tbuckley/cabot-search huggingface dataset:
Abstract 1449: The MAPK pathway regulates cellular identity in lung and pancreatic adenocarcinoma
Authors: Sydney N. Larsen, Walter Orellana, Katherine Gillis, Eric Snyder
Journal: Cancer Research (2025)

Abstract Recently published data from our lab indicates that downstream signaling from oncogenic KRAS can alter the differentiation state of NKX2-1-negative lung adenocarcinoma (LUAD), a subtype of lung cancer with a foregut-like identity similar to classical pancreatic ductal adenocarcinoma (PDAC). In NKX2-1-negative LUAD, inhibition of the MAPK pathway induces a FoxA1/2-dependent lineage switch marked by the down regulation of gastric surface mucosal epithelium markers and induction of genes associated with zymogenic chief cells of the stomach. We used a pharmacological approach to investigate whether MEK/ERK signaling regulates the differentiation state of classical PDAC. Treatment of murine PDAC organoid lines with a MEK inhibitor led to the induction of zymogenic chief cell markers. Further analyses showed that the deletion of either Foxa1/2 or Hnf4α blocked the induction of chief cell transcripts in response to MEK inhibition. Moreover, exogenous expression of FoxA1/2 revealed that the expression of FoxA1/2 alone was sufficient to rescue MEK inhibitor-induced chief cell programming in genetically FoxA1/2-null organoids. This prompted the hypothesis that the genomic localization and activity of FoxA1/2 and HNF4α are regulated by MAPK signaling in PDAC. To elucidate the mechanisms by which FoxA1/2 and HNF4α activate the zymogenic chief cell program in PDAC in response to MAPK pathway inhibition, we treated KRAS-driven, P53-null murine PDAC organoids with various MEK inhibitors. We then performed ChIP-seq for FoxA1/2 and HNF4α on these organoid lines with pharmacological MEK/ERK manipulation to determine whether MEK/ERK activity modulates binding FoxA1/2 and HNF4α to zymogenic chief targets, facilitating this lineage switch. The evaluation of FoxA1/2 binding patterns and differential binding analysis revealed no direct binding of FoxA1/2 and chief cell targets of interest in these PDAC organoids upon MEK/ERK inhibition. This suggests that the induction of the chief cell lineage switch may not be directly orchestrated by FoxA1/2 relocalization but by alternative methods. We are currently investigating potential indirect mechanisms by which FoxA1/2 and HNF4α induce this lineage switch using ChIP-seq and ATAC-seq. Citation Format: Sydney N. Larsen, Walter Orellana, Katherine Gillis, Eric Snyder. The MAPK pathway regulates cellular identity in lung and pancreatic adenocarcinoma [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 1449.
Abstract 2119: Targeting KIT in chromophobe renal cell carcinoma
Authors: Michel Alchoueiry, Hadi Mansour, Damir Khabibullin, Tiegang Han, Saireudee Chaturantabut, Jessica F. Williams, Michelle S. Hirsch, Carmen Priolo, William R. Sellers, Elizabeth P. Henske
Journal: Cancer Research (2025)

Background: Chromophobe renal cell carcinoma (ChRCC) arises from the specialized intercalated cells of the distal nephron. There are no proven therapies for patients with metastatic ChRCC. In the metastatic setting median survival is estimated to be 27 months. KIT (CD117) is a membrane-associated tyrosine kinase receptor. Binding of the ligand stem cell factor (SCF) to KIT results in kinase activation and internalization. Antibody-drug conjugates (ADC) targeting KIT were previously found to be effective in preclinical models and safe in primates, but have not been tested in ChRCC. Results: In The Cancer Genome Atlas (TCGA), KIT (CD117) mRNA expression is higher in ChRCC than any other tumor type with the mean expression 12 times higher than matched normal kidney. In contrast, in clear cell RCC (ccRCC), KIT (CD117) is 5 times lower than matched normal kidney. Immunohistochemistry demonstrates KIT protein expression on the membrane of ChRCC tumor cells. Of the 14 metastatic ChRCC specimens stained for KIT at our institution, 85% (12) were positive. In the TCGA, mRNA levels of SCF (KITLG), the KIT ligand, in ChRCC are the second highest compared to other tumors, and in published single-cell RNA sequencing data, KIT and SCF are co-expressed in ChRCC tumor cells. We found that KIT (CD117) mRNA expression is significantly higher in ChRCC-derived cells compared to ccRCC-derived cells and HK cells (derived from normal human kidney). Western blot analysis confirmed KIT expression in five ChRCC cell lines. Despite the high KIT expression, knockdown of KIT or treatment with Imatinib, a tyrosine kinase inhibitor that targets KIT, did not decrease the proliferation of ChRCC-derived cells. This indicates that KIT is not driving the proliferation of ChRCC cells. LOP628 is a KIT ADC consisting of the anti-KIT antibody LMJ729 conjugated to the microtubule destabilizing maytansinoid DM1. The two ChRCC cell lines with the highest expression of KIT (RCJ T1 and RCJT2) and ccRCC-derived 786-0 cells (with low KIT expression, as a control) were treated with 20nM of LOP628 for 24 hours. LOP628 decreased the viability of the ChRCC-derived cells by ∼60% with no effect on the ccRCC cells. Conclusions: KIT and its ligand SCF are highly expressed by ChRCC cells and LOP628, a KIT ADC, decreases ChRCC cell proliferation. Citation Format: Michel Alchoueiry, Hadi Mansour, Damir Khabibullin, Tiegang Han, Saireudee Chaturantabut, Jessica F. Williams, Michelle S. Hirsch, Carmen Priolo, William R. Sellers, Elizabeth P. Henske. Targeting KIT in chromophobe renal cell carcinoma [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 2119.
Abstract 595: CMOS sensor-based micro-dosimetry for radiation theranostics: A novel approach
Authors: Rao V. Papineni, Prem Saganti, Huichen Wang, M Rahman
Journal: Cancer Research (2025)

CMOS Sensor based micro-dosimetry allowing measuring radiation tracks at micron level by the track structure detector (TSD) have been established by us with 1.67 micron / pixel resolution. In radiation theranostics, individual organ dosimetry is critical for predicting absorbed doses to normal organs and target tissue in terms of therapeutic efficacy and toxicity reduction with radiopharmaceutical therapy. We designed and applied our well characterized micro dosimetry system utilizing a CMOS (complementary metal oxide)-based radiation Track Structure Detector (TSD) device to analyze radiation quality and quantity from different forms of radiation and radiopharmaceutical drugs. The TSD system allowed capturing and analyzing heavy ion tracks at cellular dimensions with a 1.67 microns per pixel resolution and more than 10 M pixels on a 0.6 cm x 0.4 cm sensor. Further towards individualized radiopharmaceutical treated patients, we propose Integrated Wearable Micro Dosimetry for Remote Monitoring-VASTRA. Here, we demonstrate the capability to objectively detect, measure, and spatially resolve the imaging radiation activity of radiopharmaceutical therapeutic radionuclides including 18F-FDG, TC99m and validates the VASTRA in a smart phantom. Consequently, the approach is capable to measure patient-specific temporal activity data in radiopharmaceutical therapy. As an integrated ergonomical wearable dosimetry, VASTRA in Post cancer treatment, has unique opportunities and a profound impact on the quality assurance in the cancer treatment. Citation Format: Rao V. Papineni, Prem Saganti, Huichen Wang, Rahman M. CMOS sensor-based micro-dosimetry for radiation theranostics: A novel approach [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 595.
Abstract 1478: A novel HK2 inhibitor HIC-29 exhibits synthetic lethality with PARP inhibitors in ovarian cancer
Authors: Xiu Shi
Journal: Cancer Research (2025)

Abstract Purpose: In this study, we developed a novel HK2 inhibitor, HIC-29, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. Methods: The HK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 50 candidate compounds were tested for their interaction with HK2 and downstream substrates, CHK2-pS19 . HIC-29 emerged as the most promising drug candidate and was further evaluated using multiple assays. Results: HIC-29 exhibited selective and potent inhibition of HK2. The IC50 of HIC-29 correlated inversely with endogenous HK2 expression in ovarian cancer cell lines. Treatment with HIC-29 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, HK2 knockdown and HIC-29 treatment reduced CHK2 phosphorylation at Ser19, impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of HK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by HIC-29 in ovarian cancer. Conclusions: HIC-29, a novel HK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with CHK2-mediated DNA HR repair. Furthermore, HIC-29 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients. Citation Format: Xiu Shi. A novel HK2 inhibitor HIC-29 exhibits synthetic lethality with PARP inhibitors in ovarian 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 1478.
Abstract 3541: A novel chimeric RNA as a source of neoantigens in CRC
Authors: Sarah A. Lynch, Amanda M. Lulu, Samir Lalani, Justin Elfman, Craig L. Slingluff, Hui Li
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) is the second-leading cause of cancer-related death worldwide, affecting over 100, 000 men and women in the United States every year. There is an unmet need for early biomarker discovery and the identification of novel therapeutic targets in CRC. Chimeric RNAs and their protein products are well-established as ideal biomarkers and drug targets for malignant cancers. Additionally, cancer-specific fusion proteins present attractive targets for neoantigen vaccines. Using RNA-seq from The Cancer Genome Atlas (TCGA) database, we have identified a chimeric RNA prevalent in approximately 50% of CRC samples, but absent in non-cancer colon tissue. This transcript correlates with worse overall survival, is expressed as early as stage I CRC, and is present in both microsatellite stable and instable disease. This chimeric RNA arises from readthrough transcription and cis-splicing between adjacent genes, producing a previously unidentified chimeric protein. Importantly, this protein includes a splice variant of the 5’ gene, leading to a frameshift in the 3’ gene and resulting in a novel 101 amino acid peptide sequence. This sequence is not detected by mass spectrometry in any healthy tissue but is present in multiple CRC cases within the Clinical Proteome Tumor Analysis Consortium (CPTAC) data portal. Using an antibody generated against the frameshift sequence, we have confirmed this protein is expressed in patient CRC samples, regardless of disease stage, sex, age, race, or microsatellite instability status. Finally, we have demonstrated that T cells from healthy donors and patients with CRC exhibit activation following co-culture with autologous dendritic cells pulsed with peptides derived from this protein. Additionally, these T cells display cytotoxicity against HLA-matched CRC cell lines. These findings highlight the potential of chimeric RNAs and their protein products as both biomarkers and therapeutic targets, presenting a previously unexplored class of tumor antigens as an innovative strategy for improving patient outcomes. Citation Format: Sarah A. Lynch, Amanda M. Lulu, Samir Lalani, Justin Elfman, Craig L. Slingluff, Hui Li. A novel chimeric RNA as a source of neoantigens in CRC [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 3541.
Abstract 1150: Fluorescent dCFPyL (GUL-Cy5) for detecting circulating tumor and immune cells containing cancer extracellular vesicles in early metastatic prostate cancer prognostication
Authors: Omar Alawamry, Shuyang Feng, Minzhi Sheng, John Hayward, Kristen Cimolai, John F. Trant, Nesan Bandali, Bianca L. Tiglao, Urban Emmenegger, Stanley Liu, Hon S. Leong
Journal: Cancer Research (2025)

Abstract Introduction: Circulating tumor cell (CTCs) liquid biopsies for metastatic prostate cancer are in need of clinically relevant biomarkers. We propose using the GUL probe (GUL-Cy5), which is already used in PSMA PET imaging. Additionally, we synthesized an isotype for GUL-Cy5, called tBu-Cy5, to quantitate non-specific binding. To validate GUL-Cy5, we used a commercial antibody specific for PSMA. These reagents were utilized with imaging flow cytometry (imFC) to characterize the probes (GUL-Cy5 and anti-PSMA mAb) and their distribution on CTCs and in immune cells. Methods: Metastatic prostate cancer (mPCa) whole blood samples were processed using the density isolation medium Ficoll-Paque to isolate PBMCs and CTCs. The isolated samples were stained with DAPI for nucleus staining, CD45 as a marker for immune cells, EpCAM as a lead marker for CTCs, GUL-Cy5 for PSMA, and a commercial antibody specific for PSMA. Imaging software for visualizing probe binding patterns to define several subclasses of CTCs and immune cells containing cancer extracellular vesicles was used. Results: CTCs were successfully detected in mPCa patient samples and classified into various subclasses based on combinations of EpCAM, GUL, and PSMA biomarkers. Notably, events positive for desired markers and those specific to prostate markers were observed. The GUL signal pattern was primarily cytoplasmic, and similar to the signal from anti-PSMA mAbs. Surprisingly, a large proportion of CD45+ve events contained PSMA punctuate signal representing cancer EVs. Conclusion: GUL-Cy5 shows promise as a next-generation probe for PSMA in liquid biopsies. Imaging flow cytometry effectively detects and characterizes CTCs and immune cells that contain cancer EVs, allowing investigators to gain insights into their biology, providing a powerful tool for cancer research and future oncology applications. Citation Format: Omar Alawamry, Shuyang Feng, Minzhi Sheng, John Hayward, Kristen Cimolai, John F. Trant, Nesan Bandali, Bianca L. Tiglao, Urban Emmenegger, Stanley Liu, Hon S. Leong. Fluorescent dCFPyL (GUL-Cy5) for detecting circulating tumor and immune cells containing cancer extracellular vesicles in early metastatic prostate cancer prognostication [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 1150.
Abstract 600: Targeting STAT pathways with oridonin derivatives to suppress triple negative breast cancer
Authors: Gabrielle Vontz, Jun Li, Zhipin Liang, Jia Zhou, Qiang Shen
Journal: Cancer Research (2025)

Abstract Breast cancer remains the most common cancer type and second leading cause of cancer related deaths among women in the U.S. Despite progress in detection, surveillance, and targeted therapies, aggressive subtypes like triple-negative breast cancer (TNBC), along with challenges such as drug resistance and disease recurrence, remain significant clinical hurdles. To address these unmet needs in TNBC treatment, our group has developed a series of oridonin-derived analogs (oridonalogs), including CYD0618. These analogs exhibit enhanced drug-like properties and significantly improved potency against various cancers in both in vitro and in vivo models. This study aims to characterize the mechanism of action of CYD0618 against TNBC cells. Our findings demonstrate that CYD0618 effectively reduces the proliferation of TNBC cells in vitro with IC50s at the nanomolar level. Additionally, CYD0618 exhibits high potency against TNBC in vivo, significantly suppressing tumor growth and prolonging survival in a xenograft mouse model. Preliminary results reveal that CYD0618 inhibits activation of STAT3, a key transcription factor involved in proliferation, survival, and transformation of epithelial cells. Given that STAT3 is constitutively active in ∼70% of human cancers, there has been a tremendous effort to develop STAT3 targeting therapies; however, none have achieved FDA approval. In addition to STAT3, our study shows that CYD0618 also suppresses other STAT family transcription factors. Compared to selective STAT3 degradation by PROTAC treatment, poly-STAT targeting by CYD0618 exhibits superior activity against TNBC cells. These findings identify CYD0618 as a novel poly-STAT inhibitor with promising activity against TNBC. Citation Format: Gabrielle Vontz,Jun Li,Zhipin Liang,Jia Zhou,Qiang Shen. Targeting STAT pathways with oridonin derivatives to suppress triple negative 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 600.
Abstract 902: Examining the impact of chromosome 1q-located gamma secretase subunits in the resistance to BCMA-targeted therapies in multiple myeloma patients
Authors: Sejal Chikhale, Mansour Poorebrahim, Holly Lee, Elham Hasheminasabgorji, Anja Barbour, David Jung, Paola Neri, Nizar J. Bahlis
Journal: Cancer Research (2025)

Abstract Multiple Myeloma (MM) is an incurable hematological malignancy originating from abnormal plasma cells in the bone marrow. A common genetic abnormality in MM is the gain or amplification of chromosome arm 1q (chr1q), present in 30-40% of MM patients and typically associated with poor prognosis. Chr1q includes three subunits of the gamma-secretase (GS) enzyme- Nicastrin (NCSTN), Presenilin-2 (PS2), and Anterior Pharynx Defective 1 Homolog A (APH1A)—which catalyze the conversion of membrane-bound BCMA (mBCMA) to soluble BCMA (sBCMA). BCMA is a crucial target receptor for anti-BCMA therapies. Elevated sBCMA levels are linked to poor prognosis and reduced efficacy of BCMA-targeted therapies, apparently due to the sink effect. We hypothesize that chr1q amplification in MM leads to increased GS expression, resulting in reduced mBCMA and elevated sBCMA levels, which may drive resistance to BCMA-targeted therapies and contribute to adverse patient outcomes. To investigate this, we employed cloning and lentiviral transduction techniques to overexpress NCSTN, PS2, and APH1A individually, as well as in various combinations, in OPM2 myeloma cell lines, generating seven novel cell lines. Each subunit was fused with distinct tags to confirm successful transduction and overexpression. Using flow cytometry with BCMA-PE antibodies and sBCMA ELISA, we assessed mBCMA and sBCMA levels across these GS subunit-overexpressing cell lines compared to an empty vector control. Our results demonstrated that all seven GS subunit-overexpressing OPM2 cell lines exhibited decreased mBCMA levels. The triple-overexpressing cell line (NCSTN, PS2, and APH1A) showed a remarkable ten-fold reduction in mBCMA compared to the control. Additionally, differences in sBCMA levels were observed across the GS subunit-overexpressing cell lines relative to the control. These findings underscore the pivotal role of GS subunits encoded by chr1q in driving the poor prognosis associated with chr1q gain or amplification in MM. Ongoing analyses aim to elucidate the resistance mechanisms of these GS subunit-overexpressing OPM2 cell lines to anti-BCMA CAR-T therapies and T-cell engagers (TCEs). Citation Format: Sejal Chikhale, Mansour Poorebrahim, Holly Lee, Elham Hasheminasabgorji, Anja Barbour, David Jung, Paola Neri, Nizar J. Bahlis. Examining the impact of chromosome 1q-located gamma secretase subunits in the resistance to BCMA-targeted therapies in multiple myeloma patients [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 902.
Abstract 953: Oncolytic viruses as in situ personalized tumor vaccines for durable efficacy
Authors: William WEI GUO Jia
Journal: Cancer Research (2025)

Tumor vaccines have shown clinical promise in treating certain cancers. However, their long-term effectiveness is often hindered by two major challenges: 1. The immune-suppressive tumor microenvironment (TME). 2. Selective targeting of antigen-positive tumor cells, which can lead to the expansion of antigen-negative cells and eventual tumor relapse. To address these challenges, we explored a combination approach using mRNA tumor vaccines and oncolytic virotherapy in HPV and HER2 mouse tumor models. Our findings reveal that while mRNA vaccines effectively eradicate antigen-positive tumors and suppress tumor growth, resistance quickly emerges, enabling tumors to evade the vaccine's effects. When mRNA vaccination was followed by intratumoral administration of an oncolytic virus—either with or without HPV or HER2 antigen expression—a significantly more durable anti-tumor response was achieved in both models. The oncolytic virus initiated broad tumor antigen presentation by lysing tumor cells, releasing diverse tumor-associated antigens, and increasing the overall antigenic load within the tumor. Furthermore, the lytic activity of the virus reprogrammed the TME, transforming it from an immune-suppressive environment into one more favorable for anti-tumor immune responses. This combination therapy elicited a potent local immune response, leveraging enhanced antigen presentation by the virus. The modified TME allowed the systemic immune response generated by the mRNA vaccine to penetrate and act effectively within the tumor. Additionally, the treatment induced systemic antigen-specific T-cell responses, and treated animals developed resistance to subsequent tumor challenges, demonstrating the establishment of immune memory. Our study highlights the unique role of oncolytic virotherapy as an intratumoral "boost" mechanism. By lysing tumor cells, oncolytic viruses amplify the range of tumor antigens presented to the immune system and reshape the TME to support robust immune activity. This synergy between mRNA vaccination and oncolytic virotherapy—when employed in a prime-boost regimen—produces a powerful and durable anti-tumor immune response that is both localized and systemically protective against recurrence. In conclusion, this research underscores the potential of combining mRNA tumor vaccines with oncolytic virotherapy to overcome immune evasion mechanisms, enhance tumor antigen presentation, and reprogram the TME, providing a promising strategy for achieving long-lasting anti-tumor immunity. Citation Format: William WEI GUO Jia. Oncolytic viruses as in situ personalized tumor vaccines for durable efficacy [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 953.