tbuckley/cabot-search huggingface dataset:
Abstract 7126: Divergent molecular features associated with immune checkpoint blockade response
Authors: Travis D. Kerr, Patrick G. Pilie, Hui Dai, Amy B. Heimberger, Renata Ferrarotto, Jeffrey M. Rosen, Shiaw-Yih Lin, Daniel J. McGrail
Journal: Cancer Research (2025)

Abstract The advent of immune checkpoint blockade (ICB) has revolutionized cancer management. However, not all patients will benefit from this powerful therapy, necessitating clinical biomarkers and combination treatment strategies to enhance therapeutic efficacy. Recently, high tumor mutation burden (TMB-H) was FDA-approved as a pan-cancer biomarker for treatment with ICB based on a limited sample size and diversity of tumors. In systematic analysis across cancer types, we observed that immune cell infiltration was only associated with TMB in a subset of cancers. Based on this, we divided cancers into “Category I” cancers where TMB is associated with increased immune infiltration, and “Category II” cancers where TMB is not associated with immune infiltration. Using these classifiers, we analyzed the ability of TMB to predict ICB outcomes across over 2, 000 patients. We found that TMB-H predicted ICB outcomes in Category I, but not Category II, cancers. As Category II cancers represent many of the most common cancers in the United States, including those of the breast, prostate, kidney, and brain, we next sought to identify biomarkers relevant to this subset of cancers. We identified that defects in DNA replication stress response predicts ICB response in 12 cohorts of Category II cancers, but not Category I cancers. Furthermore, induction of replication stress response defects sensitized otherwise resistant tumors to ICB. Based on these divergent molecular correlates of ICB response, we hypothesized that different mechanisms may underlie ICB activity in these tumors. Using single-cell RNA sequencing, we identified a non-canonical PD1+ dendritic cell population uniquely in mouse and human Category II cancers, and that this population undergoes extensive transcriptional rewiring following treatment with ICB. Together, this work illustrates the need for context-specific biomarkers for treatment with immune checkpoint blockade. Citation Format: Travis D. Kerr, Patrick G. Pilie, Hui Dai, Amy B. Heimberger, Renata Ferrarotto, Jeffrey M. Rosen, Shiaw-Yih Lin, Daniel J. McGrail. Divergent molecular features associated with immune checkpoint blockade 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 7126.
HTD1801 Demonstrates Promising Potential for Histologic Improvements in MASH in Both a Preclinical and Phase 2 Study
Authors: Vincent Wai-Sun Wong, Guy W Neff, Adrian M Di Bisceglie, Ru Bai, Junwei Cheng, Meng Yu, Alexander Liberman, Liping Liu, Nadege Gunn
Journal: Clinical and Molecular Hepatology (2025)

Berberine ursodeoxycholate (HTD1801) has been shown to significantly reduce liver fat content (LFC) in an 18-week, placebo-controlled Phase 2 study in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes (T2DM). The purpose of this assessment was to establish proof of concept in liver histologic improvement with HTD1801 treatment based on preclinical and clinical evidence. The efficacy of HTD1801 was evaluated in a preclinical MASH/dyslipidemia model (golden hamsters fed a high fat diet, eight/group) after six weeks of daily treatment. Additionally, in a secondary analysis of a Phase 2 clinical study, 100 patients with presumed MASH were evaluated by multiple noninvasive markers associated with MASH resolution and/or fibrosis improvement. These include magnetic resonance imaging proton density fat fraction (MRI-PDFF; ≥30% LFC reduction), iron-corrected T1 (≥80 ms reduction), alanine aminotransferase (≥17 U/L reduction), weight loss (≥5% reduction), Fibrosis-4 index (shift to <1.3), and MASH Resolution Index (achieving ≥‑0.67). Preclinical findings in the MASH/dyslipidemia hamster model showed that HTD1801 significantly improved histologic fibrosis and the Nonalcoholic Fatty Liver Disease Activity Score to such a degree that improvements approximated the appearance of the normal controls. In the clinical study, 52% of HTD1801-treated patients achieved MRI response criteria compared to 24% of placebo (p<0.05). Dose-dependent improvements were observed across biomarkers, with more HTD1801-treated patients achieving response criteria associated with improvements in the histologic features of MASH. These findings suggest that HTD1801 has strong potential to produce histological improvements in patients with MASH.
Abstract 5026: Discovery of oncogenic mediator genes in rectal cancer chemotherapy response using gene expression data from matched tumor and patient-derived organoids
Authors: Hanchen Huang, Wini Zambare, Chao Wu, Antonio Colaprico, Janet Alvarez, Min Jung Kim, Aron Bercz, Paulina Bleu, Lily Wang, Philip B. Paty, Paul B. Romesser, J. Joshua Smith, X. Steven Chen
Journal: Cancer Research (2025)

Abstract Rectal cancer (RC) remains a significant clinical challenge, in part due to chemotherapy resistance encountered in neoadjuvant treatment approaches. To address this, we utilized a unique platform integrating gene expression data from RC tumor tissues and matched patient-derived organoids (PDO). Gene expression data were analyzed using the computational tool Moonlight to investigate the molecular mechanisms underlying chemotherapy response. We hypothesized that combining genomic data from RC PDOs and matched tumors would implicate molecular targets predicting chemotherapy response and clinical outcomes better than targets identified using RC tumor tissue or RC PDO input alone. We analyzed 18 tissue samples and 32 matched PDOs, capturing a comprehensive representation of tumor biology. Our integrative approach involved differential expression analyses (DEAs) and gene regulatory network (GRN) studies, identifying 5,199 genes regulating at least one potential regulon. Focusing on cancer-associated biological processes curated in Moonlight, we highlighted 2,118 regulator-regulon pairs with potential roles in oncogenic processes. Further integration with DEA results revealed 334 regulator-regulon pairs significantly enriched in both tissue and PDO samples, designating these regulators as oncogenic mediators (OMs). Among them, five genes—BTK, CDK1, LAX1, NAT2, and RAD51AP1—were associated with FOLFOX response. Survival analysis across four independent cohorts further validated CDK1, LAX1, NAT2, and RAD51AP1 as indicators of prolonged recurrence-free survival (RFS), demonstrating consistent patterns associated with good prognosis. These findings provide new insights into the molecular mechanisms of chemotherapy response in RC, and validation of these targets is ongoing. Our integrated approach underscores the translational relevance of PDOs and demonstrates the utility of Moonlight in identifying potential therapeutic targets, setting a new benchmark for precision medicine in rectal cancer. Citation Format: Hanchen Huang, Wini Zambare, Chao Wu, Antonio Colaprico, Janet Alvarez, Min Jung Kim, Aron Bercz, Paulina Bleu, Lily Wang, Philip B. Paty, Paul B. Romesser, J. Joshua Smith, X. Steven Chen. Discovery of oncogenic mediator genes in rectal cancer chemotherapy response using gene expression data from matched tumor and patient-derived organoids [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 5026.
Abstract 5434: Quantitative profiling of mitochondrial DNA copy number across hereditary renal cell carcinoma subtypes
Authors: Vaishnavi S. Srirama, Christopher J. Ricketts, Cathy D. Vocke, Laura S. Schmidt, Ye Yang, Maria J. Merino, Martin Lang, Mark W. Ball, Sandeep Gurram, Daniel R. Crooks, W Marston Linehan
Journal: Cancer Research (2025)

Mitochondrial DNA mutations and alterations in mitochondrial DNA copy number (mtDNA CN) have been reported in many cancer types. In hereditary renal cell carcinoma (RCC), each subtype is defined by a unique metabolic, pathologic, and clinical phenotype, and mtDNA CN can reflect the altered metabolic state of the originating tumor tissue. For example, in fumarate hydratase (FH)-deficient primary renal tumors and metastases associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), the loss of FH enzymatic activity leads to fumarate accumulation, loss and mutation of tumor mtDNA due to impairment of DNA Polymerase-γ, and a metabolic shift to aerobic respiration. In another RCC subtype, FLCN deficient Birt-Hogg Dubé (BHD) tumors have been characterized with high expression of PPARGC1A, a gene promoting mitochondrial biogenesis. The genotype-specific alterations in mtDNA CN, however, remain to be evaluated in many of the hereditary RCC syndromes. Here, we aim to establish a precise database of mtDNA CN alterations across the spectrum of hereditary RCC syndromes via a highly accurate droplet digital PCR (ddPCR) system. Analysis of mtDNA CN was achieved by quantifying the mitochondrial NADH-ubiquinone oxidoreductase chain 1 (MT-ND1) and mitochondrial NADH-ubiquinone oxidoreductase chain 4 (MT-ND4) genes in comparison to the nuclear reference beta-2-microglobulin (β2M) and brain-derived neurotropic factor (BDNF) genes. We employed our ddPCR protocol across multiple cohorts of RCC tumor subtypes, including Von-Hippel Lindau, BHD, FH-deficient HLRCC tumors and metastases, hereditary type 1 papillary renal carcinoma, and SDH-deficient RCC. We also studied a subset of multi-sampled tumors to assess intra-tumoral mtDNA CN heterogeneity. Our results offer a comprehensive overview of mtDNA CN quantifications across different RCC subtypes using ddPCR. Ultimately, we present a precision method to characterize mtDNA CN alterations, and we propose that tumor mtDNA CN alterations may serve as an additional biomarker to improve the clinical diagnoses of both hereditary and sporadic kidney cancers. Funded by the Intramural Research Program of the National Cancer Institute and FNLCR Contract HHSN261201500003I Citation Format: Vaishnavi S. Srirama, Christopher J. Ricketts, Cathy D. Vocke, Laura S. Schmidt, Ye Yang, Maria J. Merino, Martin Lang, Mark W. Ball, Sandeep Gurram, Daniel R. Crooks, W Marston Linehan. Quantitative profiling of mitochondrial DNA copy number across hereditary renal cell carcinoma subtypes [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 5434.
Abstract 4776: Preclinical study of bispecific antibody drug conjugates (bsADCs) targeting DLL3 and SEZ6 demonstrated potent anti-tumor activity in small cell lung cancer (SCLC) xenograft models
Authors: Ting Yi, Liu Yang, Kunying Hao, Wenpeng Cao, Yu Qi, Jushi Gai, Luheng Du, Gao An, Chengzhang Shang, Yi Yang, Frank An
Journal: Cancer Research (2025)

Abstract Lung cancer is the most common type of cancers and the leading cause of cancer-related mortality worldwide with 2.5 million new cases and 1.8 million deaths in 2022. Small-cell lung cancer (SCLC) accounts for ∼15% of all lung tumors, representing the most aggressive high-grade neuroendocrine carcinoma with a five-year survival rate less than 4%. Majority of patients are diagnosed with extensive stage SCLC (ES-SCLC) with brain metastases identified in ∼80% of cases and the prognosis is dismal with 5-year survival under 2%. Patients often relapse from front line therapies and current treatments in the second-line setting are very limited. Delta-like ligand 3 (DLL3) expression is highly restricted to SCLC, neuroendocrine tumors, and glioblastoma with minimally or no expression in normal tissues, making it a very specific and attractive tumor associated target (TAA) for SCLC. Like DLL3, seizure-related homolog protein 6 (SEZ6) is also expressed in SCLC, neuroendocrine tumors, and glioblastoma. Tarlatamab, a T cell engager targeting DLL3, was recently approved for SCLC. ADCs targeting DLL3 have shown robust anti-tumor activities in clinical trials. Similarly, anti-SEZ6 ADCs have also shown promising clinical activities. We constructed a bispecific ADC (bsADC) that targets both DLL3 and SEZ6 (DLL3xSEZ6) for SCLC and other tumor types where both DLL3 and SEZ6 are co-expressed. We hypothesized that dual targeting of these clinically validated targets would provide more selective and more potent anti-tumor activity, help overcome tumor heterogeneity in tumoral DLL3 and SEZ6 expression levels and allow a broader patient population for treatment. The bispecific antibody (bsAb) moiety of the bsADC was 1+1 format and was conjugated to a novel TOP1 inhibitor payload with potent bystander effect (DAR 8) and a highly hydrophilic, enzyme-cleavable linker. In vitro, the bsAb showed robust internalization capability in multiple double positive SCLC cell lines. In vivo, the bsADC exhibited robust anti-tumor efficacy in SCLC xenograft models. In summary, our DLL3xSEZ6 bsADC showed promising in vitro and in vivo preclinical activities with first-in-class potential for treatment of SCLC. Citation Format: Ting Yi, Liu Yang, Kunying Hao, Wenpeng Cao, Yu Qi, Jushi Gai, Luheng Du, Gao An, Chengzhang Shang, Yi Yang, Frank An. Preclinical study of bispecific antibody drug conjugates (bsADCs) targeting DLL3 and SEZ6 demonstrated potent anti-tumor activity in small cell lung cancer (SCLC) xenograft 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 4776.
Abstract 4781: Generation and in vivo characterization of a novel antibody targeting Prostatic Acid Phosphatase (ACP-3)
Authors: Claudia Comacchio, Stefanie Pfister, Domenico Ravazza, Samuele Cazzamalli, Ettore Gilardoni, Emanuele Puca, Tobias Weiss, Michael Weller, Dario Neri, Roberto De Luca
Journal: Cancer Research (2025)

Prostate cancer is the second deadliest tumor in men globally, despite the advent of novel drugs. Therapeutic modalities targeting Prostate Specific Membrane Antigen (PSMA) have provided benefit to patients but suffer from on-target off-tumor liabilities responsible for the side effects observed in clinical practice. These liabilities are a result of the expression of PSMA in healthy tissues, such as salivary glands, lacrimal glands, intestine, and kidneys. Innovative targeting ligands against better prostate cancer targets are therefore needed. Here, we present the generation and characterization of a first-in-class fully human antibody targeting ACP-3, a tyrosine phosphatase produced by prostate epithelial cells. Compared to PSMA, ACP-3 is expressed at significantly higher levels in the majority of prostate cancer lesions (both primary and metastatic), while being nearly undetectable in most healthy organs, including salivary glands, intestine and kidneys. A novel anti-ACP3 antibody was isolated from a phage display synthetic library containing 3 billion human single chain variable fragment clones. The antibody was thoroughly characterized, and its binding properties for the cognate target were studied in vitro using ELISA, flow cytometry and immunofluorescence on human prostate cancer specimens. Two orthogonal in vivo biodistribution studies were conducted in mice bearing HT1080 tumors stably transfected with human ACP-3. The first method relied on mass spectrometry to quantify the uptake antibody in tumors and healthy organs. The second method relied on the use of the immunofluorescence imaging to evaluate the microscopic distribution of the anti-ACP-3 antibody in tumors and healthy organs. The analyses were performed 24 hours post intravenous injection of the antibody. The results confirmed that the novel anti-ACP-3 antibody can selectively bind to its target in vitro and can preferentially localize to the tumor when injected intravaneously in tumor-bearing mice. In conclusion, given the exceptional binding selectivity and tumor-targeting performance, this novel anti-ACP-3 antibody promises to be an attractive scaffold for the generation of new best-in-class tumor targeted pharmaceuticals for the treatment of prostate cancer. Citation Format: Claudia Comacchio, Stefanie Pfister, Domenico Ravazza, Samuele Cazzamalli, Ettore Gilardoni, Emanuele Puca, Tobias Weiss, Michael Weller, Dario Neri, Roberto De Luca. Generation and in vivo characterization of a novel antibody targeting Prostatic Acid Phosphatase (ACP-3) [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 4781.
Abstract 7211: Proteolysis targeting chimeras (PROTACs) of oncogenic RET protein
Authors: Shriya Pandey, Yafeng Wang, Xueqing Hu, Ujjwol Khatri, Tao Shen, Vivek Subbiah, Blaine H. Mooers, Ting Chao, Shaohui Wang, Huaxuan Yu, Xingmin Sun, Jianfeng Cai, Jie Wu
Journal: Cancer Research (2025)

Abstract The REarranged during Transfection (RET) kinase is an oncoprotein and a therapeutic target for RET alteration-positive cancer. Two RET-selective protein tyrosine kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have been approved for treating RET-alteration-positive cancer. However, achieving a complete response with a RET kinase inhibitor remains a challenge in most patients. In cell cultures, these inhibitors increase the expression of CCDC6-RET fusion protein, which may affect their effectiveness at low concentrations. To tackle this problem, we synthesized and characterized a panel of RET PROTACs for the dual action of inhibiting RET kinase activity and degrading the oncogenic protein. A lead compound, YW-N-7, was selected based on in vitro PROTAC analyses and in vivo PK data. YW-N-7 exhibited the dual action of specifically inhibiting and degrading RET protein. Proteomic analysis identified RET as the only significantly down-regulated protein in the entire proteome by YW-N-7 compared with the RET kinase inhibitor. In the BaF3/KIF5B-RET tumor model, YW-N-7 inhibited and degraded KIF5B-RET oncoprotein in xenograft tumors in animals, and significantly inhibited tumor growth. This work illustrates the potential of developing a RET PROTAC for simultaneously inhibiting and degrading oncogenic RET kinase for cancer therapy. Citation Format: Shriya Pandey, Yafeng Wang, Xueqing Hu, Ujjwol Khatri, Tao Shen, Vivek Subbiah, Blaine H. Mooers, Ting Chao, Shaohui Wang, Huaxuan Yu, Xingmin Sun, Jianfeng Cai, Jie Wu. Proteolysis targeting chimeras (PROTACs) of oncogenic RET protein [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 7211.
Abstract 6338: CRISPR/Cas9 <i>in vitro</i> modelling of a VUS mutation found in Peruvian patients diagnosed with hereditary breast cancer
Authors: Solange R. Paredes-Moscosso, Claudio Villegas-Llerena, Bernardo E. Quispe-Bravo, José Buleje, Maria L. Guevara-Fujita, Ricardo Fujita
Journal: Cancer Research (2025)

Abstract Breast cancer is the most common neoplasm in women worldwide. In Latin America, rapid economic growth has driven epidemiological and demographic transitions that have increased the breast cancer burden. In Peru, breast cancer is the leading malignancy among women, with approximately 10% of cases linked to hereditary factors, primarily mutations in the BRCA1 and BRCA2 tumor suppressor genes. Many genetic variants are classified as Variants of Uncertain Significance (VUS), as their biological and clinical impacts remain unknown. In a previous work, our group identified six novel VUS in Peruvian families with hereditary cancer, including the c.5074+28T&amp;gt;A variant found in seven families. The overriding aim of the present study was to model the c.5074+28T&amp;gt;A VUS in a healthy breast tissue cell line (SVCT) using CRISPR/Cas9 technology. Gene editing was performed using ribonucleoprotein complexes (RNPs), whereby 03 different guide RNAs were tested. RNPs were transfected into SVCT cells by electroporation. Transfection and VUS insertion were verified via flow cytometry, T7EI assay, and Sanger sequencing. Single-cell clones were expanded, cryopreserved, and analyzed by PCR and enzymatic digestion (RFLP). Positive clones were further analyzed by Sanger sequencing, where 01 clone carrying the VUS c.5074+28T&amp;gt;A was identified (SVCT-VUS, clone C59). RT-PCR analyses showed no difference between unmodified SVCT cells (ctrl) and clone C59 at the mRNA sequence level. BRCA1 gene expression was then assessed by qPCR (Taqman assay), where BRCA1 downregulation was observed on SVCT-VUS compared to unmodified SVCTs. Although RNA from patients carrying the c.5074+28T&amp;gt;A variant was not available for analysis, SVCT-VUS cells showed a comparable BRCA1 gene expression to MDA-MB-231 breast cancer cell line, which possess a reportedly reduced BRCA1 mRNA and protein expression levels. Functional studies are still needed to confirm whether c.5074+28T&amp;gt;A affects BRCA1 expression at a protein level. These findings demonstrate a proof-of-concept for a CRISPR/Cas9 cell-modeling platform to study VUS in Peruvian patients with breast cancer and other diseases. Citation Format: Solange R. Paredes-Moscosso, Claudio Villegas-Llerena, Bernardo E. Quispe-Bravo, José Buleje, Maria L. Guevara-Fujita, Ricardo Fujita. CRISPR/Cas9 in vitro modelling of a VUS mutation found in Peruvian patients diagnosed with hereditary 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 6338.
Abstract 1778: MALAT1 and TUG1 long non-coding RNAs signalling mechanisms in response to SRPK1 inhibitor in prostate cancer
Authors: Linomtha Gabada, Zodwa Dlamini, Rahaba Makgotso Marima
Journal: Cancer Research (2025)

Abstract Introduction: Prostate cancer (PCa) is a leading cause of cancer death, and there are significant racial disparities in patient outcomes. Non-coding RNAs (lncRNAs) MALAT1 and TUG1 are recognised for their roles in oncogenic pathways. Their precise interacting mechanisms with splicing factors and splicing factor kinases is understudied. Aim: This study aims to map the biological pathways influenced by TUG1, MALAT1 in response to SRPK1 inhibitor prostate cancer cells Materials and Methods: Bioinformatics tools LncSEA 2.0, STRING, DAVID and Reactome were used to analyse the interactions between MALAT1, TUG1 and relevant miRNAs and their target genes. Resozuring cell viability assay was used to measure PCa cell viability (PC-3 cells vs HEK) in response to Sphinx31 at 24hrs and 48hrs. Next, RT-qPCR was used to measure gene expression levels of the lncRNAs. Results and Discussion: MALAT1 and TUG1 act as competing endogenous RNAs (ceRNAs) to sponge miRNAs that regulate critical tumour proliferation and migration genes, including PTEN and BCL2. SRPK1 regulates splicing factors to enhance tumour aggressiveness. The MALAT1-miR-125b-BCL2 and TUG1-miR-29b-PTEN axes are critical pathways for PCa progression, especially in advanced stages. Sphinx31 is cytotoxic in a time dependent manner to the PCa cells, while the 2 lncRNAs expression is elevated in PCa cells prior to Sphinx31 treatment. Conclusion: Targeting lncRNA-miRNA networks and splicing factor interactions, especially MALAT1 and SRPK1, is a potential therapeutic target for PCa. Citation Format: Linomtha Gabada, Zodwa Dlamini, Rahaba Makgotso Marima. MALAT1 and TUG1 long non-coding RNAs signalling mechanisms in response to SRPK1 inhibitor 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 1778.