tbuckley/cabot-search huggingface dataset:
Abstract 1533: Regulatory mechanism of bile acid-induced hepatokine ORM2 expression and its implication in the liver cancer
Authors: Ji Ho Suh, Inyoung Cheon, Hyun-Jung Jung, Sung Ho Lee, Mi Jeong Heo, Matthew DeBerge, Clavia Ruth Wooton-Kee, Young-Ho Ahn, Kang Ho Kim
Journal: Cancer Research (2025)

Abstract Bile acids (BAs) are increasingly recognized as key signaling molecules with various metabolic effects in diverse pathophysiologic contexts. Uncontrolled BA synthesis or impaired BA flow leads to cholestasis, a severe liver disease, characterized by extensive hepatic damage and progression to liver failure or liver cancer. The nuclear receptors (NRs) farnesoid X receptor (FXR) and small heterodimer partner (SHP) play critical roles in maintaining BA homeostasis; consequently, FXR/SHP double knockout mice (FS-DKO) exhibit juvenile onset cholestasis that ultimately develops liver cancer. We recently identified orosomucoid 2 (ORM2) a novel liver-secreted hormone (i.e., hepatokine), which is highly induced in response to hepatic BA stress. In this study, we identified the molecular mechanism underlying BA-induced Orm2 transcription, potentially mediated by activation of the xenobiotic NRs, constitutive androstane receptor (CAR) and pregnane X receptor (PXR). BA supplementation directly upregulated Orm2 expression whereas it was completely abolished in CAR/PXR double knockout livers. Given the diverse roles of BAs and ORM2 in metabolic and carcinogenic processes, our study highlights that BA stress activates CAR and PXR to induce ORM2 expression, which initially exerts a protective function in acute liver injury but eventually promotes liver cancer. These insights suggest a potential link between hepatic BA signaling, CAR/PXR activation, and systemic outcomes in the pathology from cholestasis to liver cancer. Citation Format: Ji Ho Suh, Inyoung Cheon, Hyun-Jung Jung, Sung Ho Lee, Mi Jeong Heo, Matthew DeBerge, Clavia Ruth Wooton-Kee, Young-Ho Ahn, Kang Ho Kim. Regulatory mechanism of bile acid-induced hepatokine ORM2 expression and its implication in the liver 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 1533.
Abstract 2236: A novel SIRPαxPD-L1 bispecific antibody remodels the innate and adaptive tumor microenvironment, and enhances tumor control
Authors: Mariela Navarrete, Cristobal Costoya, Erik van Buijtenen, Simone Wouters, Joost Kreijtz, Paul Vink, Hans van Eenennaam, Sergio A. Quezada
Journal: Cancer Research (2025)

Checkpoint blockade immunotherapy has transformed cancer treatment. However, many patients fail to respond to these therapies, underscoring the urgent need for new therapeutic strategies. Targeting alternative pathways and immune cell subsets within the tumor microenvironment (TME) holds promise for improving outcomes in these patients. One key mechanism of anti-tumour immunity is the phagocytosis of tumor cells by myeloid cells, which can be suppressed by the interaction between the SIRPα receptor on myeloid cells and its ligand CD47, a "do not eat me" signal, on tumor cells. Inhibition of the SIRPα/CD47 axis restores myeloid cell activity, promotes antigen presentation and enables tumor cell elimination. In this study, we evaluated a novel bispecific antibody that simultaneously blocks SIRPα and PD-L1 (SIRPαxPDL1), critical immune checkpoint molecules frequently overexpressed in the TME. SIRPαxPDL1 demonstrated enhanced macrophage-mediated phagocytosis of tumour cells in vitro. Moreover, in the MC38 murine tumor model, SIRPαxPDL1 significantly improved tumor control and survival, compared to monotherapies targeting either PD-L1 or SIRPα alone or in combination. High-dimensional flow cytometry revealed the unique ability of SIRPαxPDL1 to promote monocyte-to-macrophage differentiation whilst enhancing CD8+ T cell infiltration and activation within the TME compared to the combination of SIRPα and PDL1 antibodies. Remarkably, SIRPαxPDL1 synergized with a tumour-targeting antibody, further augmenting tumor control and survival. These findings highlight, for the first time, the potential of SIRPαxPDL1 to remodel the myeloid compartment and activate antitumor immunity, offering a promising novel avenue in cancer immunotherapy and combination approaches. Citation Format: Mariela Navarrete, Cristobal Costoya, Erik van Buijtenen, Simone Wouters, Joost Kreijtz, Paul Vink, Hans van Eenennaam, Sergio A. Quezada. A novel SIRPαxPD-L1 bispecific antibody remodels the innate and adaptive tumor microenvironment, and enhances tumor control [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 2236.
Abstract 4367: ERAS-4001 is a pan-KRAS inhibitor with robust anti-tumor activity in KRAS altered solid tumors
Authors: Jae Hyun Bae, Bingzhen Lin, Erin D. Lew, Alexei Brooun, Joanne Oh, Taylor Sullivan, Corine Holub, Alex Stromitis, Brian Qua, Robert F. Shoemaker
Journal: Cancer Research (2025)

Abstract KRAS is one of the most frequently mutated proteins in cancer (approximately 16% of all cancers), including non-small cell lung (∼30%), pancreatic (∼90%), colorectal (∼40%), and other cancers. Targeting both wild type (WT) KRAS and oncogenic KRAS mutant proteins within the tumor cell is a potentially more promising therapeutic strategy than targeting the mutant KRAS protein alone since WT KRAS activity can act as a resistance mechanism to mutant selective KRAS inhibition. Pan-KRAS inhibitors enable simultaneous mutant/WT KRAS inhibition and have the potential to show improved tolerability relative to pan-RAS inhibitors by sparing NRAS and HRAS. ERAS-4001 is a novel pan-KRAS inhibitor that binds to WT KRAS and KRAS G12X mutants and prevents KRAS from signaling downstream via effector proteins, such as the RAF protein family, with single digit nanomolar potency. ERAS-4001 was selective for KRAS G12X mutants and WT KRAS over WT HRAS and WT NRAS in surface plasmon resonance (SPR) studies, possibly providing an expanded therapeutic index. In the biochemical KRAS G12D-RAF1 RBD (RAS-binding domain protein) assay, ERAS-4001 inhibited complex formation when KRAS G12D was either in the active state (i.e., GMPPNP-bound) or inactive state (i.e., GDP-bound) with single digit nanomolar IC50s. ERAS-4001 showed potent cellular activity in a panel of KRAS WT amplified and KRAS G12X mutant NSCLC, PDAC, and CRC cell lines in both ERK1/2 phosphorylation (pERK) inhibition and 3-dimensional Cell-Titer Glo (3D-CTG) assays with IC50s in the range of 0.7-56 nM. In vivo, oral administration of ERAS-4001 at 100 mg/kg BID resulted in significant tumor growth inhibition in KRAS G12D and G12V mutant subcutaneous xenograft models from 77% TGI to 83% tumor regression. ERAS-4001 achieved a dose dependent increase in plasma concentrations and significant concomitant reduction in pERK. We hypothesize that the potency and selectivity profile of the pan-KRAS inhibitor ERAS-4001 will provide efficacy and tolerability for patients with tumors driven by oncogenic KRAS alterations. An IND submission is intended for the first quarter of 2025. Citation Format: Jae Hyun Bae, Bingzhen Lin, Erin D. Lew, Alexei Brooun, Joanne Oh, Taylor Sullivan, Corine Holub, Alex Stromitis, Brian Qua, Robert F. Shoemaker. ERAS-4001 is a pan-KRAS inhibitor with robust anti-tumor activity in KRAS altered solid 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 4367.
Abstract 408: CETSA-based evaluation of non-degraded PROTAC targets
Authors: Tomas Friman, Tuomas Tolvanen, Alexey Chernobrovkin, Daniel Martinez Molina
Journal: Cancer Research (2025)

Abstract Protein degradation is a non-classical modality with the potential to tackle therapeutically interesting proteins, even those previously deemed undruggable. The molecular effect that a productive interaction between target proteins and a bifunctional degrader/PROTAC can easily be monitored by measuring protein degradation. However, not all proteins that bind degraders are in fact degraded, which suggests that not all effects of PROTACs are based on the degradation of targets, but also the effects of traditional binary protein - ligand interactions. The Cellular Thermal Shift Assay (CETSA) is a powerful technology for identifying the interactions between compounds and their cognate protein targets. Coupling CETSA with mass spectrometric (MS) readout allows for profiling of binding selectivity of both the warhead that binds the protein of interest (POI) but also to investigate the selectivity for different PROTAC scaffolds. CETSA can be carried out in both lysates and intact cells, always without the need to modify the compound, the proteins or the cellular environment. In a typical CETSA workflow we can address both the degradation profile of proteins in the proteome that is accessible by MS, and also provide insights into the binding of the degrader to both the E3 ligase and the POI. This allows us to identify any disconnect between degradation and binding of degrader as well as to follow the downstream cellular and molecular effects. Here we will exemplify how CETSA can be applied in deconvoluting protein binding of a CDK9 targeting PROTAC: THAL SNS 032, which is composed of the cereblon (E3-ligase) binder Thalidomide and the CDK (POI) binder SNS 032. THAL SNS 032 induces degradation of the annotated target CDK9 and its associated protein Cyclin-T1, but target engagement can also be observed for additional proteins, including other kinases. In turn, the non-productive interactions from a degradation point of view can still result in biological effects, as exemplified here where GSK3A and GSK3B as well as their downstream substrate FOXK1 are thermally shifted but not degraded by the PROTAC. The effects on the GSK3 - FOXK1 signaling axis would have been missed if only protein degradation had been considered. By combining mass spectrometric data from CETSA experiments with degradation readouts it is possible to correlate cellular target engagement potencies with degradation efficiency and importantly, also identify any drug - protein binding that do not result in degradation Citation Format: Tomas Friman, Tuomas Tolvanen, Alexey Chernobrovkin, Daniel Martinez Molina. CETSA-based evaluation of non-degraded PROTAC targets [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 408.
Abstract 3801: Serine starvation inhibits SRSF protein expression and modulates RNA splicing in breast cancer cells
Authors: Philippa Burns, Negar Tabatabaei, Laura Selfors, Aanshi Vashi, Debolanle O. Dahunsi, Patrick Murphy, Soroush Tahmasebi, Jonathan Coloff
Journal: Cancer Research (2025)

Breast cancer is the most common cancer in women worldwide, and luminal/estrogen receptor positive (ER+) breast cancer accounts for ∼50% of breast cancer deaths. Our lab has identified serine auxotrophy as a metabolic vulnerability of luminal/ER+ breast tumors due to low levels of the serine synthesis enzyme phosphoserine aminotransferase 1 (PSAT1). Serine is critically important for cancer cell growth due to its multiple downstream functions in protein, nucleotide, and lipid biosynthesis. There is considerable interest in starving serine auxotrophic tumors of serine for therapy, including an ongoing clinical trial in pancreatic cancer. While the metabolic effects of serine starvation have been extensively investigated, our goal is to better understand how serine starvation affects protein synthesis and expression. We found that serine starvation inhibits global translation, while inducing adaptive translation of ATF4, and causes ribosome stalling and fall-off at serine TCC codons. Analysis of changes in the proteome upon serine starvation in auxotrophic luminal breast cancer cells shows that serine-rich proteins are particularly sensitive to serine starvation; this includes the serine/arginine-rich splicing factor (SRSF) family that are important regulators of mRNA splicing. Accordingly, replicate multivariate analysis of transcript splicing (rMATS) on RNA-sequencing data suggests that serine starvation dramatically changes alternative mRNA splicing in multiple breast cancer cell lines, with many differential splicing events being conserved across cell lines. These results have led to our current hypothesis that serine starvation induces splicing changes due to reduced translation of serine-rich members of the SRSF family (such as SRSF6), which ultimately impacts DNA damage and cell survival. We believe that SRSF6 depletion and subsequent alteration of RNA splicing upon serine starvation may sensitize to DNA damaging agents (e.g., chemotherapy). Citation Format: Philippa Burns, Negar Tabatabaei, Laura Selfors, Aanshi Vashi, Debolanle O. Dahunsi, Patrick Murphy, Soroush Tahmasebi, Jonathan Coloff. Serine starvation inhibits SRSF protein expression and modulates RNA splicing in breast cancer cells [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 3801.
Abstract 406: Targeting NSD2 aberrations in hematological malignancies with a potent and selective NSD2 PROTAC degrader
Authors: Yihan Liu, Abhijit Parolia, Lianchao Liu, Tongchen He, Yuanyuan Qiao, Sanjana Eyunni, Jie Luo, Zhen Wang, Arul Chinnaiyan, Ke Ding
Journal: Cancer Research (2025)

Abstract Nuclear receptor-binding SET domain-containing 2 (NSD2) is a methyltransferase that predominantly catalyzes the dimethylation of lysine 36 on histone 3 (H3K36me2). It has been implicated as an oncogene, with a hotspot gain-of-function mutation frequently identified in B-cell acute lymphoblastic leukemia (B-ALL) and chromosomal translocations involving NSD2 reported in approximately 20% of multiple myeloma cases. Despite its clinical significance, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. To address these limitations, we developed LLC0424, a novel NSD2 degrader engineered using proteolysis-targeting chimera (PROTAC) technology based on a PWWP1 domain binder. LLC0424 demonstrated potent degradation of NSD2 protein in acute lymphoblastic leukemia (ALL) RPMI-8402 cells, with a DC50 value of 20 nM and a Dmax value of 96%. TMT quantitative proteomics confirmed LLC0424’s high selectivity for NSD2, underscoring its specificity. Intravenous or intraperitoneal administration of LLC0424 achieved robust NSD2 degradation in vivo, validating its systemic effectiveness. In B-ALL cells harboring the NSD2 point mutation, LLC0424 treatment led to sustained downregulation of H3K36me2, a critical epigenetic mark associated with NSD2 activity. Additionally, LLC0424 exhibited cytotoxicity in ALL cell lines with NSD2 mutations, inhibiting cell growth and reducing colony formation capacity. Overall, these findings highlight the therapeutic potential of NSD2 degradation as a novel strategy to target cancers driven by NSD2 aberrations. Citation Format: Yihan Liu, Abhijit Parolia, Lianchao Liu, Tongchen He, Yuanyuan Qiao, Sanjana Eyunni, Jie Luo, Zhen Wang, Arul Chinnaiyan, Ke Ding. Targeting NSD2 aberrations in hematological malignancies with a potent and selective NSD2 PROTAC degrader [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 406.
Abstract 1906: Comprehensive genomic profiling for solid tumors
Authors: Shobit Gupta, Amit Kumar, Pankaj Khanna, Rama Chandran, Samir Agarwal
Journal: Cancer Research (2025)

Abstract Background: Next-generation sequencing technologies provides deep knowledge into the foundation of tumors and can advance the field of precision oncology. It can be used to effectively select the treatment based on druggable genomic alterations. In the present study, we prospectively investigated the clinical utility of a CGP assay in patients with metastatic tumors of the lung, breast, gynecologic, and colon etc. Methods: Genomic profiling was done on FFPE tumor samples using Genes2Me PanCancer assay. This assay, specifically adapted for the present molecular screening, is validated for clinical use and accredited by CEIVD and based on the guidelines published by the Association for Molecular Pathology, College of American Pathologists. It is a NGS-based product especially designed to identify genomic alterations, based on Food and Drug Administration, National Comprehensive Cancer Network guideline references, European Medicine Agency approvals, European Society for Medical Oncology (ESMO), updated every 3-6 months. It Targets around 681 genes with the size of 1.7 Mb containing different biomarkers such as DNA/RNA fusions, TMB, MSI and HPV related genes. It also incudes homologous recombinational repair (HRR) related genes. This panel was also designed to identify large scale rearrangements and special biomarkers such as MET exon 14skipping. Sequencing was done on Illumina platform. Bioinformatics analysis was performed using standard GATK.v4.1.2 somatic variant calling pipeline. Results: Most of the samples were sequenced with average depth of &amp;gt;1000X. On target ration ranged between 82-94% with coverage % at 10X and 30X was more than 99%. In all the samples mutations were identifies with VAF ranges from 8-28%. mutations More than 50% samples have identified mutations with actionable FDA approved drugs. Conclusion: Although further studies are needed to support, this CGP assay is a noninvasive assay to guide therapeutic choice in oncology. It provides tumor heterogeneity profile that could be incorporated in routinely clinical practice. These findings may support the modification of the primary treatment in patients with metastatic solid tumors thus be the first step for future advances in precision oncology. Citation Format: Shobit Gupta, Amit Kumar, Pankaj Khanna, Rama Chandran, Samir Agarwal. Comprehensive genomic profiling for solid 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 1906.
Abstract 383: Discovery of potent, selective, and orally bioavailable GSPT1 molecular glue degraders (MGDs) for the treatment of MYC-driven tumors
Authors: Zhimin Zhang, Min Chen, Cancan Cai, Li Teng, Sirui Liu, Yujie Chang, Xinxin Jin, Xiaohua Zhang, Dongzhou Liu
Journal: Cancer Research (2025)

Background: MYC is a well-recognized proto-oncogene, which is mutated and overexpressed in various tumors. However, MYC is challenging to target due to its disordered structure and nuclear localization. There is a significant unmet clinical need for the effective treatments for MYC-driven tumors. G1 to S phase transition 1 (GSPT1) is a translation termination factor regulating protein expression. GSPT1 is involved in many biological processes, including the regulation of cell proliferation, migration, growth cycle and apoptosis. MYC-driven tumors are highly dependent on protein translation to sustain their growth, creating a reliance on the GSPT1 activity. Recent studies have shown that molecular glue degraders (MGDs) targeting GSPT1 affect protein synthesis, thus interfering with the expression of MYC and its downstream target genes. Therefore, GSPT1 is a potential therapeutic target for MYC-driven tumors. Results: Through a comprehensive artificial intelligence-driven drug design and structure-based approach, we designed and synthesized a series of GSPT1 degraders. The most potent degrader effectively degrades GSPT1 proteins in the MDA-MB-468 cells in a dose-dependent manner and achieves a DC50 value of less than 2 nM. The maximum degradation (Dmax) value observed is &amp;gt;95%. The degradation of GSPT1 induced the associated downregulation of MYC (EC50&amp;lt;10 nM), resulting in preferential anti-proliferative activity in MYC-driven cancer cells with IC50 values of 3.28 nM in MDA-MB-468 cells and 0.82 nM in NCI-H1155 cell lines. PK studies revealed low clearance, high plasma exposure, and oral bioavailability in mice. Furthermore, the MGD induced robust and statistically significant tumor growth inhibition (TGI) in the NCI-H1155 and MDA-MB-468 Xenograft Models, with TGI values of 99.57% and 97.93%, respectively. Conclusion: A novel, selective, potent oral GSPT1 degrader was discovered and demonstrated robust anti-tumor activity in mouse xenograft tumor models as a single agent. Collectively, we have identified novel GSPT1 MGDs as promising candidates for the treatment of MYC-driven tumors. Citation Format: Zhimin Zhang, Min Chen, Cancan Cai, Li Teng, Sirui Liu, Yujie Chang, Xinxin Jin, Xiaohua Zhang, Dongzhou Liu. Discovery of potent, selective, and orally bioavailable GSPT1 molecular glue degraders (MGDs) for the treatment of MYC-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 383.