tbuckley/cabot-search huggingface dataset:
Abstract 4139: Targeting USP10 to enhance chemotherapy and immunotherapy in NSCLC
Authors: Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh, Babita Kushwaha, Prahlad Parajuli, Yubin Ge, Navnath S. Gavande
Journal: Cancer Research (2025)

Abstract Non-small cell lung cancer (NSCLC) remains a leading cause of death from cancer. While platinum-based chemotherapy is initially effective for early-stage NSCLC, drug resistance often limits its long-term success. Combining platinum-based chemotherapy with immunotherapy has emerged as a first-line treatment for metastatic NSCLC. However, many patients still experience limited benefits due to various resistance mechanisms. One critical mechanism underlying drug resistance is the increased capacity of DNA damage response (DDR). The deubiquitinase USP10 plays a crucial role in regulating the DDR by stabilizing oncogene proteins such as HDAC6. Inhibition of USP10 disrupts the USP10-HDAC6 axis, leading to enhanced DNA damage and cell death. Further, HDAC6 inhibition enhances immunogenic cell death-inducing radiotherapy-induced immune responses. Furthermore, HDAC6 inhibition leads to decreased expression of CD47 that acts as a "don't eat me" signal to prevent immune cells from phagocytosing tumor cells. Based on these findings, we hypothesize that targeting USP10 leads to HDAC6 degradation and DNA damage, resulting in sensitization of NSCLC cells to chemotherapy. Additionally, we propose that USP10 inhibition can sensitize NSCLC cells to immune checkpoint inhibitors and immunotherapy targeting CD47. Our extensive computational and structure-activity-relationship (SAR) studies led to the discovery of potent USP10 inhibitors. Our preliminary data show that the lead compound, GL-320, selectively inhibits USP10 activity, as confirmed by in vitro deubiquitinase (DUB) and cellular thermal shift assays. GL-320 dose-dependently inhibited the in vitro cell proliferation of H1299, a p53 null lung cancer cell, whereas it was significantly less effective against A549 cells with w/t p53. We also show that by inhibiting USP10, we can disrupt the DDR pathway, leading to increased DDR and cell death, as confirmed by western blotting and flow cytometry analyses. Our preliminary data show that USP 10 is a validated drug target to enhance the efficacy of existing chemotherapy and immunotherapy in NSCLC. Citation Format: Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh, Babita Kushwaha, Prahlad Parajuli, Yubin Ge, Navnath S. Gavande. Targeting USP10 to enhance chemotherapy and immunotherapy in NSCLC [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 4139.
Abstract 2066: Magnifying glass on sinonasal NUT carcinoma heterogeneity using spatial transcriptomics
Authors: Diana Bell, Garret Choby, Michelle Afkhami, Ellie Maghami, Ehab Hanna, Raja Seethala
Journal: Cancer Research (2025)

Abstract Introduction: Nuclear protein in testis (NUT) carcinomas (NCs) are clinically aggressive, with signature translocation NUTM1::BRD4 genes (70%), BRD3::NUTM1 (15%), NSD3::NUTM1 (6%). Histologically, NCs depict undifferentiated basaloid cells with squamous differentiation; broad lineage immunomarkers lack in NCs. Demonstration of translocation is imperative for NC diagnosis; NUT immunostaining is a surrogate. NC treatment faces obstacles (drug resistance, metastasis). Spatial transcriptomics (ST) technology emerged as ideal approach to elucidate cancer cell heterogeneity and spatial distributions within tissues. Methods: 3 cases of sinonasal NC carcinoma with FFPE formed the study material. Next generation sequencing confirmed NC diagnosis: BRD3::NUTM1 in NC #1, BRD4::NUTM1 in NC # 2, NC # 3. A representative region of each of NCs was subjected to 10X Genomics Visium Spatial Gene Expression analysis. Ingenuity Pathway Analysis (IPA) employed for pathways and network analyses. Resulting data were visualized/ analyzed in 10X Genomics Loupe Browser. Results: All cases demonstrated statistically distinct (graph-neural network based) transcriptomic clusters. These clusters were correlated with histologic characteristics by parsing all spots by region types based on tissue distribution including tumor, limited stroma and normal epithelium. Cluster constitution and transcriptomic pattern were consistent with the morphologic features of each tissue region. NC #3 had relatively low number of tumor clusters in comparison to NC #1, NC#2. Table 1 Table 1 Summary of results Case NC #1 NC #2 NC #3 Age (yo) 63 53 28 Sex F M M Outcome NED AWD DOD Fusion type BRD3::NUTM1 BRD4::NUTM1 BRD4::NUTM1 #Tumor Cell Clusters 5 3 1 Shared within top 100 of all 3 cases Rank NTS 28 30 9 HOXB3 41 21 10 HOXB6 59 62 21 PRSS21 55 39 38 NUTM1 48 33 49 KRT14 40 41 99 Top 10 Genes LOR, SPRR2A, DLK1, IV/involucrin, SPINK5, SPRR1B, SPINK6, SPINK7, SPRR2F, HMGCS2 SPINK6, SPINK5, CA9, CA2, EPHA7, TRPC6, GPR174, HDAC9, PIK3C2G, PTPRD OPN5, NRN1, NTS, DSG1, DSC1, NKX2-8, HOXB3, MMP12, AFP, ALB . Conclusions: Spatial transcriptomic profiling corresponds to histopathologic features in NC and yet highlights cell type diversity across tumors and in the case of NC#2, within a given tumor. Behavior correlates are speculative, but NC#3 for which the patient had a rapidly lethal outcome showed a preponderance of neural gene expression which may be of interest in tumor cell progression/ evolution. Citation Format: Diana Bell, Garret Choby, Michelle Afkhami, Ellie Maghami, Ehab Hanna, Raja Seethala. Magnifying glass on sinonasal NUT carcinoma heterogeneity using spatial transcriptomics [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 2066.
Abstract 2249: Selective degradation of Helios induces Treg cell reprogramming and enhanced antitumor immunity
Authors: Michael J. Barnes
Journal: Cancer Research (2025)

Abstract Regulatory T (Treg) cell suppression of antitumor immunity can limit responses to immunotherapy in multiple solid tumor indications. The transcription factors Helios (IKZF2) and Eos (IKZF4) are abundantly expressed by Treg cells in the tumor microenvironment and act as critical nodes in a transcriptional network that enforces a stable immunosuppressive Treg cell phenotype. In preclinical models, inducible genetic loss of Helios in Foxp3-expressing Treg cells alone or with anti-PD-1 immune checkpoint blockade yields improved or complete responses to subcutaneous MC38 tumors, respectively, highlighting Helios as a druggable target for immunotherapy. BMS-986449 is a CELMoD molecular glue that redirects the E3 ubiquitin ligase Cereblon to interact with and induce the degradation of Helios and Eos. It was optimized to induce rapid and deep degradation of Helios and Eos in primary Treg cells with selectivity over other CELMoD neosubstrates, as assessed by global proteomic analysis of primary T cells. When primary human Treg cells were cultured under activating conditions with BMS-986449, a reprogrammed transcriptional phenotype emerged by 8 days in culture, including increased protein expression of effector molecules, such as Granzyme B, and abundant expression of inflammatory gene transcripts. In tumor bearing hCRBN-KI mice, BMS-986449 daily dosing induced monotherapy activity in the CT26, MB49, and MC38 tumor models with TGI values of up to 75%, 62%, and 42%, respectively; in combination with anti-PD-1 immune checkpoint blockade more robust efficacy was achieved with TGI values of 95%, 97%, and 92%, respectively. Additionally, in cynomolgus monkeys, daily dosing of BMS-986449 (0.1 mg/kg) maintained greater than 80% degradation of Helios in circulating Treg cells, supporting the advancement of BMS-986449 into Phase 1/2 clinical trials for patients with advanced solid tumors. Citation Format: Michael J. Barnes. Selective degradation of Helios induces Treg cell reprogramming and enhanced antitumor immunity [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 2249.
Abstract 4409: Exploring PBX1's role in enzalutamide resistance in advanced prostate cancer
Authors: Ephraim J. Gardner, Surendra Gulla, Leslie McClinton, Jonathan E. Bard, Remi Adelaiye-Ogala
Journal: Cancer Research (2025)

Aggressive prostate cancer (PCa) is often driven by upscaled activity of the androgen receptor (AR), and second-generation AR antagonists such as Enzalutamide have become standard therapeutics for men with advanced PCa. While patients initially respond to treatment, many develop resistance, with disease progression and poor prognosis. We have focused on a mechanism involving an AR cistrome switch from a canonical to a non-canonical cistrome as PCa becomes Enzalutamide-resistant. As collaborating protein partners drive transcriptional activity, we employed core regulatory circuitry analysis in Enzalutamide-resistant PCa cell line models to identify novel Transcription Factor (TF) candidates that may be involved in non-canonical AR cistrome reprogramming. One identified candidate is Pre B-Cell Leukemia Homeobox 1 (PBX1), a TALE homeodomain TF involved in embryonic development and cellular differentiation. PBX1 is known to work with other TFs to modulate gene expression and has been implicated as an oncogenic driver in hematologic and solid cancers, including PCa. Our group has shown that PBX1 is highly expressed in prostate cancer cell line models of castrate- and Enzalutamide-resistance compared to Enzalutamide-sensitive models. Through multi-ome single-cell ATAC + gene expression analysis of a heterogenous patient-derived xenograft (PDX) model, we identified clusters of cells that are enriched for PBX1, AR, and non-canonical AR target CREB5, while simultaneously expressing low levels of KLK3, a prominent canonical AR target. Based on these findings, we hypothesize that PBX1 works in tandem with AR to drive non-canonical AR cistrome and mediate Enzalutamide resistance in advanced PCa. To test this hypothesis, we first determined the impact of silencing PBX1 activity in Enzalutamide-resistant PCa models. By targeting PBX1 pharmacologically in our cell lines and PDX models, we have observed an anti-proliferative effect specifically in a castration-resistant, Enzalutamide-resistant cell line model. This effect was not observed when treating an Enzalutamide-sensitive cell line model, which has low PBX1 expression. Our observations were consistent across several models and our ongoing mechanistic studies will provide further insight into PBX1’s exclusive role in Enzalutamide-resistant CRPC. In addition, we are currently assessing the impact of inhibition or perturbation of PBX1 in Enzalutamide-resistant PCa cell lines and PDX models on canonical and non-canonical AR cistrome activity using multi-omic approaches. Citation Format: Ephraim J. Gardner, Surendra Gulla, Leslie McClinton, Jonathan E. Bard, Remi Adelaiye-Ogala. Exploring PBX1's role in enzalutamide resistance in advanced prostate 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 4409.
Abstract 4412: Characterization and targeting of an androgen receptor pre-mRNA stem loop structure to inhibit AR-V7 splicing in prostate cancer
Authors: Marek D. Zorawski, James P. Falese, Riley S. Spingler, Jason A. Somarelli, Andrew J. Armstrong, Amanda E. Hargrove
Journal: Cancer Research (2025)

Abstract Alternatively spliced mRNAs can contribute to aggressiveness and resistance to androgen receptor pathway inhibitors (ARPIs) in castration-resistant prostate cancer (CRPC). Among these spliced mRNAs, the androgen receptor (AR) splice isoform AR-V7 participates in AR signaling independent of androgen levels or ARPIs, such as enzalutamide. AR-V7 detection correlates strongly with ARPI treatment resistance and poor patient outcomes in CRPC. AR-V7 incorporates cryptic exon 3 (CE3) within the AR gene that prematurely terminates the full-length transcript. While several proteins have been described that may promote splicing of CE3, the impact of the pre-mRNA structures in this region is unknown. Using selective 2′-hydroxyl acylation analyzed by primer extension with mutational profiling (SHAPE-MaP), we developed the first experimentally informed pre-mRNA secondary structure model of the CE3 3′ splice site from cellular RNA. In this structural model, we observe a novel stem loop structure, which we hypothesized could inhibit AR-V7 biogenesis. We used an AR-V7 minigene assay to evaluate structure-modulating mutations in AR-V7 biogenesis and observed concordant changes in AR-V7 abundance in response to stabilization of this repressive structure, leading us to term this structure the cryptic exon 3-splicing inhibitory stem loop (CE3-SISL). Protein binding site identification of the region through the Δ-SHAPE pipeline suggests a repressive protein interaction that may be lost in androgen independence and ARPI resistance. Together, these data suggest the importance of RNA structure in AR-V7 biogenesis and indicate a potentially targetable interface for the development of AR-V7-depleting agents, as we have exemplified using structure-guided antisense oligonucleotides (ASOs) that are able to inhibit AR-V7 splicing during enzalutamide treatment. These ASOs would represent the first RNA structure-targeted splicing modulators being developed for patients with AR-V7-driven CRPC. Citation Format: Marek D. Zorawski, James P. Falese, Riley S. Spingler, Jason A. Somarelli, Andrew J. Armstrong, Amanda E. Hargrove. Characterization and targeting of an androgen receptor pre-mRNA stem loop structure to inhibit AR-V7 splicing in prostate 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 4412.
Abstract 2863: TAVO307, a novel ADC targeting CDH17, for the therapy of gastrointestinal cancers
Authors: Guangmao Mu, Fulai Zhou, Zhengxia Zha, Sheng Huang, None Ying jin, Yuanting Chen, Mark Chiu, Di Zhang
Journal: Cancer Research (2025)

Abstract Background: Gastrointestinal (GI) cancers account for about 28% of all cancers globally, however, the treatment options remain limited partly due to the lack of appropriate cancer targets. Cadherin-17 (CDH17) is a cell adhesion membrane protein predominantly expressed at the tight junctions of intestinal epithelial cells of healthy individuals. However, the aberrant expression of CDH17 in 50-90% of GI tract tumors (including stomach, pancreas, liver/bile duct and colon cancers) is associated with poor prognosis and shorter survival of GI cancer patients. In these tumors, CDH17 interacts with α2β1 integrin to drive the proliferation, adhesion, and metastasis of tumor cells. Such overexpression of CDH17 makes it an attractive target for the developing novel treatments of GI tract cancers. Methods and Results: We discovered an anti-CDH17 antibody with high binding affinity to CDH17 with an EC50 at sub nM range. We prepared an ADC molecule loaded with the anti-mitotic toxin MMAE/MMAF via a lysosomal cleavable dipeptide linker. CDH17-ADC showed potent cytotoxicity (IC50 at sub nM level) to multiple GI and pancreatic cancer cell lines in in vitro cell cytotoxicity assays. In addition, CDH17-MMAE (DAR=4) treatment led to potent tumor growth inhibition (70% to 95% TGI) in multiple CDX and PDX pancreatic, colon, and gastric cancer xenograft models. The mice in the CDH17-MMAE treatment group maintained normal body weight throughout the treatment course without observed toxicity. Conclusions: Targeting CDH17 in GI tract cancers, our lead CDH17-MMAE molecule (TAVO307) showed potent tumor cell cytotoxicity in multiple tumor cell lines in cytotoxicity assays as well as in CDX and PDX tumor models. Further preclinical safety assessment, pharmacokinetics and IND-enabling studies are on-going with the goal to develop TAVO307 as the “best-in-class” ADC molecule for the treatment of colon, gastric, pancreatic and oesophagus cancers with significant unmet medical needs. This antibody can also be applied to alternative targeting modalities. Citation Format: Guangmao Mu, Fulai Zhou, Zhengxia Zha, Sheng Huang, Ying jin, Yuanting Chen, Mark Chiu, Di Zhang. TAVO307, a novel ADC targeting CDH17, for the therapy of gastrointestinal cancers [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 2863.
Abstract 2231: CY-101 inhibits the tumor growth and improves anti-PD-1 immunotherapy in beta-catenin-driven tumors
Authors: Margaux Poussard, Muhammad Zaeem Noman, Kris Van Moer, Jubayer Hossain, Ruize Gao, Ege Solel, Federico Grego, Lars Prestegarden, Rolf Bjerkvig, Bassam Janji
Journal: Cancer Research (2025)

Abstract CY-101 is a bi-functional peptide with a dual mechanism of action. It selectively targets cancer cell membranes, forming pores that release neoantigens to the tumor microenvironment, thereby triggering a robust anti-tumor immune response. In addition, CY-101 inhibits the oncogenic Wnt/beta-catenin signaling pathway, which is frequently dysregulated in several cancers such as colorectal carcinoma (CRC), adrenocortical carcinoma (ACC), and melanoma. Given the high prevalence of beta-catenin mutations in these tumors, targeting this pathway offers significant therapeutic potential. We show that CY-101 induces a dose-dependent cell death across mouse and human beta-catenin-driven CRC, ACC, and melanoma cell lines in vitro following suppression of the Wnt/beta-catenin pathway. In preclinical animal models, CY-101 elicited a potent anti-tumor activity by completely eradicating ACC tumors and significantly enhancing the efficacy of anti-PD-1 therapy in CRC and melanoma models. Notably, CY-101 treatment reshaped the tumor immune landscape by modulating cytokine expression, leading to increased infiltration of cytotoxic CD8+ T cells. Mechanistically, CY-101-treated tumors exhibited downregulation of Wnt/beta-catenin downstream target genes, emphasizing its role as a potent Wnt/beta-catenin inhibitor. These preclinical findings support the observations seen in the first in human CICILIA Phase 1/2a trial, which reported clinical activity in ACC and melanoma patients. Collectively, our study demonstrates the therapeutic potential of CY-101 in beta-catenin-driven tumors, both as monotherapy and in combination with anti-PD1 checkpoint inhibitors. Citation Format: Margaux Poussard, Muhammad Zaeem Noman, Kris Van Moer, Jubayer Hossain, Ruize Gao, Ege Solel, Federico Grego, Lars Prestegarden, Rolf Bjerkvig, Bassam Janji. CY-101 inhibits the tumor growth and improves anti-PD-1 immunotherapy in beta-catenin-driven 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 2231.
Abstract 2592: The osteoblastic microenvironment determines the fate of breast cancer cells disseminated in the bone marrow
Authors: Hong-Li Wang, Xiao-Min Yue, Rui Zhang, Yu-Fan Huang, Rong Meng, Xiao-Qing Li
Journal: Cancer Research (2025)

Abstract Bone is the most common destination for metastatic breast cancer cells. When cancer cells disseminate to the bone, they may either colonize or settle into a quiescent state, depending on their interaction with the bone microenvironment. In this study, we elucidated how the differentiation status of the osteoblastic microenvironment determines the fate of cancer cells disseminated in the bone marrow. We analyzed clinical survival data and demonstrated that luminal-like cancer cells with high Runt-related transcription factor 2 (RUNX2) expression exhibited an increased risk of bone metastases in breast patients. By using RUNX2-overexpressing cancer cells as bone-tropic seeds and establishing various osteoblastic microenvironments with different differentiation statuses in vitro and in vivo, we observed that both luminal-like and basal-like cancer cells remained quiescent as disseminated tumor cells (DTCs) or micrometastases within an inactive osteoblastic microenvironment. In contrast, luminal-like cancer cells colonize the bone within both nonmineralized and mineralized active osteoblastic (osteogenic) microenvironments. Basal-like cancer cells, however, remained quiescent within highly mineralized osteogenic microenvironment but colonized bone in a nonmineralized osteogenic niche rich in nonmineralized bone matrix (osteoid). In the active microenvironments, well-differentiated osteoblasts were observed to be responsible for recruiting cancer cells, whereas the nonmineralized bone matrix supported the proliferation of both luminal-like and basal-like cancer cells, with luminal-like cells gaining additional growth advantages from well-differentiated osteoblasts. Furthermore, we explored the possibility that activation of the osteoblastic microenvironment due to abnormal bone metabolism and fluctuating estrogen levels reactivate quiescent DTCs or micrometastases, leading to increased risk of bone metastasis. Additionally, in a supportive osteogenic microenvironment, both cancer cells and well-differentiated osteoblasts were found to contribute to the activation of osteoclasts, resulting in the development of osteolytic lesions. Thus, this study provides a comprehensive explanation for the divergent outcomes of disseminated cancer cells in the bone, whether they colonize the bone or become dormant, and suggests promising therapeutic strategies to block the reactivation of quiescent tumor cells. Citation Format: Hong-Li Wang, Xiao-Min Yue, Rui Zhang, Yu-Fan Huang, Rong Meng, Xiao-Qing Li. The osteoblastic microenvironment determines the fate of breast cancer cells disseminated in the bone marrow [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 2592.