tbuckley/cabot-search huggingface dataset:
Abstract 5103: Digital spatial profling with GeoMx to identify differential protein expression in Non-Hispanic/Latino and Hispanic/Latino Patients with metastatic hormone sensitive prostate cancer
Authors: Peter D. Zang, Joe Bonner, Alexander Chehrazi-Raffle, Lixin Yang, Natasha Garg, Swapnil Rajurkar, James Shen, Naveen Gupta, Amartej Merla, Sumanta Pal, Raju Pillai, Stephen Gruber, Tanya B. Dorff
Journal: Cancer Research (2025)

Background: Emerging evidence suggests that there is a complex interplay between ethnicity and disease biology in metastatic hormone sensitive prostate cancer (mHSPC). We examined digital spatial profiling with GeoMx to evaluate differential protein expression between non-Hispanic/non-Latino (NHL) and Hispanic/Latino (HL) patients with mHSPC. Methods: Pre-treatment prostate biopsy specimens were obtained from patients on a clinical trial as part of an IRB approved protocol. The GeoMx Digital Spatial Profiler (DSP) was used to evaluate protein expression in selected regions of interest (ROIs). Differential expression analysis was performed using R (v 4.4.2). To determine significant differences in protein expression, a false discovery rate (FDR)-adjusted q-value was applied and a Log2Fold change (Log2FC) with a q-value &amp;lt; 0.01 was considered significantly differentially expressed. Results: A total of 8 patients (4 NHL and 4 HL) were enrolled at City of Hope including network sites and who had pre-treatment biopsy specimens that were available for digital spatial profiling analysis. We examined the Log2FC between protein expression in NHL and HL patients and filtered for q-values &amp;lt; 0.01. We identified multiple proteins that were significantly differentially expressed. Proteins that were more highly expressed (Log2FC &amp;gt; 1) in NHL patients included CD44, fibronection, and Ki-67. Proteins that were more moderately expressed (Log2FC &amp;lt; 1) in NHL patients included beta-2 microglobulin and. In contrast, HL patients were found to have higher expression in BCL6, CD68, CD80, Foxp3, PARP, and STING (Log2FC &amp;lt; 0). Conclusions: Digital spatial profiling with GeoMx reveals significant differences in protein expression in NHL vs. HL patients with mHSPC. Notably, these include markers of cancer stem cells (CD44), DNA damage pathway proteins (PARP), and both immunoregulatory (Foxp3) and immunostimulatory (STING) proteins. This may have both prognostic and therapeutic implications. Citation Format: Peter D. Zang, Joe Bonner, Alexander Chehrazi-Raffle, Lixin Yang, Natasha Garg, Swapnil Rajurkar, James Shen, Naveen Gupta, Amartej Merla, Sumanta Pal, Raju Pillai, Stephen Gruber, Tanya B. Dorff. Digital spatial profling with GeoMx to identify differential protein expression in Non-Hispanic/Latino and Hispanic/Latino Patients with metastatic hormone sensitive 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 5103.
Abstract 4199: Defining roles of telomerase reverse transcriptase in DNA damage response
Authors: Leon L. Zhou, Stephen J. Kron
Journal: Cancer Research (2025)

Abstract Telomerase Reverse Transcriptase (TERT), the catalytic subunit of telomerase, is essential for telomere maintenance, elongating the G-strand of telomeric DNA using its associated RNA template (TR). Recruitment of TERT to telomeres is mediated by the shelterin component TPP1. While TERT is highly expressed in cancer cells, efforts to target its telomeric function have shown limited clinical efficacy. Recent studies have identified noncanonical roles for TERT, particularly in the DNA damage response (DDR), suggesting alternative therapeutic opportunities. Notably, TERT inhibitors sensitize cancer cells to radiotherapy, though the mechanisms underlying this effect remain unclear. To address this gap, we established a mutant TERT phenotyping system to study how TERT variants affect the DDR. Using a tetracycline-inducible shRNA-miR knockdown system in MCF7 and HeLa cells, we targeted endogenous TERT and complemented with transfected wildtype or mutant TERT, validating expression by Western blot. Cells expressing only transfected TERT were irradiated with 6 Gy to induce double-strand breaks (DSBs), and DDR effects were assessed by 53BP1 or γH2AX foci resolution, cell survival, and senescence onset. Knockdown of TERT led to persistent DNA damage foci, confirming a role for TERT in DSB repair. Foci resolution was restored by WT TERT but not by the catalytic mutant TERT D712A, V713I. Similarly, the TERT R132E, K78E mutant, defective in TPP1 binding, exhibited persistent foci, implicating TERT-TPP1 interactions in DDR. Supporting this, TPP1 mutants unable to bind TERT also caused persistent DNA damage foci. Combined with evidence that shelterin complexes, including TPP1, localize rapidly to nontelomeric DSBs after DNA damage, these results suggest that TPP1 recruits TERT to DSBs, analogous to its role at telomeres. Ongoing studies aim to elucidate how TERT's catalytic activity promotes DSB repair and to explore TERT as a target for sensitizing cancer cells to therapy. Citation Format: Leon L. Zhou, Stephen J. Kron. Defining roles of telomerase reverse transcriptase in DNA damage response [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 4199.
Abstract 4465: Molecular docking studies on the factors affecting histone deacetylase inhibition: Design, rigidity, and chirality of the inhibitors
Authors: Qinliang Zhao, Jacquelyn Ann Tang, Karina Artero, Audrey Huang, Rabeya Bosri
Journal: Cancer Research (2025)

Abstract Histone deacetylase (HDAC) has become one of the targets for cancer therapy since it was found overexpressed in cancer cells. New HDAC inhibitors were designed and investigated to demonstrate how the molecules interact with HDAC enzymes, using the molecular docking software ICM-Pro. Multiple families of HDAC inhibitors, derivatized from the FDA-approved HDAC inhibitors, were constructed and optimized for in silico screening. Detailed analyses of the docking results showed that the addition of an aromatic ring on the linker domain could boost or diminish the interactions of the molecules with the enzyme, depending on the location and size of the aromatic ring. The rigidity of the molecules was tuned by installing heterocyclic rings of various sizes at different positions. Molecules of specific rigidity could greatly enhance the dock scores and binding affinity, thus theoretically the enzyme inhibition. Modification of protein recognition and zinc-binding domains and chirality of the molecules were also explored to seek inhibitors for specific HDAC inhibitions. Drug candidates with the desired binding affinity and selectivity were selected for chemical synthesis and biological activity examination in the lab. Citation Format: Qinliang Zhao, Jacquelyn Ann Tang, Karina Artero, Audrey Huang, Rabeya Bosri. Molecular docking studies on the factors affecting histone deacetylase inhibition: Design, rigidity, and chirality of the inhibitors [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 4465.
Abstract 3943: SFPQ-TFE3 gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis
Authors: Kaushal V. Asrani, Adrianna Amaral, Juhyung Woo, Sanaz Abadchi, Thiago Vidotto, Kewen Feng, Hans B. Liu, Mithila Kasbe, Masaya Baba, Yuichi Oike, Patricia Outeda, Terry Watnick, Avi Z. Rosenberg, Laura S. Schmidt, Marston Linehan, Pedram Argani, Tamara L. Lotan
Journal: Cancer Research (2025)

Abstract The MiT/TFE family gene fusion proteins, such as SFPQ-TFE3, drive both epithelial (eg, translocation renal cell carcinoma, tRCC) and mesenchymal (eg, perivascular epithelioid cell tumor, PEComa) neoplasms with aggressive behavior. However, no prior mouse models for SFPQ-TFE3-related tumors exist and the mechanisms of lineage plasticity induced by this fusion remain unclear. Here, we demonstrate that constitutive murine renal expression of human SFPQ-TFE3 using Ksp Cadherin-Cre as a driver disrupts kidney development leading to early neonatal renal failure and death. In contrast, post-natal induction of SFPQ-TFE3 in renal tubular epithelial cells using Pax8 ERT-Cre induces infiltrative epithelioid tumors, which morphologically and transcriptionally resemble human PEComas. As seen in MiT/TFE fusion-driven human tumors, SFPQ-TFE3 expression is accompanied by the strong induction of mTORC1 signaling, which is partially amino acid-sensitive and dependent on increased SFPQ-TFE3-mediated RRAGC/D transcription. Remarkably, SFPQ-TFE3 expression is sufficient to induce lineage plasticity in renal tubular epithelial cells, with rapid down-regulation of the critical PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and concomitant up-regulation of PEComa differentiation markers in transgenic mice, human cell line models and human tRCC. Pharmacologic or genetic inhibition of mTOR signaling downregulates expression of the SFPQ-TFE3 fusion protein and rescues nephric lineage marker expression and transcriptional activity in vitro. These data provide evidence of a potential epithelial cell-of-origin for TFE3-driven PEComas and highlight a reciprocal role for SFPQ-TFE3 and mTOR in driving lineage plasticity in the kidney, expanding our understanding of the pathogenesis of MiT/TFE-driven tumors. Citation Format: Kaushal V. Asrani, Adrianna Amaral, Juhyung Woo, Sanaz Abadchi, Thiago Vidotto, Kewen Feng, Hans B. Liu, Mithila Kasbe, Masaya Baba, Yuichi Oike, Patricia Outeda, Terry Watnick, Avi Z. Rosenberg, Laura S. Schmidt, Marston Linehan, Pedram Argani, Tamara L. Lotan. SFPQ-TFE3 gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis [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 3943.
Abstract 4823: CDH3-targeted ADC and CAR-T immunotherapies for metastatic double-negative prostate cancer and triple-negative breast cancer
Authors: Guoqiang Liu, Shiyu Wang, Loan Duong, Xin Lu
Journal: Cancer Research (2025)

Abstract Double-negative prostate cancer (DNPC) and triple-negative breast cancer (TNBC) are two challenging malignancies characterized by frequent metastasis and resistance to current therapies. Among them, DNPC may share similar traits with basal-like prostate cancer. These aggressive cancer subtypes demand new treatment strategies. This study investigates CDH3 (P-cadherin), a cell adhesion molecule, as a new target for antibody-drug conjugate (ADC) and chimeric antigen receptor (CAR) T-cell immunotherapeutics. We conducted comprehensive in silico analysis and confirmed the enriched expression of CDH3 in DNPC and metastatic TNBC. We hypothesize that CDH3-positive (CDH3+) prostate and breast cancer cells will be effectively targeted and eradicated using anti-CDH3 immunotherapeutics in vitro and in vivo. Both anti-CDH3 ADC and CAR-T cell therapies were developed and they both demonstrated significant target-specific cytotoxicity against CDH3high DU145 and MDA-MB-468 cell lines, while sparing CDH3low and CDH3-/- cell lines, highlighting their selectivity in vitro. In vivo efficacy was further validated using NOD-SCID mice engrafted with prostate and breast cancer cell lines in an experimental metastasis setting, where treatment with ADC or CAR-T therapy significantly reduced metastasis burden. Notably, CAR-T therapy, in combination with anti-PD-1 therapy, exhibited enhanced therapeutic potential.This study establishes the robust target-specific cytotoxicity of anti-CDH3 ADC and CAR-T therapies against the most virulent subtypes of metastatic prostate and breast cancers in vitro and in vivo, paving the way for potential clinical development of these therapeutic agents in patients with metastatic DNPC and TNBC. Citation Format: Guoqiang Liu, Shiyu Wang, Loan Duong, Xin Lu. CDH3-targeted ADC and CAR-T immunotherapies for metastatic double-negative prostate cancer and 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 4823.
Abstract 4827: Cell state targeting CAR T cell therapies for glioblastoma
Authors: Christopher Mount, Emily Boxer, Sophia Kovatsis, Demi Gerovasilis, Sydney Dumont, Jun Zhong, Jack Lu, Itay Tirosh, Mario Suva
Journal: Cancer Research (2025)

Abstract Despite decades of concerted research and clinical efforts, patient outcomes in glioblastoma (GBM) remain dismal. The emergence of chimeric antigen receptor (CAR) T cell therapies offer great promise as immunotherapies in this disease. To date, efforts to utilize CAR T cell therapies in GBM have resulted in isolated reports of impressive efficacy in individual patients, but these have yet to generalize to larger trial populations. It is thought that inter and intra patient tumor heterogeneity contributes to the variability of these responses. Single cell RNA sequencing has demonstrated that this heterogeneity can be organized along axes representing cellular states. The ability of existing CAR T cell therapies to target these cell states is unclear, and the dynamics of this heterogeneity under the selective pressure of therapy is uncertain. We present the development of a panel of tool CAR T cells targeting cell state associated surface markers with the objective of selective targeting of these cellular states in GBM. We show that these CAR T cells have target specific activity against GBM model systems representing these cellular states. Using single cell RNA sequencing, we model the dynamics of these treatment effects, with the aim of understanding the mechanisms of GBM dynamics in response to the selective pressure of CAR T cell therapies. We demonstrate global shifts in the transcriptional landscape at the single cell level and identify state dependent and state independent effects. We anticipate that these cell state targeted CAR T cells have great potential to elucidate mechanisms of GBM adaptation to the selective pressure of CAR T cell activity and will inform foundational biology necessary for rational design of multi target constructs for therapeutic application. Citation Format: Christopher Mount, Emily Boxer, Sophia Kovatsis, Demi Gerovasilis, Sydney Dumont, Jun Zhong, Jack Lu, Itay Tirosh, Mario Suva. Cell state targeting CAR T cell therapies for glioblastoma [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 4827.
Abstract 1774: A novel role of SNORA71D in the regulation of proteasome inhibitor induced apoptosis
Authors: Alexei F. Kisselev, Olasubomi A. Akintola, Addison M. Wilson
Journal: Cancer Research (2025)

Abstract Small nucleolar RNAs (snoRNA) are 60-300 nucleotide long RNAs that guide modification of rRNAs during ribosome biogenesis. Many of them have non-canonical functions, such as regulation of splicing of specific mRNAs. We have made a serendipitous discovery that treatment of cells with proteasome inhibitors (PIs) induces expression of a poorly characterized snoRNA, SNORA71D. Two other agents that induce production of misfolded proteins, tunicamycin and thapsigargin, also induced SNORA71D, but DNA-damaging agent doxorubicin did not. Knocking SNORA71D down reduced PI-induced apoptosis. The mechanisms of SNORA71D involvement in this process is under investigation. These findings indicate a novel and unexpected role of SNORA71D in cellular response to proteotoxic stress. Citation Format: Alexei F. Kisselev, Olasubomi A. Akintola, Addison M. Wilson. A novel role of SNORA71D in the regulation of proteasome inhibitor induced apoptosis [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 1774.
Abstract 4449: SIRT5 promotes chemoresistance through metabolic rewiring for nucleotide replenishing in refractory triple negative breast cancer
Authors: Zuen Ren, Kiran Kurmi, Tiziano Bernasocchi, Eric Zaniewski, Shakchhi Joshi, Garrett Lam, Chenxu (Vincent) Guo, Ilze Smidt, Preshita Dave, Agustina Maccio, Johannes Kreuzer, Gabrielle Elena Gioia, Veerle I. Bossuyt, Brian N. Dontchos, Gary X. Wang, Shinn-Huey S. Chou, Michael Lawrence, Esther Rheinbay, Laura M. Spring, Wilhelm Haas, Raul Mostoslavsky, Marcia C. Haigis, Leif W. Ellisen
Journal: Cancer Research (2025)

Abstract Drug resistance is the leading cause of neoadjuvant chemotherapy (NAC) failure to achieve pathological complete response (pCR) in more than 40% of patients with triple negative breast cancer (TNBC). Thus, understanding the potential drug resistance mechanisms in TNBC patients is a critical unmet clinical need. Using quantitative high-throughput metabolomic and proteomic approaches, we systematically analyzed clinicopathological, metabolic, and proteomic data profiled from NAC treatment-naive biopsy samples derived from primary TNBCs. Particularly, we identified that non-pCR TNBC primary tumors are uniquely and highly enriched in metabolic pathways for the TCA cycle and oxidative phosphorylation (OXPHOS) along with nucleotide metabolism relative to pCR TNBC tumors. In addition, sirtuin 5 (SIRT5) as a master regulator of mitochondrial metabolism is dramatically increased in non-pCR TNBC primary tumors. Of note, we found that SIRT5 is frequently overexpressed in TNBC tumors due to copy number gain and amplification. Furthermore, metabolomics and 13C-glucose tracing uncovered that SIRT5 gain of function promotes chemoresistance by diverting TCA cycle intermediates into the pentose phosphate pathway (PPP) for nucleotide replenishing. Moreover, SIRT5 knockout restores chemosensitivity to TNBC cells. We anticipate that blocking SIRT5-mediated metabolic rewiring may reverse chemoresistance in refractory TNBC patients. Citation Format: Zuen Ren, Kiran Kurmi, Tiziano Bernasocchi, Eric Zaniewski, Shakchhi Joshi, Garrett Lam, Chenxu (Vincent) Guo, Ilze Smidt, Preshita Dave, Agustina Maccio, Johannes Kreuzer, Gabrielle Elena Gioia, Veerle I. Bossuyt, Brian N. Dontchos, Gary X. Wang, Shinn-Huey S. Chou, Michael Lawrence, Esther Rheinbay, Laura M. Spring, Wilhelm Haas, Raul Mostoslavsky, Marcia C. Haigis, Leif W. Ellisen. SIRT5 promotes chemoresistance through metabolic rewiring for nucleotide replenishing in refractory 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 4449.
Abstract 4452: Targeting matrix metalloproteinase-3 to reverse chemotherapy resistance in high-grade serous ovarian cancer
Authors: Víctor G. Reyes-Burgos, Marienid Flores-Colón, Eliud Hernández-O’Farrill, Luis E. Vázquez-Quiñones, Pablo E. Vivas-Mejía
Journal: Cancer Research (2025)

Abstract High-Grade Serous Ovarian Cancer (HGSOC) remains the most aggressive and lethal gynecological malignancy, with most patients developing resistance to platinum-based chemotherapies. Matrix Metalloproteinase-3 (MMP3), an enzyme involved in extracellular matrix remodeling, has been implicated in this resistance. Prior work in our lab demonstrated that MMP3 is overexpressed in chemotherapy-resistant ovarian cancer cell lines, including the cisplatin resistant cells, OVCAR3CIS and A2780CP20, compared to their sensitive counterparts, OVCAR3 and A2780, respectively. Our team previously showed that knockdown of MMP3 with small interference RNA (siRNA) reduce cell growth and invasion of cisplatin-resistant ovarian cancer cells. We have progressed toward therapeutic applications by developing small molecule inhibitors (SMIs) to target MMP3. Bioinformatics was used to select potential MMP3 inhibitor candidates starting with a library of 370,000 compounds. Cell viability assays showed that four out of 30 preselected SMIs significantly reduced cell viability in cisplatin resistant cell lines. Further evaluation in combination therapy revealed promising results, as pre-treating cisplatin-resistant HGSOC cells with SMIs resensitized the cells to cisplatin treatment. These findings provide compelling evidence that MMP3 inhibition can restore chemotherapy sensitivity in resistant HGSOC cells, offering a promising dual-therapy approach. This research represents a significant advancement in developing novel therapeutic strategies to overcome chemotherapy resistance and improve outcomes for HGSOC patients. Citation Format: Víctor G. Reyes-Burgos, Marienid Flores-Colón, Eliud Hernández-O’Farrill, Luis E. Vázquez-Quiñones, Pablo E. Vivas-Mejía. Targeting matrix metalloproteinase-3 to reverse chemotherapy resistance in high-grade serous 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 4452.