tbuckley/cabot-search huggingface dataset:
Abstract 3170: Epigenetic identification and functional characterization of a novel RING finger protein tumor suppressor in nasopharyngeal carcinoma and esophageal carcinoma
Authors: Xiaoxue Chai, Feifei Luo, Shujie Bao, Liuzhen Meng, Anthony T. Chan, Brigette B. MA, Qian Tao, li LiLi
Journal: Cancer Research (2024)

Abstract RING finger proteins play crucial roles in normal physiology and pathophysiology as important regulators of ubiquitin-dependent proteasomal protein degradation. Many RING finger proteins have also been implicated in tumorigenesis either as oncogenes or tumor suppressors. Through cancer CpG methylome studies, we identified RING finger protein 150 (RNF150) as a methylated target gene in nasopharyngeal carcinoma (NPC) and esophageal carcinoma (ESCC). RNF150 was found to be ubiquitously expressed in human normal tissues but frequently downregulated in NPC and ESCC cells due to its promoter methylation. Its downregulation is associated with poor survival in patients with head and neck cancer and esophageal cancer. We also found that RNF150 is a functional tumor suppressor by inhibiting tumor cell growth and inducing cell cycle arrest in NPC and ESCC cells. Furthermore, ectopic expression of RNF150 inhibited NPC and ESCC cell migration/invasion by suppressing epithelial-mesenchymal transition (EMT) through upregulation of epithelial marker E-cadherin and downregulation of mesenchymal markers (vimentin, N-cadherin, Snail, and Slug). RNF150 is located in the cytoplasm and represses several oncogenic signaling pathways including the Wnt/β-catenin and NF-kB signaling pathways. Liquid chromatography-mass spectrometry (LC-MS) was performed to elucidate RNF150 binding proteins. KEGG enrichment analysis showed that glycolysis/gluconeogenesis, pyruvate metabolism, central carbon metabolism in cancer, and AMPK signaling were the top 4 pathways with significant enrichment, suggesting potential targeting of metabolic molecules by RNF150. Thus, our results provide insights into a new ring finger protein member, RNF150, as a functional tumor suppressor for NPC and ESCC. Our study also suggests a potential epigenetic biomarker for the early dection of NPC and ESCC. Citation Format: Xiaoxue Chai, Feifei Luo, Shujie Bao, Liuzhen Meng, Anthony T. Chan, Brigette B. MA, Qian Tao, li LiLi. Epigenetic identification and functional characterization of a novel RING finger protein tumor suppressor in nasopharyngeal carcinoma and esophageal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3170.
Abstract 1129: A multifaceted study of X-Ray radiation therapy across diverse mouse tumor models
Authors: Jingqi Huang, Wentao Li, Xiaoyan He, Weiwei Cheng, Lingyun Zhang, Guannan Li, Qiuliang Li, Yongfei Wang, Xuesong Ren, Zhi Wei, Long Shi, Yiran Wei, Jing Jin, Linfeng Li, Wei Yun
Journal: Cancer Research (2024)

Abstract In this study, we showcase the application of X-ray radiation therapy of tumor-bearing mice across 13 syngeneic tumors, one intracranial tumor, and in combination with radiosensitizing drugs, aiming to develop potent cancer treatment strategies. 1.We examined the effects of different radiation levels on multiple tumor models using a therapeutic device delivering targeted radiation to the tumor site. 2.We investigated the combined benefits of radiation with the radiosensitizer Gemcitabine on the H22 liver tumor model. 3.We assessed the impact of radiation sensitization on the HCC1975-luc intracranial tumor model in combination with AZD0156, a drug that cannot cross the blood-brain barrier. The integrity of the blood-brain barrier and the presence of the pharmacodynamic marker pRAD50 of AZD0156 were evaluated. The results show that X-ray radiation has anti-tumor effects across diverse models, with combination drug treatment with both Gemcitabine and AZD0156 showing enhanced therapeutic effects. Furthermore, pRAD50 showed decreasing trend in the single dose PD study in HCC1975-luc intracranial model. We conclude that our platform provides robust methods for evaluating the therapeutic effects of X-Ray radiation, offering invaluable insights for the creation of new cancer therapies. Citation Format: Jingqi Huang, Wentao Li, Xiaoyan He, Weiwei Cheng, Lingyun Zhang, Guannan Li, Qiuliang Li, Yongfei Wang, Xuesong Ren, Zhi Wei, Long Shi, Yiran Wei, Jing Jin, Linfeng Li, Wei Yun. A multifaceted study of X-Ray radiation therapy across diverse mouse tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1129.
Abstract 7150: Molecular insights into the oncogenic influence between mutant HER3, mutant KRAS, and their synergistic interplay in colorectal cancer pathogenesis
Authors: Mary K. Kilroy, Briley Park, Rosalin Mishra, Wasim Feroz, Cecilia Wischmeier, Joan T. Garrett
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is a disease of the colon and rectum that will claim about 52,550 American lives in 2023. In recent years, more attention has been paid to HER2 and HER3’s roles in colorectal cancers, as they may cause resistance to targeted therapies. We are investigating the role of naturally co-occurring HER3 and KRAS mutations in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation and 41% contain a KRAS mutation. We have observed that there is a statistically significant co-occurrence of HER3 and KRAS mutations in CRCs while there is mutual exclusivity with mutations in EGFR or HER4 and mutant KRAS in CRC examining 6791 samples from 17 studies. There is a tendency for co-occurrence with HER2 and KRAS mutations that is not statistically significant in these CRC tumor samples. We have found that genetic knockdown of both KRAS and HER3 with siRNA targeting KRAS and HER3 in the CRC cell line SNU-407 (HER3V104M, KRASG12D) results in a statistical reduction in cell proliferation in comparison to genetic knockdown with only KRAS or HER3. Using the SW620 CRC cell line (HER3WT, KRASG12V) as a comparison, we have observed that knocking down HER3 using siRNA had no effect on cell proliferation whereas KRAS knockdown reduced proliferation and the combination showed no statistical difference compared to knocking down only KRAS. Additionally, we have found that there is a striking increase in total HER3 levels in SNU-407 cells when treated with the KRASG12D inhibitor MRTX1133. This feedback loop could limit the efficacy of the KRAS inhibitor. We wished to delineate mutant HER3’s binding partner(s) as HER3 is kinase impaired. Strikingly, we have found that EGFR immunoprecipitates with HER3 in SNU-407 cells. We are expanding our studies to CRC patient derived xenografts (PDXs) with co-occurring HER3 and KRAS mutations and have generated patient derived organoids from these PDXs. Ongoing studies are determining if there is a synergistic relationship with KRAS inhibitors and HER family inhibitors including a HER3 antibody-drug conjugate. Our findings may present a new paradigm for targeted combination therapies in colorectal cancer with the eventual goal of increased overall patient survival. Citation Format: Mary K. Kilroy, Briley Park, Rosalin Mishra, Wasim Feroz, Cecilia Wischmeier, Joan T. Garrett. Molecular insights into the oncogenic influence between mutant HER3, mutant KRAS, and their synergistic interplay in colorectal cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7150.
Abstract 7251: Surface-engineered extracellular vesicles to modulate antigen-specific T cell expansion for cancer immunotherapy
Authors: Xiabing Lyu, Tomoyoshi Yamano, Shota Imai, Toan Van Le, Rikinari Hanayama
Journal: Cancer Research (2024)

Abstract Tumor immunotherapy, including immune checkpoint therapy, CAR T cell therapy, and TCR-T cell therapy, has made significant progress in the treatment of cancer. Recently, newly developed nanomaterials have also been applied to anti-tumor immunotherapy. Among them, extracellular vesicles (EVs) have been well-engineered in recent years due to their low immunogenicity, high stability, and wide distribution in biological fluids. Despite the recent development of several EVs-based cancer immunotherapies, their clinical efficacy remains limited. In this study, we have developed engineered EVs designed to mimic the function of antigen-presenting cells, which can co-deliver multiple immune-activation signals to tumor-associated T cells. We named these vesicles Antigen-presenting Extracellular Vesicles (AP-EVs). AP-EVs express a high level of MHC I-peptide complexes, costimulatory molecules, and surface-bound cytokines, allowing for the simultaneous presentation of multiple immune modulators to antigen-specific CD8+ T cells. AP-EVs promote the clonal expansion and differentiation of antigen-specific cytotoxic T lymphocytes, resulting in potent anticancer immune responses. Notably, our findings indicate that combination therapy involving AP-EVs and anti-PD-1 yields superior anticancer immunity against established tumors compared to anti-PD-1 monotherapy. This synergistic effect underscores the potential of our engineered EVs as a novel and highly effective strategy for cancer immunotherapy. Citation Format: Xiabing Lyu, Tomoyoshi Yamano, Shota Imai, Toan Van Le, Rikinari Hanayama. Surface-engineered extracellular vesicles to modulate antigen-specific T cell expansion for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7251.
Abstract 1456: First successful engraftment of human liver cancer cell line in highly robust immunocompromised porcine model to test the tumor ablation efficacy by histotripsy
Authors: Tamalika Paul, Khan M. Imran, Jessica Gannon, Brie Trusiano, Kristin Eden, Hannah Ivester, Madeline Mott, Manali Powar, Michael Edwards, Christopher Byron, Sherrie Clark-Deener, Kiho Lee, Eli Vlaisavljevich, Irving Coy Allen
Journal: Cancer Research (2024)

Abstract Liver tumor, commonly called Hepatocellular carcinoma(HCC), is the most common type of primary liver malignancy. It is the fourth leading cause of cancer-related deaths. Late diagnosis, location of the tumor, tumor burden, and metastases makes liver tumor very challenging to treat by liver transplantation, surgical procedures, and other ablation techniques like cryoablation and thermal ablation. Also, the absence of a preclinical animal model makes it challenging to develop and explore the feasibility of treatment modalities. Histotripsy is a non-invasive, non-ionizing, non-thermal, image-guided focused ultrasound ablation treatment method that uses high-pressure pulses to create acoustic cavitation, a “bubble cloud,” at the target. The bubble cloud expands and collapses, which ablates the tissue into an acellular homogenate. Pigs are ideal animal models as they closely resemble human anatomy and are significant in improving the translation to human patients. This study aimed to establish the feasibility of successfully ablating liver tumors by histotripsy using an immunocompromised porcine model to generate HepG2 human liver cancer cell line tumors in the liver of the immunocompromised pigs. The orthotopic porcine model was established using RAG2/IL2RG double knockout immunocompromised pigs. HepG2 cells were injected orthotopically into the liver of immunocompromised pigs. Three weeks after the injections, CT images and necropsy indicated successful engraftment and growth of liver tumors in the pigs. The ultrasound images and post-histotripsy treatment histology images showed confirmed ablation zones in the liver. Therefore, in conclusion, our preliminary results in the study could demonstrate, for the first time, a highly robust model of human liver cancer in a large animal model. Soon, we plan to conduct more such studies and explore all the possible utilities of these immunocompromised porcine models to develop therapeutic strategies to increase the efficacy of liver tumor ablation by histotripsy. Citation Format: Tamalika Paul, Khan M. Imran, Jessica Gannon, Brie Trusiano, Kristin Eden, Hannah Ivester, Madeline Mott, Manali Powar, Michael Edwards, Christopher Byron, Sherrie Clark-Deener, Kiho Lee, Eli Vlaisavljevich, Irving Coy Allen. First successful engraftment of human liver cancer cell line in highly robust immunocompromised porcine model to test the tumor ablation efficacy by histotripsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1456.
Abstract 3082: The liver microenvironment promotes glycolysis in metastatic colorectal cancer by activating her3
Authors: Moeez Ghani Rathore, Kimberly Curry, Christina Boutros, Zhenghe Wang, Jordan Winter, Rui Wang
Journal: Cancer Research (2024)

Abstract Background: Liver metastasis occurs in ~80% of all metastatic colorectal cancer (mCRC) and the liver has a unique endothelial cell (EC)-rich microenvironment that promotes cancer cell survival. We previously reported that liver ECs secrete soluble factors to promote CRC growth via activating CRC-associated the HER3 signaling pathway. The present study reports that ECs promote mCRC growth by shifting cancer metabolism towards glycolysis and elucidates the involved signaling pathway. Methods: We performed mass spectrometry to profile the metabolic changes in mCRC treated with/without HER3 inhibition in a syngeneic, orthotopic mCRC model. We also performed Seahorse and lactate ELISA assays to determine the effect of liver EC-secreted factors on CRC metabolism. To further determine the role of HER3 in promoting glycolysis and CRC growth in the liver, we used siRNA silencing of HER3 and pharmacological inhibition of HER3 downstream signaling proteins to identify the key mediator(s) of HER3-induced metabolic shift in CRC. Results: We determined that HER3 inhibition leads to increased oxidative phosphorylation metabolites (OXPHOS) and decreased glycolysis metabolites in CRC liver metastases. Conditioned medium containing EC-secreted factors decreased oxygen consumption (determined by Seahorse, a readout of OXPHOS) and increased lactate secretion (determined by ELISA, a readout of glycolysis) in CRC. As HER3 inhibition reversed the metabolic shift and increased OXPHOS as an alternative survival strategy, we found that simultaneous inhibition of HER3 and OXPHOS synergistically blocked CRC cell and tumor growth. Lastly, we found that PFK2 is activated by HER3 signaling, determined by phosphorylation, and determined that the HER3-AKT-PFK2 signaling axis is the key mediator of EC-induced metabolic shifts. Conclusions: We identified that the liver microenvironment activates HER3 and the downstream AKT-PFK2 signaling to promote glycolysis and growth in CRC liver metastases by activating AKT-PFK2-dependent glycolysis. Our findings highlighted the potential of combining HER3 and OXPHOS inhibitions as a potential strategy for treating patients with mCRC. Citation Format: Moeez Ghani Rathore, Kimberly Curry, Christina Boutros, Zhenghe Wang, Jordan Winter, Rui Wang. The liver microenvironment promotes glycolysis in metastatic colorectal cancer by activating her3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3082.
Abstract 2364: Anti-CADM1 chimeric antigen receptor (CAR) is a novel therapeutic strategy against small cell lung cancer
Authors: Shiva Krishna Katkam, Sergei Zolov, Delaney Shield, Sergei Chuikov, Venkateshwar G Keshamouni
Journal: Cancer Research (2024)

Abstract Small cell lung cancer (SCLC) is a highly aggressive form accounting for 15% of all lung cancers. SCLC is characterized by high proliferative rates, early metastasis, and poor prognosis. The median survival is less than 2 years even in patients with early-stage disease and less than a year in patients with metastatic disease which highlights the need for new therapeutic strategies. Cell Adhesion Molecule (CADM) 1 encodes a glycoprotein which belongs to an immunoglobulin superfamily of cell adhesion molecules responsible for epithelial cell adhesion through its homophilic trans-interaction between the adjacent cells. CADM1 is highly expressed on the cell surface of 80% of the SCLC cells, associated with its neuroendocrine features, along with the expression of Neural Cell Adhesion Molecule (NCAM). CADM1 is known to act as tumor promoter through its interactions with actin binding proteins. Consistently, we observed CADM1 expression in H69, H82, and H510 SCLC cell lines as assessed by western immuno blot. More importantly they were all susceptible to NK mediated cytotoxicity when assessed against NK cell line, NK92. We previously demonstrated that CADM1 mediates NK-mediated immune surveillance in non-small cell lung cancer, suggesting that CADM1 could be a potential immunotherapeutic target for SCLC. Here we report the development of an anti-CADM1 chimeric antigen receptor (CAR) specific for T and NK cells engineered with T and NK cell specific adaptor domains. Assessed the specificity of CARs by expressing them in NK92 cells and testing them against CADM1 expressing and CADM1-null A549 cells as targets. Finally, we evaluated the efficacy of anti-CADM1 CAR-T and CAR-NK cells against SCLC targets and observed a robust killing, largely proportionate to the levels of CADM1 expression in them. We are further assessing the efficacy of anti-CADM1 CAR-T and CAR-NK products in inhibiting tumor growth in NSG mice against SCLC xenografts. Together, these observations demonstrate that targeting CADM1 with CAR-T and CAR-NK cells is a potential new therapeutic strategy for SCLC. Citation Format: Shiva Krishna Katkam, Sergei Zolov, Delaney Shield, Sergei Chuikov, Venkateshwar G Keshamouni. Anti-CADM1 chimeric antigen receptor (CAR) is a novel therapeutic strategy against small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2364.
Abstract 7146: HSK39775: A USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies
Authors: Jun Xu, Yangguang Li, Ju Wang, Pingming Tang, Jianmin Wang, Chen Zhang, Pangke Yan
Journal: Cancer Research (2024)

Abstract Tumors with BRCA1/2 mutations or homologous repair deficiency (HRD) are vulnerable to agents that target DNA repair pathways, including platinum-containing chemotherapeutics and poly (ADP-ribose) polymerase-1 (PARP1) inhibitors. Despite the significant therapeutic benefits in patients with BRCAm or HRD, innate and acquired resistance to PARPi is still a challenge in the clinic. To address this clinical challenge, we developed HSK39775, a potent, highly selective inhibitor of ubiquitin carboxyl-terminal hydrolase 1 (USP1), which acts as an oncogenic and PARP inhibitor resistance driver involved in DNA damage repair pathway through the deubiquitylation of proteins in Translesion Synthesis pathway and Fanconi Anemia pathway, paired with BRCA as a synthetic lethality target. HSK39775 was active in enzymatic level to inhibit USP1/UAF1 complex. Enzymatic panel screening containing 50 deubiquitinase demonstrated high selectivity of HSK39775. Ubiquitinated PCNA was accumulated treated by HSK39775, indicating target engagement. HSK39775 also demonstrated potent anti-proliferation activity against cancer cell lines with BRCA mutation and excellent selectivity between BRCA WT vs. BRCAm. Combining HSK39775 with PARP inhibitors indicated synergy in cell lines with partial or insensitivity to each agent alone. Triple-negative BRCA mutant breast cancer xenograft model demonstrated strong dose-dependent tumor growth inhibition of HSK39775 as a single agent with Tumor Growth Inhibition (TGI) of 63.2% at 30 mg/kg QD, and ubiquitinated PCNA was also accumulated in HSK39775 treated tumor tissue. Meanwhile, combination with PARP inhibitors significantly enhanced the therapeutic efficacy of HSK39775 in xenograft model and led to tumor regressions and durable tumor control even at low dose (TGI:89% (HSK39775, 5 mg/kg + Olaparib, 50 mg/kg)). Interestingly, HSK39775 inhibited the tumor growth of a HRP and BRCA wild-type lung cancer xenograft as a single agent with TGI of 94% at 30 mg/kg QD, suggesting the therapeutic effect of USP1 inhibitors beyond canonical BRCA mutant or HRD tumors. In summary, these results indicate HSK39775 as a potent and selective USP1 inhibitor and support further development. Citation Format: Jun Xu, Yangguang Li, Ju Wang, Pingming Tang, Jianmin Wang, Chen Zhang, Pangke Yan. HSK39775: A USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7146.