tbuckley/cabot-search huggingface dataset:
Abstract 1358: Elucidating the contribution of T cell-intrinsic VISTA to the suppression of antitumor T cell immunity
Authors: Sachin Patnaik, Elizabeth Delaney, Cassandra Gilmour, Keman Zhang, Amin Zakeri, Hieu M. Ta, Prerana B. Parthasarathy, Tyler Alban, Timothy Chan, Li Lily Wang
Journal: Cancer Research (2024)

Abstract Immune checkpoint receptors (ICRs) negatively regulate antitumor immune responses. While significant advances have been made in understanding the mechanisms of well-established ICRs such as PD-1 and CTLA-4, other checkpoint proteins remain incompletely characterized and may be targeted to synergistically boost antitumor immunity. One such protein is V-domain immunoglobulin suppressor of T-cell activation (VISTA), an ICR whose expression curtails the function of several lymphoid and myeloid lineages, including tumor-reactive cytotoxic T cells. Globally blocking VISTA elicits potent T cell-mediated antitumor immunity and systemic myeloid cell-mediated inflammatory responses. Mechanistically, VISTA has been shown to inhibit T cell activation by acting as an inhibitory ligand on antigen-presenting cells. However, the impact of T cell-intrinsic VISTA on modulating tumor-reactive T cell responses has not been thoroughly investigated, and it remains unclear whether blocking T cell-specific VISTA is adequate for revitalizing T cell-mediated tumor control. In this study, we utilized VISTA conditional knockout mice models to examine the relative contribution of T cell-intrinsic VISTA versus myeloid-derived VISTA in the regulation of antitumor immunity. We present evidence that blocking VISTA on T cells alone is insufficient to induce strong antitumor immune responses, whereas blocking VISTA on myeloid cells counteracts its dominant role in orchestrating T cell suppression. Citation Format: Sachin Patnaik, Elizabeth Delaney, Cassandra Gilmour, Keman Zhang, Amin Zakeri, Hieu M. Ta, Prerana B. Parthasarathy, Tyler Alban, Timothy Chan, Li Lily Wang. Elucidating the contribution of T cell-intrinsic VISTA to the suppression of antitumor T cell immunity [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 1358.
Abstract 1220: Deep mutational scanning of EGFR reveals potential domain-specific TKI sensitivities in lung cancer and glioblastoma
Authors: Tikvah Hayes, Elisa Aquilanti, Erica Kim, Nicole Persky, Lisa Brenan, Amy Goodale, Ted Sharpe, Doug Alan, Robert Shue, Lior Golomb, Brianna Silverman, Yvonne Li, Lindsay Westlake, Federica Piccioni, Andrew Cherniack, Xiaoping Yang Yang, David Root, J. Kevin Hicks, Andrew Chi, Jorg Dietrich, Daniel Cahill, Cory Johannessen, Tracy Batchelor, Matthew Meyerson
Journal: Cancer Research (2024)

Abstract The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We performed saturation mutagenesis of EGFR and assessed function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach revealed enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, lacking approved targeted therapies, were sensitive to dacomitinib. Strikingly, at least two glioblastoma patients with G598V dimerization domain mutations showed responses to dacomitinib treatment together with subsequent off-target resistance in one case. In summary, this comprehensive screen reveals novel functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations. Citation Format: Tikvah Hayes, Elisa Aquilanti, Erica Kim, Nicole Persky, Lisa Brenan, Amy Goodale, Ted Sharpe, Doug Alan, Robert Shue, Lior Golomb, Brianna Silverman, Yvonne Li, Lindsay Westlake, Federica Piccioni, Andrew Cherniack, Xiaoping Yang Yang, David Root, J. Kevin Hicks, Andrew Chi, Jorg Dietrich, Daniel Cahill, Cory Johannessen, Tracy Batchelor, Matthew Meyerson. Deep mutational scanning of EGFR reveals potential domain-specific TKI sensitivities in lung cancer and glioblastoma [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 1220.
Abstract 1219: In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables ATAD3A gene depletion to enhance RAS-targeted therapy
Authors: Fanghui Chen, Liwei Lang, Yamin Li, Wei Zheng, Yong Teng
Journal: Cancer Research (2024)

Abstract Targeting mitochondrial oncoproteins presents a new concept in developing effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme that contributes to mitochondrial dynamics, cholesterol metabolism, and signal transduction. Our previous study has demonstrated elevated expression of ATAD3A in head and neck squamous cell carcinoma (HNSCC) primary tissues and cultured cell lines. Loss of function suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice. Mechanistically, ATAD3A interacts with ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion. CRISPR-Cas9 has revolutionized genome engineering and has been intensively used to modify cancer-associated genes. However, challenges remain as CRISPR editing components must be transported into cells to exert their function. There is a need to explore effective in vivo delivery systems to accelerate the clinical use of CRISPR-Cas9. As no drug is available to target ATAD3A directly, we developed CRISPR-based ATAD3A-targeting nanodrugs by loading Cas9 mRNA and anti-ATAD3A sgRNAs into lipid nanoparticles (LNPs) that have become clinically acceptable delivery system due to low toxicity and high delivery efficacy and biocompatibility. As expected, treatment tongue tumors established in NSG mice with LNP-sgATAD3A remarkably repressed tumor growth. Most interestingly, the addition of LNP-sgATAD3A to the RAS inhibitor salirasib potentiated anticancer activity for HNSCC compared with the efficacy resulting from single-arm treatment. These novel and significant findings demonstrate a novel approach to inhibiting ATAD3A in tumor cells and provide a possible therapeutic strategy to enhance the success of multimodality therapy in cancer patients. Citation Format: Fanghui Chen, Liwei Lang, Yamin Li, Wei Zheng, Yong Teng. In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables ATAD3A gene depletion to enhance RAS-targeted therapy [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 1219.
Abstract 1697: Phase separation of BHLHE40 up-regulates SREBF1 and inhibits ferroptosis in pancreatic cancer cells
Authors: Yizhi Cao, Xuelong Wang, Yang Liu, Pengyi Liu, Jiejie Qin, Youwei Zhu, Shuyu Zhai, Minmin Shi, Weishen Wang, Xiaxing Deng, Chenghong Peng, Hao Chen, Ruibao Ren, Lingxi Jiang, Baiyong Shen
Journal: Cancer Research (2024)

Abstract Pancreatic cancer (PCa) is one of the most lethal malignancies in human cancers. The enhanced infiltration of stromal tissue of PCa tumor microenvironment limits the identification of key tumor-specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multi-omics analysis of paired PCa organoids indicated that the basic helix-loop-helix transcription factor 40 (BHLHE40) was significantly upregulated in tumor samples. Increased chromatin accessibility at promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation (ChIP)-seq, RNA-seq and high-through chromosome conformation capture (Hi-C) data together with chromosome conformation capture (3C) assay indicate that BHLHE40 not only regulates the sterol regulatory element-binding factor 1 (SREBF1) transcription as a classic transcription factor, but also links the enhancer and promoter regions of SREBF1 via forming liquid-liquid phase-separated droplets. Then, we find the BHLHE40-SREBF1-stearoyl-CoA desaturase (SCD1) axis protects PCa cells from ferroptosis, leading to the reduced accumulation of lipid peroxidation in cells. Moreover, SREBF1 inhibitor, Fatostatin, significantly suppresses the cell growth of PCa tumors with higher expression of BHLHE40. This study highlights the important roles of BHLHE40 mediated lipid peroxidation in inducing ferroptosis of PCa cells and provides a novel mechanism underlying the SREBF1 overexpression in PCa. Citation Format: Yizhi Cao, Xuelong Wang, Yang Liu, Pengyi Liu, Jiejie Qin, Youwei Zhu, Shuyu Zhai, Minmin Shi, Weishen Wang, Xiaxing Deng, Chenghong Peng, Hao Chen, Ruibao Ren, Lingxi Jiang, Baiyong Shen. Phase separation of BHLHE40 up-regulates SREBF1 and inhibits ferroptosis in pancreatic cancer cells [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 1697.
Abstract 1440: Retinoblastoma binding protein 9 regulates intestinal inflammation and inflammation-associated carcinogenesis
Authors: Yuki Nakanishi, Kensuke Hamada, Mayuki Omatsu, Kosuke Iwane, Hiroki Kitamoto, Maokoto Okabe, Yu Muta, Shuji Yamamoto, Akihisa Fukuda, Hiroaki Kasashima, Hiroshi Seno
Journal: Cancer Research (2024)

Abstract The intestinal epithelium constitutes the mucosal barrier, and its dysfunction promotes microbial invasion from the gut lumen, which further induces the intestinal inflammation. Chronic intestinal inflammation, as observed in poorly controlled inflammatory bowel diseases (IBD), leads to the development of inflammation-associated cancer. Thus, a deeper understanding of the regulatory system that controls intestinal homeostasis is essential. Retinoblastoma-binding protein 9 (RBBP9) is expressed in a range of human cancer cells. RBBP9 was initially reported to have the ability to regulate the cell cycle pathway. More recent studies have identified RBBP9 as a serine hydrolase (SH) that promotes cancer progression by subverting the anti-proliferative function of TGFβ in a pancreatic cancer model. However, little is known about the roles RBBP9 plays in the development of intestinal cancer. In this study, we investigated the role of RBBP9 in inflammation and inflammation-associated cancer in the intestine. Analyses of surgically resected human samples and publicly available datasets demonstrated that RBBP9 expression was reduced in patient samples of ulcerative colitis (UC) and colitis-associated cancer (CAC). Genetically knockout mice for Rbbp9 (Rbbp9−/−) were susceptible to experimental colitis induced by dextran sulfate sodium (DSS). Furthermore, Rbbp9−/− mice exhibited enhanced azoxymethane/DSS-induced tumorigenesis, a model for human CAC. Mechanistically, RNA sequencing of these tumors showed increased enrichment of inflammation-associated signatures, including interferon signaling pathways. Ex vivo organoid experiments revealed the suppressive function of RBBP9 in interferon signaling-mediated apoptosis of the intestinal epithelium. Simultaneous inhibition of RBBP9 and STAT1, a downstream transcription factor of interferon signaling, reverted the apoptotic phenotype of Rbbp9−/− organoids. Collectively, our data provide insight into the understanding of the crucial role of RBBP9 in protecting against intestinal inflammation and inflammation-related tumorigenesis via regulating the interferon signaling-mediated apoptotic pathway. Citation Format: Yuki Nakanishi, Kensuke Hamada, Mayuki Omatsu, Kosuke Iwane, Hiroki Kitamoto, Maokoto Okabe, Yu Muta, Shuji Yamamoto, Akihisa Fukuda, Hiroaki Kasashima, Hiroshi Seno. Retinoblastoma binding protein 9 regulates intestinal inflammation and inflammation-associated carcinogenesis [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 1440.
Abstract 1439: Elucidation of the pathogenesis of prostate cancer harboring mutations of epigenetic factor UTX using genetically engineered mice
Authors: NOBUHITO MURAMOTO, Masayuki Iwasaki, Yasuyuki Sera, Hisamitsu Ide, Shoichiro Mukai, Tsuyoshi Fukushima, Shigeo Horie, Hiroaki Honda
Journal: Cancer Research (2024)

Abstract Introduction and Objective: Histone modifications are important for tissue homeostasis, and their mutations are involved in carcinogenesis. Mutations in a histone modifier, UTX (KDM6A) are common in prostate cancer (PCa), which is frequently associated with loss of its counterpart UTY (KDM6C). However, mechanisms underlying the development of UTX-deficient PCa are not clear. We aimed to address this issue by generating and analyzing genetically-engineered mice. Methods: We generated mice with deletion of both Utx and Uty in the prostate tissue (UtxΔ, UtyΔ) and crossed with mice with a heterozygous deletion of p53 (p53+/−) to create UtxΔ, UtyΔ and p53+/− compound mice. High-fat diet (HFD) that is known to promote cancer growth was administered to mice. We found that UtxΔ, UtyΔ, p53+/− mice treated with HFD developed PCa with Gleason score (GS) = 3+3. Isolated prostate tissues were subjected to pathologic, molecular, and cellular analyses. In addition, RM-2 mouse PCa cells which do not express UTY were knocked down for Utx (siUtx) and control (siNC) by siRNAs to assess changes in the abilities of proliferation and migration. Results: RM-2 siUtx cells showed increased proliferation and migration compared with RM-2 siNC cells. By performing high-throughput RNA sequencing (RNA seq) and gene set enrichment analysis (GSEA) using mouse prostate tissues, we found that loss of UTX in the prostate activated inflammatory pathways, whereas inactivated DNA damage repair pathways. Immunostaining prostate tissues with an antibody to a macrophage marker, F4/80, exhibited significant accumulation of macrophages in UtxΔ, UtyΔ, p53+/+ mice compared to Utx+, UtyΔ, p53+/+ mice. In addition, immunofluorescent staining of irradiated prostate tissues with an antibody against a DNA repair marker, γH2AX, revealed that the time required for DNA damage repair was markedly prolonged in UtxΔ, UtyΔ, p53+/+ mice compared with Utx+, UtyΔ, p53+/+ mice. Conclusions: These results suggest that loss of UTX contributes to prostate cancer development through promoting inflammation and impairing DNA damage repair, which may serve as novel therapeutic targets in PCa patients with UTX mutations. Citation Format: NOBUHITO MURAMOTO, Masayuki Iwasaki, Yasuyuki Sera, Hisamitsu Ide, Shoichiro Mukai, Tsuyoshi Fukushima, Shigeo Horie, Hiroaki Honda. Elucidation of the pathogenesis of prostate cancer harboring mutations of epigenetic factor UTX using genetically engineered mice [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 1439.
Abstract 2097: ABT co-dose accelerated target validation with a fit-for-purpose HPK1 inhibitor tool
Authors: Joey L. Methot, Joanna L. Chen, Elsie Yu, Ryan D. Otte, Haiyan Xu, Zangwei Xu, Brian Lacey, Jason Laskey, Robbie Mcleod, Dustin Smith, Alexander Pasternak
Journal: Cancer Research (2024)

Abstract Target validation can be challenging when mouse efficacy studies require achieving a high therapeutic exposure of a tool compound, ideally with a low peak-to-trough (P/T) ratio to avoid Cmax-induced toxicity. Herein, we describe the daily co-administration of the CYP inhibitor aminobenzotriazole (ABT) as a well-tolerated PK enhancer for medium-term efficacy studies in mice, enabling faster decision-making in the early space with imperfect tools. Genetic studies in mice have suggested that HPK1 inhibition would lead to enhanced effector T-cell function, decreased tumor growth and enhanced αPD-L1 efficacy. However, it remains unknown whether immune activation by pharmacological inhibition of HPK1 will recapitulate the genetic deletions. We developed a fit for purpose tool compound with picomolar HPK1 potency, excellent kinome selectivity (98% &amp;gt;100x, ATP-Km corrected), dose-dependent inhibition of pSLP76, sustained IL2 elevation in PBMCs, and IL6/TNFa elevation in dendritic cells. The mouse PK for this tool was inadequate, having a low exposure (AUC 16 uM-hr at 100 mg/kg po) and a high P/T ratio of 13 that could lead to an erosion of kinome selectivity in vivo; complicating efficacy interpretation and limiting overall tolerability. However, when co-dosed with ABT (50 mg/kg po 2 h prior to the HPK1 inhibitor), improved exposure of our tool was achieved (AUC 63 uM-hr at 100 mg/kg po), 90% inhibition of pSLP76 was maintained at C(trough), and the P/T ratio was reduced to 3 to avoid Cmax-induced toxicity. The inhibitor was well-tolerated co-dosed with ABT for three weeks in mice, enabling studies sooner to probe HPK1 pharmacological inhibition in cancer immunotherapy as a monotherapy as well as in combination with a mouse anti-PD-1 antibody. Citation Format: Joey L. Methot, Joanna L. Chen, Elsie Yu, Ryan D. Otte, Haiyan Xu, Zangwei Xu, Brian Lacey, Jason Laskey, Robbie Mcleod, Dustin Smith, Alexander Pasternak. ABT co-dose accelerated target validation with a fit-for-purpose HPK1 inhibitor tool [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 2097.
Abstract 1690: LSD1 and CoREST2 demethylate STAT3 to promote enteroendocrine cell differentiation in mucinous colorectal cancer
Authors: Christopher A. Ladaika, Ahmed H. Ghobashi, William C. Boulton, Heather M. O'Hagan
Journal: Cancer Research (2024)

Abstract Across different cancer types, tumor heterogeneity has been shown to drive tumor progression, metastasis, and therapeutic resistance. Adenocarcinoma to neuroendocrine lineage transition is an emergent mechanism of targeted therapy resistance in several cancer types, including lung and prostate cancer. Therefore, understanding the dynamics and mechanisms driving neuroendocrine cell fates in cancer is critical. Mucinous colorectal cancer accounts for upwards of 20% of colorectal cancer cases and is characterized by tumors with mucous accounting for at least 50% of the tumor volume. The normal colon epithelium consists of several specialized cell types, including hormone secreting enteroendocrine cells (EECs), which are the neuroendocrine cell of the intestine. We have previously shown that EEC progenitors are enriched in mucinous colorectal cancer and promote cancer cell survival via secreted factors. Additionally, we have shown that lysine specific demethylase 1 (LSD1) promotes EEC differentiation in these tumors; however, the mechanism by which LSD1 promotes EEC differentiation has remained unknown. Typically to carry out its enzymatic function, LSD1 must be a part of a transcriptional regulatory complex. One such complex is the CoREST complex, which contains LSD1, HDAC1, and one of three CoREST protein family members. Here we report that LSD1 and CoREST2 promote EEC differentiation by demethylating the transcription factor signal transducer and activator of transcription 3 (STAT3) to promote STAT3 chromatin binding. Additionally, we demonstrate that knocking down CoREST2 decreases tumor growth and lung metastases of mucinous colorectal cancer cells injected orthotopically into the colons of immunocompromised mice. Furthermore, we utilized single cell multi-omics that combines single cell RNA sequencing with single cell ATAC sequencing to show that during EEC differentiation there is an increase in chromatin accessibility at regulatory regions of known EEC-promoting transcription factors. Finally, through our single cell multi-omics analysis we identify a new rare cell type with neuron-like but not secretory characteristics. Mucinous colorectal cancer is an aggressive and chemotherapeutically intractable form of CRC that is enriched for EEC progenitors. Our data demonstrates that LSD1 and STAT3 promote EEC differentiation, suggesting that inhibiting LSD1 and or STAT3 may have benefits for patients with mucinous colorectal cancer. Citation Format: Christopher A. Ladaika, Ahmed H. Ghobashi, William C. Boulton, Heather M. O'Hagan. LSD1 and CoREST2 demethylate STAT3 to promote enteroendocrine cell differentiation in mucinous colorectal 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 1690.
Abstract 1551: Succinyl-CoA synthetase Beta-A: A novel metastasis promoting factor in lung cancer
Authors: Jihoon Kang, Jung Seok Hwang, Austin C. Boese, Sydney Shuff, Jaehyun Kim, Kiyoung Eun, Sumin Kang
Journal: Cancer Research (2024)

Abstract Changes in metabolism occur when cancer cells disseminate from primary sites and metastasize. Mitochondrial metabolism plays an essential role in various biological processes of cancer cells, but the underlying mechanism through which mitochondrial factors contribute to cancer metastasis remains largely elusive. Anoikis is a form of apoptosis induced by loss of cell adhesion, and metastatic tumor cells must be anoikis resistant to survive during circulation before forming metastatic foci in distant organs. We performed an unbiased RNAi screen using a customized mitochondrion shRNA library and identified succinyl-CoA synthetase beta-A (A-SCS, also called SUCLA2), which is known to catalyze the reversible conversion of succinyl-CoA and ADP to succinate and ATP in the TCA cycle as an essential factor that promotes the survival of disseminated cancer cells during metastasis. We demonstrate that A-SCS manages redox balance during tumor metastasis, and this metabolic contribution is independent of its role in the TCA cycle. Mechanistically, A-SCS relocates from the mitochondria to the cytosol and binds to stress granules, promoting stress granules to express the redox-scavenging enzyme catalase upon cell detachment. This mitigates oxidative stress and makes cancer cells survive through anoikis, eventually promoting metastasis. A clinical correlation study comparing primary and metastasized tumors collected from lung cancer patients demonstrated that A-SCS levels align with catalase expression as well as the metastatic progression of lung cancer. Our finding provides an academic basis for developing new treatment targets against metastasis, which strikes elevated mitochondrial metabolism during cancer cell dissemination. Citation Format: Jihoon Kang, Jung Seok Hwang, Austin C. Boese, Sydney Shuff, Jaehyun Kim, Kiyoung Eun, Sumin Kang. Succinyl-CoA synthetase Beta-A: A novel metastasis promoting factor in 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 1551.