tbuckley/cabot-search huggingface dataset:
Abstract 351: Preclinical development of MHB009C: A novel anti-B7-H4 ADC with a potent topoisomerase I inhibitor
Authors: Liyuan Zhu, Bo Liu, Yile Chen, Xiang Meng, Ao Li, Li Liu, Zhili Yao, Yan Wang, Xialian Weng, Xuefeng Zhu, Yang Liu, Shiyu Zhou, Junwei Shi, Guoqing Cao
Journal: Cancer Research (2025)

Abstract B7-H4, a member of B7 family, is a transmembrane protein that inhibits T cell immunity. It is overexpressed in various malignancies, including breast, ovarian, and endometrial cancers, as well as cholangiocarcinoma, where it has been associated with tumor progression and poor patient outcomes. Antibody-drug conjugates (ADC) targeting B7-H4 have demonstrated promising clinical activity. Here, we present the development and preclinical characterization of MHB009C, a novel B7-H4 ADC. MHB009C comprises a human IgG1 antibody against B7-H4, conjugated to the SuperTopoiTM payload, a novel DNA topoisomerase I inhibitor that is 3∼5 times more potent than DXd, with a drug-antibody ratio of ∼4.0. Fc function was silenced to minimize nonspecific ADC uptake, and the linker was designed to enhance hydrophilicity and prevent the retro-Michael reaction, improving plasma stability. MHB009C demonstrated strong binding affinity to B7-H4 and was efficiently internalized by SK-BR-3 cells. It exhibited potent cytotoxicity in B7-H4-positive breast cancer cell lines and showed significant antitumor activity in an MX-1 breast cancer xenograft model. GLP study in monkeys revealed a favorable safety profile with no off-target toxicities, and the highest non-severely toxic dose (HNSTD) was determined to be 30 mg/kg Q3W, the maximum dose tested. In conclusion, MHB009C demonstrated potent anti-tumor activity both in vitro and in vivo, along with a favorable safety profile, supporting further clinical development. Citation Format: Liyuan Zhu, Bo Liu, Yile Chen, Xiang Meng, Ao Li, Li Liu, Zhili Yao, Yan Wang, Xialian Weng, Xuefeng Zhu, Yang Liu, Shiyu Zhou, Junwei Shi, Guoqing Cao. Preclinical development of MHB009C: A novel anti-B7-H4 ADC with a potent topoisomerase I inhibitor [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 351.
Abstract 514: Therapeutic potential of antidepressant amitriptyline in medulloblastoma
Authors: Frank B. Wang, Prabhakar Pitta Venkata, Andrew Brenner, William Kelly, Gangadhara R. Sareddy, Manjeet K. Rao
Journal: Cancer Research (2025)

Abstract Introduction: Medulloblastoma, the most common malignant brain tumor in children, primarily arises in the posterior fossa, predominantly affecting the cerebellum. Accounting for approximately 20% of all pediatric brain tumors, medulloblastoma has an annual incidence of about 500 cases in the United States, with a peak age of diagnosis between 5 and 7 years and a slight male predominance. Advances in genomic and epigenomic profiling have identified four distinct subgroups—WNT, Sonic Hedgehog (SHH), Group 3, and Group 4—each characterized by unique molecular features, patient demographics, and prognostic outcomes. Current treatment strategies, including surgical resection, craniospinal irradiation, and adjuvant chemotherapy, have improved survival rates; however, up to 40% of patients experience incurable recurrence or metastasis, the leading cause of mortality. Furthermore, survivors often endure debilitating long-term side effects from these aggressive therapies, underscoring the urgent need for more effective and less toxic therapeutic approaches. Methods: To evaluate the anticancer activity of Amitriptyline, we utilized SHH (DAOY) and Group 3 (HDMB03, D556, D425) medulloblastoma cell lines. Cell viability, survival, and apoptosis were assessed through established functional assays. The impact of Amitriptyline on cancer stemness was investigated using sphere formation and extreme limiting dilution assays. Mechanistic studies were conducted through RNA sequencing, quantitative RT-PCR, and Western blot analysis to elucidate molecular pathways. The therapeutic potential of Amitriptyline was further validated in vivo using orthotopic xenograft mouse models of medulloblastoma. Results: Amitriptyline treatment significantly inhibited cell viability, colony formation, and migratory capacity while promoting apoptosis in medulloblastoma cell lines. Additionally, Amitriptyline reduced the viability and sphere-forming ability of medulloblastoma stem cells, indicating a potent effect on cancer stemness. Notably, Amitriptyline enhanced the therapeutic efficacy of Vincristine in medulloblastoma cell lines. In vivo studies demonstrated that Amitriptyline treatment significantly prolonged survival in the orthotopic xenograft mouse model, with no sign of toxicity, highlighting its therapeutic potential. Conclusion: Collectively, our findings suggest that Amitriptyline may serve as a viable therapeutic option for medulloblastoma, providing a basis for potential clinical application. Citation Format: Frank B. Wang, Prabhakar Pitta Venkata, Andrew Brenner, William Kelly, Gangadhara R. Sareddy, Manjeet K. Rao. Therapeutic potential of antidepressant amitriptyline in medulloblastoma [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 514.
Abstract 3526: A novel strategy to treat advanced, late-stage tumors with real-time tumor vaccination “Online Vaccine”
Authors: Piotr Jachimczak, Paul Jachimczak
Journal: Cancer Research (2025)

Abstract Malignant cells acquired immunoevasive properties by numerous mechanisms allowing them to form locally invasive and metastatic tumors resistant to current therapeutic strategies. TGF-beta overexpression in tumor cells correlates with malignant progression by induction of “immune-escape phenomenon” in cancer bearing patients. Real-Time approach to generate a Tumor Vaccine in vivo (“Online Vaccine”) aims at avoiding this, immune-escape phenomenon“ by intratumoral inhibition of TGF-beta function while simultaneously and synergistically inducing an efficient anti-tumor immune response. The synergistic effects of the proposed combination of a TGF-beta inhibitor with immunostimulating cytokines IL-2 and GM-CSF (RealTVac®) upon human immune cell activation has been demonstrated in vitro and in vivo. This, four-dimensional (4D)-approach to treat advanced, late-stage, malignant tumor by use of repetitive spacio (intratumoral) - temporal (real-time) combination therapy allow the host immune system to scan in real-time all Tumor Associated Antigens (TAAs) being currently expressed by those tumor cells that are exposed to sufficient TGF-beta inhibition. The repetitive administration of the RealTVac® approach is furthermore expected to provide a continuous update of the immune response, reflecting the changing pattern of TAAs related to the dynamic intratumoral heterogeneity in malignant tumors. Thus, intratumoral immunization as applied for RealTVac® may create a new paradigm for cancer therapy in the future. Citation Format: Piotr Jachimczak, Paul Jachimczak. A novel strategy to treat advanced, late-stage tumors with real-time tumor vaccination “Online Vaccine” [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 3526.
Abstract 461: A screening platform to target intrinsically disordered regions (IDRs) of chromatin factors in disease
Authors: Laura Hsieh, Philamer Calses, Muryam Gourdet
Journal: Cancer Research (2025)

Abstract Aberrant chromatin is expanding as a new class of disease and resistance driver for multiple disease pathologies. While billions of dollars have been poured into drugging chromatin regulatory factors, the toxicity of previous approaches limits potential and promise. Conventional drug discovery strategies have focused on targeting only the stable interfaces of chromatin regulators. However, the specific regulation of chromatin function occurs in large part from the unstructured intrinsically disordered regions (IDRs). IDRs help specify the functionality of structured domains and play a critical role in regulating both physiological and disease-driving multi-protein assemblies. TippingPoint Biosciences has developed a first-of-a-kind screening platform that now enables targeting of IDRs in chromatin proteins by exploiting unique inter-molecular interfaces only found in disease driving chromatin states. TippingPoint’s approach should increase specificity, reduce toxicity and be less susceptible to drug resistance. To validate our drug discovery approach we are focusing our efforts on developing novel small molecule therapeutics for a rare pediatric brain tumor, Diffuse Intrinsic Pontine Glioma (DIPG), a disease driven by a very specific chromatin mutation that is difficult to target using conventional approaches. DIPG is driven by the H3.3 K27M mutation. Recognition of H3.3K27M by Polycomb Repressive Complex (PRC2), renders PRC2 inactive leading to a reduction in global H3K27me3. As a result, there are increased levels of H3K27ac and altered gene expression. Using our platform we generated a synthetic DIPG chromatin state, mimicking the stabilized interactions between PRC2-H3.3K27M chromatin IDRs. We successfully screened thousands of molecules against the DIPG chromatin state and identified molecules that disrupted PRC2 and H3K27M IDR interactions. These small molecule hits partially restored H3K27me3 levels, reduced H3K27ac levels, and decreased oligodendrocyte transcription factor 2 (OLIG2) expression in DIPG cell-lines to promote differentiation. These results successfully show that our platform can identify small molecules that uniquely target aberrant chromatin to rescue disease pathology. Citation Format: Laura Hsieh, Philamer Calses, Muryam Gourdet. A screening platform to target intrinsically disordered regions (IDRs) of chromatin factors in disease. [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 461.
Abstract 473: Inhibition of SUMOylation reverses T-cell metabolic exhaustion in large B-cell lymphoma
Authors: Joseph Lownik, Larry Milshteyn, Anton Villamejor, Akil Merchant
Journal: Cancer Research (2025)

Abstract Immune based therapies for large B cell lymphoma (LBCL) have transformed our approach to this disease. Therapies such as CD3 bispecific T cell engagers and chimeric antigen receptor (CAR) T cells, have diverse mechanisms of action, yet they all depend on activation of T cells to affect an anti-cancer response. While the often-dramatic responses seen to immune therapies have captured wide-spread attention, the majority of patients treated with immune based therapies for relapsed lymphoma will not achieve long term cure, and poor T cell function is a common mechanism for treatment failure. Several seminal studies have identified T-cell metabolic reprogramming as a key mechanism behind T-cell exhaustion. Mechanisms to reverse metabolic exhaustion and reinvigorate T-cells has been shown to lead to increased anti-tumor responses. Small ubiquitin-like modifiers (SUMO) proteins regulate a variety of cellular processes in tumor and immune cells. Inhibitors of SUMOylation (SUMOi) have shown anti-tumor activity in a CD8 T-cell dependent manner, however, the mechanism behind this T-cell dependence is unknown. We show that a novel covalent SUMOi, SB-4826 leads to a robust anti-tumor response which is dependent on CD8+ T-cells in lymphoma. Using single cell metabolic studies, we demonstrate that SUMOi increases the metabolic rate, glycolytic dependency and proliferative capacity of tumor infiltrating PD1+ CD8+ T cells. We further show that SUMOylation is increased following T-cell activation, and exhausted CD8+ TILs have the highest levels of total SUMOylation of T-cell subsets. We validate these findings of increased SUMOylation in CD8+ TILs in human lymphoma samples. In a CD19 CAR T-cell model, we show that pulse treatment of CAR T-cells with SUMOi leads to enhanced anti-lymphoma activity in vitro. Using a mass-spectroscopy/immunoprecipitation approach, we identified more than 1, 000 proteins which are SUMOylated in T-cells. We found that multiple T-cell transcriptional regulators, including TBET, LEF1 and TCF1 are all SUMOylated either during a resting or activation state in CD8+ T-cells. Together, these findings suggest a novel role for SUMOylation in regulating T-cell effector activation and exhaustion, by modulating metabolic state likely through the regulation of key transcriptional T-cell programs. Citation Format: Joseph Lownik, Larry Milshteyn, Anton Villamejor, Akil Merchant. Inhibition of SUMOylation reverses T-cell metabolic exhaustion in large B-cell lymphoma [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 473.
Abstract 462: TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss
Authors: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Wenhai Zhang, Alan Huang, Jannik N. Andersen, Kevin M. Cottrell
Journal: Cancer Research (2025)

Abstract MTAP deletions occur in 10-15% of all human cancers, providing one of the largest precision oncology patient populations. MTA-cooperative PRMT5 inhibitors leverage the well-characterized synthetic lethal relationship between PRMT5 inhibition and MTAP deletion. TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 are clinical-stage MTA-cooperative PRMT5 inhibitors for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant. TNG456 is a next-generation, highly potent and selective MTA-cooperative PRMT5 inhibitor designed for patients with MTAP-null cancers including gliomas and other tumors which frequently metastasize to the brain, such as NSCLC. In vitro, TNG456 is 55X selective for MTAP-null cancer cell lines over isogenic MTAP WT cell lines (compared to 15X for TNG908) and has marked selectivity for MTAP-null cancer cell lines independent of lineage in a large, diverse cell line panel. TNG456 is brain-penetrant in preclinical species with a Kpuu range of 0.5-1.1 in non-human primates and dogs. Oral administration of TNG456 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including gliomas and CNS metastases. Citation Format: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Wenhai Zhang, Alan Huang, Jannik N. Andersen, Kevin M. Cottrell. TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss [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 462.
Abstract 516: SOX4 dictates gastric cancer progression by modulating the tumor immune microenvironment
Authors: Gengyi Zou, Katsuhiro Yoshimura, Yibo Fan, Ruiping Wang, Kohei Yamashita, Shan Shao, Ailing Scott, Jiankang Jin, Melissa P. Pizzi, Matheus Silva, Xiaodan Yao, Calena Brown, Rebecca Waters, Shumei Song, Linghua Wang, Shilpa Dhar, Jaffer A. Ajani
Journal: Cancer Research (2025)

Abstract SOX4 upregulation is common in multiple tumors, yet its role in shaping the immune microenvironment of gastric adenocarcinoma (GAC) remains unclear. This study investigates the influence of SOX4 on GAC progression and immune modulation. Using single-cell RNA sequencing, patient-derived models, and functional analyses, we examined SOX4 expression and its target genes in GAC. SOX4 was found to be highly expressed in both primary and metastatic GAC tissues, correlating with poor prognosis. Knockdown of SOX4 in GAC cells reduced tumor growth, migration, and colony formation and suppressed metastasis. Furthermore, SOX4 depletion enhanced T-cell cytokine production and promoted M2-macrophage repolarization in cocultures with patient-derived PBMCs and U937 cells. Conversely, SOX4 overexpression reinforced these aggressive phenotypes. RNA-seq analysis of SOX4 wildtype and knockout cells led to the identification of six drugs that could mimic the effects of SOX4 deletion, with Cucurbitacin-I and Tunicamycin emerging as potent inhibitors of GAC cell growth in patient-derived models. These findings highlight SOX4's role in driving GAC progression and immune evasion, offering potential therapeutic avenues for targeting SOX4 in GAC treatment. Citation Format: Gengyi Zou, Katsuhiro Yoshimura, Yibo Fan, Ruiping Wang, Kohei Yamashita, Shan Shao, Ailing Scott, Jiankang Jin, Melissa P. Pizzi, Matheus Silva, Xiaodan Yao, Calena Brown, Rebecca Waters, Shumei Song, Linghua Wang, Shilpa Dhar, Jaffer A. Ajani. SOX4 dictates gastric cancer progression by modulating the tumor immune microenvironment [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 516.
Abstract 463: Preclinical evaluation of CNS drug penetration of a novel series of MTA-cooperative PRMT5 inhibitors including TNG456
Authors: Alice Tsai, Charles B. Davis, Kimberly J. Briggs, Kevin M. Cottrell, John P. Maxwell, Adam S. Crystsal, Ellen Hooper, Jannik N. Andersen
Journal: Cancer Research (2025)

Abstract Treatment of brain tumors and brain metastases remains a significant unmet medical need. This is especially true for high-grade gliomas, where up to 50% of cases exhibit loss of MTAP, creating a dependency on PRMT5 and a susceptibility to MTA-cooperative PRMT5 inhibitors. For preclinical drug discovery, the accurate prediction of drug exposure in the human CNS compartment is therefore of critical importance. This study evaluates the utility of preclinical models, specifically the monkey cerebrospinal fluid (CSF) model, alongside the physicochemical properties of compounds, including permeability and efflux characteristics, to predict free brain drug exposure in humans. The non-terminal monkey CSF model permits assessment of CNS penetration with minimal invasiveness. Complementary to this, as part of the 14-day terminal dose range finding toxicology studies, brain tissues were collected at necropsy to verify and correlate predicted brain penetration with actual exposure levels. Our findings demonstrate a strong correlation between CSF concentrations in the monkey model and free brain drug exposure, suggesting that incorporating these datapoints, in addition to optimizing permeability and efflux properties, enhances the reliability of CNS drug delivery predictions. This research highlights the importance of integrating non-terminal preclinical models and physicochemical analysis to improve the safety and efficacy of CNS-targeted therapeutics. In addition, utility of rodent terminal brain drug exposure models and the importance of deriving unbound free brain drug exposures will be discussed. Citation Format: Alice Tsai, Charles B. Davis, Kimberly J. Briggs, Kevin M. Cottrell, John P. Maxwell, Adam S. Crystsal, Ellen Hooper, Jannik N. Andersen. Preclinical evaluation of CNS drug penetration of a novel series of MTA-cooperative PRMT5 inhibitors including TNG456 [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 463.
Abstract 86: The role of truncated O-glycans in PDAC progression: Linking C1GALT1 loss to metabolic alterations
Authors: Wyatt Petersen, Venkatesh Varadharaj, Zahraa I. Alsafwani, Surinder K. Batra, Moorthy P. Ponnusamy
Journal: Cancer Research (2025)

Abstract Pancreatic cancer (PC) remains one of the leading causes of cancer death, often advancing undetected until late stages. Aberrant O-glycosylation, including the expression of truncated carbohydrate antigens such as Tn and STn, is a hallmark of PC; however, the mechanisms linking these glycan alterations to tumor progression and metastasis are poorly understood. This study investigates the role of truncated O-glycans, driven by the loss of the O-glycosyltransferase core 1 synthase (C1GALT1), in promoting metabolic reprogramming and early metastatic dissemination in pancreatic cancer. C1GALT1 catalyzes the biosynthesis of mucin-type O-glycans, but its inactivity in PC leads to the accumulation of truncated glycans. Analysis of poorly differentiated human PC tissues revealed a significant loss of C1GALT1 expression. CRISPR/Cas9-mediated knockout (KO) of C1GALT1 in PC cell lines also results in increased Tn and STn glycan expression, enhanced tumorigenic potential, and increased metastatic capacity. Using genetically engineered mouse models (C1galt1 KO with KrasG12D/Trp53R172H/+ mutations), we observed early-onset and widespread metastasis, mirroring the heightened aggressiveness associated with C1GALT1 loss in pancreatic cancer. Transcriptomic profiling through RNA sequencing and pathway enrichment analysis in C1GALT1 KO PC cells revealed significant upregulation of cholesterol metabolism pathways, suggesting that the loss of C1GALT1 may drive metabolic changes to support the aggressive behavior of PC cells. Supporting this, functional assays demonstrate a significant increase in wound healing and migratory capacity of C1GALT1 KO cells compared to control PC cells, highlighting their enhanced motility and potential for metastasis. These findings underscore the role of C1GALT1 loss in driving aggressive tumor phenotypes, potentially through metabolic and functional adaptations that promote the need for further investigation. This work highlights a previously underexplored link between aberrant glycosylation and metabolic rewiring in pancreatic cancer. By elucidating the role of C1GALT1 loss in driving these processes, our findings provide novel insights into the mechanisms of tumor progression and identify potential vulnerabilities for therapeutic intervention. Targeting the interplay between glycosylation and metabolic pathways offers a promising avenue to disrupt the aggressive phenotype of pancreatic cancer. Citation Format: Wyatt Petersen, Venkatesh Varadharaj, Zahraa I. Alsafwani, Surinder K. Batra, Moorthy P. Ponnusamy. The role of truncated O-glycans in PDAC progression: Linking C1GALT1 loss to metabolic alterations [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 86.