231, targeting ATM and Chek2 transcripts under doxycycline control via dCAS9 technology. Responses to the PARP inhibitor talazoparib, with and without decitabine were assessed with and without doxycycline induction. We evaluated colony formation, cell death, cell cycle fraction alterations, DNA damage and measured PARP1-DNMT1 adduct formation using proximity ligation assays. Results: Preliminary findings show that the combination of talazoparib and decitabine resulted in greater synergistic efficacy at lower doses than talazoparib alone. In the ATM dCas9, and CHEK2 dCas9 cell lines, the combined treatment led to substantial DNA damage, prolonged trapping of PARP1-DNMT1 complexes on DNA, and significant induction of cell death. Accordingly, potent growth inhibition was also seen in xenografts models with clinically relevant ATM and CHEK2 mutations. Conclusion: These results support further investigation into the combined use of PARP and DNMT inhibitors in tumors with these mutations. The synergistic effects observed in the MDA-MB231-derived models suggest that this combination could provide a more effective treatment option for HRD cancers, particularly in overcoming resistance to PARPi monotherapy. Citation Format: Fateme Karimi Dermani, Sibapriya Chaudhuri, Luika Timmerman, Scott Thomas, Pamela Munster. Synergistic efficacy of PARP and DNMT inhibition in ATM and CHEK2 CRISP-engineered in vitro and in vivo 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 5153.
Abstract 5215: IL-17RA expression by NSCLC is vital for restraining homeostatic tumor cell proliferation and baseline cytokine production
Authors: Dongpu Li, Jun Wang
Journal: Cancer Research (2025)

Abstract Background: Lung cancer is the leading cause of cancer-related death worldwide. The Cancer Genome Atlas shows over 30% of non-small cell lung cancer (NSCLC) samples carrying genetic alterations in the IL17RA gene, and deletion of IL17RA is linked to poor overall survival rates. IL17RA is a transmembrane protein with multiple intracellular signaling motifs. The SEFIR domain is required for IL17-induced signaling, which is negatively regulated by A20 (TNFAIP3) via a self-feedback loop. The objective of our study is to examine the impact of IL17RA-deletion in NSCLC and the underlying molecular mechanisms. Methods: Two complementary approaches were used in our study. IL17RA knockdown subclones were created in murine lung cancer cell lines (LLC and CMT167) via shRNA. Human NCIH23 cells carry homozygous deletion of IL17RA gene, whereas human A549 cells possess normal copy number of IL17RAgene. We expressed IL17RA in both human cell lines via a lentiviral vector. The effects of IL17RA expression on the tumor cell proliferation and the production of soluble mediators were compared in paired cell lines, with and without IL17RA expression. Domain-specific IL17RA mutants were constructed in NCIH23 cells to dissect their functional contributions. Western blots and human phosphorylation pathway profiling arrays were used to study how signaling pathways were affected by IL17RA-deletion. Results: The knockdown of IL17RA significantly augmented the proliferation of cancer cells in LLC and CMT167 cells. Conversely, the expression of full-length IL17RA in both NCIH23 and A549 cells diminished proliferation rates. Furthermore, IL17RA knockdown increased the production of multiple proinflammatory cytokines, chemokines, and growth factors, whereas IL17RA expression in NCIH23 markedly inhibited their production. We showed that the SEFIR domain was not required for the effects of IL17RA expression on restraining tumor cell proliferation, while it is known to be vital for IL17A-induced cytokine production. The reduced expression of IL17RA was consistently associated with diminished A20 expression in all tested cell lines. Finally, we demonstrate that IL17RA-deletion caused a marked increase of Glycogen synthase kinase 3 beta (GSK3β) Serine-9 phosphorylation, an inactivated form of GSK3β, in NCIH23 cells. Conclusion: Collectively, our data clearly demonstrate that IL17RA expression is critically required for restraining homeostatic tumor cell proliferation and baseline cytokine production via a previously undefined IL17RA-A20-GSK3β axis. Citation Format: Dongpu Li, Jun Wang. IL-17RA expression by NSCLC is vital for restraining homeostatic tumor cell proliferation and baseline cytokine production [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 5215.
Abstract 5242: YTHDF2 is a radiotherapy checkpoint in dendritic cells
Authors: Dapeng Chen, Hua Liang, Ralph Weichselbaum
Journal: Cancer Research (2025)

Abstract Dendritic cells (DCs) play a central role for initiating anti-tumor immunity of T cells in radiotherapy (RT), yet its generalized success to cancer RT has been hampered by insufficient antigen presentation and induction of suppressive regulators from tumor microenvironment. Here, we reveal that ionized radiation (IR) induces the expression of m6A reader YTHDF2 in DCs with clinical significance, and the depletion of Ythdf2 in DCs augments the anti-tumor effect of RT. We observed that following IR, SPI-1 promotes the transcription of YTHDF2 in DCs. The IR-induced YTHDF2 in DCs directly targets and degrades m6A-binded Mfng, Aph-1b, and Aph-1c, which are essential for notch activation. YTHDF2 blockades in DCs activates notch signaling to promote the expression of MHC-I family gene Gm8909, thus enhancing cross-priming of CD8+ T cells to afford amplified anti-tumor effect of RT. Pharmacological inhibition of YTHDF2 in DC vaccines contributes to RT efficacy in both local tumor control and distant metastasis suppression. Our findings identify IR-induced YTHDF2 as an immunosuppressor in DCs, reveal the mechanism for regulating anti-tumor immunity, and open a new path for the development of m6A-mRNA targeting therapies Citation Format: Dapeng Chen, Hua Liang, Ralph Weichselbaum. YTHDF2 is a radiotherapy checkpoint in dendritic cells [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 5242.
Abstract 1767: Discovery of novel STING allosteric activators for targeted cancer immunotherapy
Authors: Jeehee Lee, Eunsu Kim, Soo Yeon Baek, Wonjin Park, Jeeyoung Lee, Ye Seul Kim, Eunha Kim, Sanghee Lee
Journal: Cancer Research (2025)

Abstract The Stimulator of Interferon Genes (STING) serves as a pivotal regulator of innate immunity, but the therapeutic modulation of this pathway poses a risk of triggering hyperimmune responses. To address this challenge, our study explores a natural STING agonist (cGAMP)-dependent STING allosteric activator as a potential solution. This novel allosteric activator demonstrates synergistic efficacy specifically under the low cGAMP conditions across various rodent and human cell lines. The compound induces structural modification in STING, enhancing its sensitivity to minimal cGAMP levels and thereby elevating type-1 interferon production. In vivo studies reveal that the compound enhances type I interferon induction, promotes a shift from innate to adaptive immune responses, and increases lymphocyte infiltration into tumors, leading to significant tumor regression with tumor-specific immune memory in a mouse model. In addition, co-administration with an immune check point inhibitor markedly enhances immuno-oncological efficacy. These findings underscore the potential of allosteric STING activators to expand the therapeutic index of cancer immunotherapy, offering new insights into the development of safer and more effective agents in cancer immunotherapy. Citation Format: Jeehee Lee, Eunsu Kim, Soo Yeon Baek, Wonjin Park, Jeeyoung Lee, Ye Seul Kim, Eunha Kim, Sanghee Lee. Discovery of novel STING allosteric activators for targeted cancer immunotherapy [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 1767.
Abstract 2993: Loss of p53 sensitizes cancer cells to oxidative phosphorylation agonism
Authors: Jianhuang Lin, Dimitra Georgopoulou, Shuzhen Wu, Svaty Sachania, Rebecca Saunders, Biju Mangatt, Geeta Sharma, Euan Stronach, Anthony Mazurek, Fiona M. Behan, Benjamin Schwartz, Brendan A. Veeneman
Journal: Cancer Research (2025)

Abstract Large scale efforts using CRISPR based gene loss-of-function screens have produced comprehensive catalogs of gene essentiality in hundreds of well annotated cancer models. The equivalent catalogs have not been generated for gene gain-of-function. While loss-of-function (LOF) mutations in TP53 are frequent in cancer, targeting these mutations pharmaceutically remains challenging. To explore synthetic lethalities with p53 LOF we performed genome-wide CRISPR activation screens in wildtype and TP53 knockout isogenic cancer cell lines. We discovered a cluster of genes associated with oxidative phosphorylation (OxPhos) whose overexpression were synthetic lethal with p53 loss. This is consistent with the literature describing a metabolic switch from OxPhos to glycolysis after p53 mutation/loss. Our screen results suggest that this metabolic switch could be a protective action for cancer cells with mutant p53 if OxPhos activation is synthetic lethal with functional p53 deficiency. Indeed we found that overexpression of two of the top OxPhos gene hits from the screen, namely ADCK3 and SCO2, were synthetic lethal with p53 loss in vitro. Moreover, overexpression of ADCK3 resulted in significant growth inhibition of tumors with p53 loss in vivo. Mechanistically, overexpression of either ADCK3 or SCO2 significantly induced cellular ROS production and mitochondrial DNA damage in cancer cells with p53 loss. Our results suggest a model that wildtype p53 is important for maintaining the homeostasis between OxPhos and glycolysis. In the absence of p53 cells cannot tolerate the ROS generated by OxPhos and they switch to glycolytic metabolism. Our results are consistent with the model that hyperactivation of ADCK3, a critical component for electron transport chain, results in an increase in OxPhos and subsequently ROS which in the context of p53 deficient cells is lethal. Similar to p53 deficient cells, cancer cells with hotspot TP53 mutations have been reported to undergo a similar OxPhos to glycolysis metabolic shift and are deficient in the repair of mitochondrial DNA damage caused by OxPhos generated ROS. Our results support that an ADCK3 agonist therapeutic could be an effective strategy to target mutant p53 cancers. Citation Format: Jianhuang Lin, Dimitra Georgopoulou, Shuzhen Wu, Svaty Sachania, Rebecca Saunders, Biju Mangatt, Geeta Sharma, Euan Stronach, Anthony Mazurek, Fiona M. Behan, Benjamin Schwartz, Brendan A. Veeneman. Loss of p53 sensitizes cancer cells to oxidative phosphorylation agonism [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 2993.
Abstract 1417: Defining the mechanism of androgen receptor activation by ABI1
Authors: Kevin Mengen Lin, David M. Solano, Baylee Porter-Hansen, Xiang Li, Leszek Kotula
Journal: Cancer Research (2025)

Abstract Prostate cancer is the most common non-skin cancer among men worldwide and the second leading cause of cancer-related deaths. Prostate tumor development is driven by androgen receptor (AR) signaling, and while early-stage prostate cancer responds well to anti-androgen therapies, resistance frequently emerges. This resistance often involves aberrant reactivation of AR signaling, underscoring the critical need for a deeper understanding of AR regulation to inform new therapeutic strategies.AR activation is mediated by the intrinsically disordered N-terminal domain (NTD), which contains several proline-rich (PXXP) motifs that serve as consensus sequences for SH3 domain binding. Our previous work identified Abelson-interactor 1 (ABI1) as a novel AR-binding protein via ABI1's SH3 domain. ABI1, a key regulator of the actin cytoskeleton as part of the WAVE complex, exhibits dysregulated expression during prostate cancer progression. We hypothesize that ABI1 regulates AR, and its splice variant AR-V7, through multivalent interactions between ABI1's SH3 domain and PXXP motifs in the AR NTD. To investigate this, we used purified AR PXXP peptides and ABI1-SH3 probes in far-western blotting assays, demonstrating that ABI1-SH3 preferentially binds to two of the seven canonical PXXP motifs within AR-NTD. In vivo studies with AR NTD-truncation mutants further confirmed that ABI1 regulates AR activity through these interactions. These findings position ABI1 as a regulator of AR activity, potentially linking AR dysregulation with cytoskeletal reorganization and cancer cell metastasis. This work enhances our understanding of ABI1's role in AR-driven tumorigenesis and provides a foundation for future studies aimed at targeting ABI1-AR interactions to develop novel therapies for advanced prostate cancer. Citation Format: Kevin Mengen Lin, David M. Solano, Baylee Porter-Hansen, Xiang Li, Leszek Kotula. Defining the mechanism of androgen receptor activation by ABI1 [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 1417.
Abstract 4738: Androgen regulation of HER3 in prostate cancer differs by duration of treatment
Authors: Reem Belal Zalloum, Robert A. Holt, John Smetana, Candice Loitz, Lillian Perez, Larisa Nonn
Journal: Cancer Research (2025)

Abstract Background: Prostate cancer (PCa) is the second most common cause of cancer-related death in men and occurs in 1 out of every 8 men. Normal prostate and PCa are responsive to androgens. The interplay between androgens and the ERBB3/HER3 receptor tyrosine kinase has recently been shown to differ by race. ERBB3 was higher in Black/African American patients and correlated with the androgen response pathway despite stable expression of the androgen receptor (AR) transcript. HER3 protein expression was negatively correlated with intraprostatic androgen in Black/African American men. Here we examined the effects of androgen dose and treatment duration on the HER3 pathway in vitro. Methods: Three PCa cell lines were used; MDA-PCa-2b, derived from an African American patient bone metastasis, LNCaP and LaPC4 derived from white patient lymph nodes. Cells were treated for 48h or 6 months with low or high dose R1881 (synthetic androgen). Endpoints include proliferation (Incucyte), gene expression (RT-qPCR), and protein levels (Western blot). Neuregulin (NRG1) was used to stimulate the HER3 pathway. Results: PCa treated for 48h with R1881 showed a biphasic effect on proliferation, whereas those treated for 6 months showed a dose-dependent increase. HER3 protein levels were increased after 48h of R1881 but decreased during the 6-month exposure. NRG1 treatment slightly increased cell proliferation. Ongoing experiments will examine NRG1 signaling in the R1881-treated cell lines. Conclusions: The crosstalk between the HER3 pathway and androgens, two key pathways known to drive aggressive prostate cancer, has been shown to play a more pronounced role in PCa in African American men compared to their White counterparts. Moreover, short-term exposures in vitro may not mimic the effects of androgens in vivo. Citation Format: Reem Belal Zalloum, Robert A. Holt, John Smetana, Candice Loitz, Lillian Perez, Larisa Nonn. Androgen regulation of HER3 in prostate cancer differs by duration of 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 4738.