tbuckley/cabot-search huggingface dataset:
Abstract 3417: Dissecting tumor microenvironment to predict clinical outcome in prostate cancer
Authors: Aritri Bhattacharjee, Manjusha Biswas, Amjad Husain, Asim Kr Das, Sourav Karmakar Karmakar, Tapan Mondal, Pinaki Roy, Manas Kr Mondal, Badal Kumar Sahu, Nabendu Murmu, Partho Nath, Chandra C. Ghosh, Pradip Kumar Majumder
Journal: Cancer Research (2024)

Abstract Prostate cancer is one of the major causes of cancer death in males, and its prevalence is particularly high in developed countries such as the United States and Western Europe. However, death rates in developing and underdeveloped countries are greater, presumably, due to a lack of routine clinical check-ups, poor health awareness, inadequate screening resources, and clinical intervention. Much progress has already been made using cutting-edge technologies like whole genome sequencing, RNAseq, phosphoproteomics, and targeted transcriptomic Nanostring profiling, etc. However, understanding of the prostate tumor microenvironment as a whole in clinical samples remains very limited. Here we use the latest genomic, proteomics, and metabolomic tools not only to understand the biology of prostate cancers but also their correlation with patient demography and clinical outcome. We recruited 80 patients from both tertiary research hospitals and clinical centers in the eastern region of India. All of their demographic information is collected along with their clinical outcome. Pathological evaluation revealed only 50 patients with positive Prostate Carcinoma. We performed a detailed analysis using experimental data (from genomic, and proteomic) in a cohort of patients' routine biomarkers (PSA and PSMA), histopathology, and clinical outcome. Our data demonstrate no linear correlation of any of the individual markers or parameters like AR status, PSA, Prostate Specific Acid Phosphatase, Prostate-Specific Membrane Antigen (PSMA), Alpha-methylacyl-CoA racemase (AMACR), Mesothelin, PD-L1, and other potential genomic and proteomic alterations or any histopathological readouts. However, a clear understanding of the relationship between these multiparameter data, disease pathology, and clinical outcomes in a group of patients has been established. The heterogeneity of these individual data for tumor microenvironments will lead us to identify novel biomarkers for the clinical response of targeted drugs, accelerating personalized treatment strategies. Citation Format: Aritri Bhattacharjee, Manjusha Biswas, Amjad Husain, Asim Kr Das, Sourav Karmakar Karmakar, Tapan Mondal, Pinaki Roy, Manas Kr Mondal, Badal Kumar Sahu, Nabendu Murmu, Partho Nath, Chandra C. Ghosh, Pradip Kumar Majumder. Dissecting tumor microenvironment to predict clinical outcome in prostate 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 3417.
Abstract 2176: Differences in gut microbial composition alter pancreatic tumorigenesis
Authors: Rian M. Howell, Jose Enriquez Ortiz, Olivia Le Roux, Vidhi Chandra, Le Li, Pratip K. Bhattacharya, Florencia McAllister
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths by 2030, and currently has a 5-year survival rate of roughly 10%. With long-term survival rates in patients being exceedingly low, understanding what factors delineate survival is imperative. When comparing spontaneous transgenic mouse models of pancreatic cancer housed in geographically distinct vivaria, regardless of a common lineage, we observed drastically different phenotype states in the respective locations. We hypothesize that the gut microbiome results in different gene expression profiles, leading to alterations in pancreatic tumorigenesis. Using various sequencing techniques, including 16s rRNA and RNA sequencing of the gut, we identified unique signatures at these respective institutions. Subsequent fecal microbiota transplantation and single bacterial species colonization experiments were performed to evaluate the ability of microbiomes/specific microbiota to alter the rate of tumorigenesis. In addition to probing the gut microbiome, circulating metabolites from individual mice were quantified, and correlated to phenotype state. Following identification of potentially tumorigenic bacterially derived metabolites, single bacteria colonization experiments were utilized to determine the downstream effects of identified metabolites as well as the ability of directly altering the metabolic landscape to drive tumorigenesis. Additionally, murine derived pancreatic cancer cells were exposed to both identified bacteria alone or bacterially produced metabolite and analyzed by metrics such as proliferation and relative expression of transcription factors associated with cancer development in vitro. Taken together, these data demonstrate the ability of distinct gut microbiomes to directly alter the metabolic landscape in mice, thus differentially altering the progression of pancreatic lesions. By better understanding the factors that stratify survivorship, we can begin to employ clinically actionable methodologies in the treatment or prevention of pancreatic cancer. Citation Format: Rian M. Howell, Jose Enriquez Ortiz, Olivia Le Roux, Vidhi Chandra, Le Li, Pratip K. Bhattacharya, Florencia McAllister. Differences in gut microbial composition alter pancreatic tumorigenesis [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 2176.
Abstract 753: CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon cancer
Authors: Krishanu Bhowmick, Kazufumi Ohshiro, Xiyan Xiang, Sahara John, Xiaochun Yang, Kevin Idicula, Nicole Beauchemin, Raja Mazumder, Keith A. Crandall, Mohammad I. Hassan, Taj Mohammad, Lopa Mishra
Journal: Cancer Research (2024)

Abstract Background: Colon cancer is rising in younger individuals in the United States. Potential causal factors are altered diets and gut microbiomes. Yet key signaling pathways, host-microbe interactions, and metabolites such as ammonia in cancer remain unclear. CEACAM1 responds to pathogenic microbes, interacts with the TGF-β/SPTBN1 and levels are raised in invasive colon cancer. Alterations in the TGF-β pathway occur ~40% of human GI cancers, and mouse models with disrupted TGF-β signaling (Tgfbr2−/−, Smad4+/−Sptbn1+/−, and Tgfb1−/−) develop colorectal cancer (CRC) that is dependent upon an altered gut microbiome. Our previous studies indicate the lipid metabolites (reactive aldehydes) form toxic adducts with cleaved SPTBN1 and divert TGF-β signaling to pro-oncogenic process. Poor prognosis CRC is associated with raised levels of microbial metabolites, such as ammonia. Thus, we hypothesized that “the intricate relationships among pathogen-binding CEACAM1, the gut microbiome, metabolites such as ammonia, and βII-Spectrin drive colon cancer development”. Methods: We examined gut microbiota composition, immune cell population, inflammation, and cancers in Smad4+/−Sptbn1+/− and Sptbn1LSKO mice fed a normal chow diet or a high-fat diet (HFD). We evaluated CEACAM1 and TGF-β member alterations in in CRCs using TCGA datasets. Alphafold-based molecular modeling predicted interaction sites between βII-Spectrin and CEACAM1 was followed by functional studies. Results: Increased CEACAM1 levels with alterations in TGF-β members were associated with lower survival (TCGA). Mice with disrupted TGF-β signaling (Smad4+/−Sptbn1+/−) develop CRC, have high CEACAM1 levels, and an altered gut microbiome signature. CEACAM1 interacts with βII-Spectrin, and levels are restored to normal in βII-Spectrin LSKO which restores the gut microbiome and blocks inflammation and cancer. Ammonia induces CASPASE-3 mediated cleavage of βII-Spectrin, forms toxic adducts and divert TGF-β signaling to pathological pro-oncogenic signaling, triggering CRC. Conclusion: We have found a critical role for CEACAMs in CRC cancer development, through diverting the TGF-β signaling pathway to a pro-oncogenic phenotype. CEACAM1 and βII-Spectrin are attractive therapeutic targets for CRC. Citation Format: Krishanu Bhowmick, Kazufumi Ohshiro, Xiyan Xiang, Sahara John, Xiaochun Yang, Kevin Idicula, Nicole Beauchemin, Raja Mazumder, Keith A. Crandall, Mohammad I. Hassan, Taj Mohammad, Lopa Mishra. CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon 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 753.
Abstract 3916: TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 immunotherapy
Authors: Ayushi Patel, Soumyadip Sahu, Ke Geng, Salman Punekar, Janaye Stephens, Jiehui Deng, Ting Chen, Leanne Ahronian, Minjie Zhang, Jannik Andersen, Brian Haines, Kwok-Kin Wong
Journal: Cancer Research (2024)

Abstract Loss of function (LOF) of the serine-threonine kinase STK11/LKB1, which has been reported in ~15% of non-small cell lung cancer (NSCLC), drives resistance to immune checkpoint therapies such as PD1. In vivo CRISPR screens in tumor-bearing immune competent mice identified the Corepressor of Repressor Element 1 Silencing Transcription (CoREST) complex as a synthetic lethal immune evasion target for STK11- mutant tumors. Here, we demonstrate that TNG260, a small molecule drug specifically targeting the CoREST complex, can sensitize STK11 mutant lung cancers to anti-PD1 immunotherapy. Combination treatment with TNG260 and anti-PD1 arrested KRAS/STK11 mutant NSCLC tumor growth with no major toxicity observed, as confirmed in both allograft and genetically engineered mouse models (GEMMs) of STK11 mutant NSCLC. Further transcriptional analysis via bulk RNA-seq revealed that treatment of KRAS/STK11 mutant lung tumors with TNG260 promotes genes related to inflammatory responses and suppresses genes related to cell cycle and mitotic checkpoint(s). This phenotype was not observed in STK11 wildtype KRAS/P53 mutant lung tumors. Furthermore, combinational treatment of TNG260 with PD1 antibody showed increased macrophages, neutrophils and dendritic cells signatures in vivo. Our data suggests that epigenetic reprogramming via TNG260 sensitizes STK11 mutant NSCLC tumors to anti- PD1 treatment via targeting of the CoREST complex. This work identifies new vulnerabilities in STK11 LOF cancers that can be exploited therapeutically. TNG260 is currently being investigated in combination with pembrolizumab for the treatment of STK11-mutant cancer (NCT05887492), including NSCLC. Citation Format: Ayushi Patel, Soumyadip Sahu, Ke Geng, Salman Punekar, Janaye Stephens, Jiehui Deng, Ting Chen, Leanne Ahronian, Minjie Zhang, Jannik Andersen, Brian Haines, Kwok-Kin Wong. TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 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 3916.
Abstract 16: CD4+ and CD8+ TCRαβ-deficient bioluminescent reporter T cells for screening and characterization of neoantigen-specific TCRs
Authors: Mei Cong, Jamison Grailer, Michael Slater, Pete Stecha, Jim Hartnett
Journal: Cancer Research (2024)

Abstract Adoptive antigen-specific T cell therapy is currently comprised of chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells. Clinical results from CAR-T cells have demonstrated promising results in treating leukemias, while TCR-engineered T cells, which have the advantage of recognizing intracellular tumor antigens, is still in early development. Here, we report the development of CD4+ or CD8+ TCRαβ-KO reporter T cell lines for the screening and characterization of transgenic TCRs. A TCRαβ-KO reporter T cell line was first developed by knocking out the endogenous TCR α and β chains in the reporter T cell line using CRISPR/Cas9. Successful knockout was confirmed by phenotypic assays and TCR v chain locus sequencing. We demonstrated that re-introduction of influenza hemagglutinin (HA) peptide-specific TCR (HA1.7) α and β chains into TCRαβ-KO reporter T cell lines results in HA peptide-dependent TCR activation and luciferase reporter expression when HA peptide is presented by a MHCII+ cell line. Similarly, re-introduction of MART-1-specific TCR (DMF5) resulted in MART-1-dependent activation in the presence of MHCI+ cells. The select expression of CD4- or CD8-expressing variants of the TCRαβ-KO reporter T cell line enables the development of transgenic TCRs for both MHCI- and MHCII-restricted tumor antigen targets. Further development of CD4/CD8 double-positive and double-negative cell lines enables screening of low and high affinity TCRs without MHC bias. Together, this TCRαβ-KO platform represents a powerful tool for the screening and characterization of neoantigen-specific TCRs. Citation Format: Mei Cong, Jamison Grailer, Michael Slater, Pete Stecha, Jim Hartnett. CD4+ and CD8+ TCRαβ-deficient bioluminescent reporter T cells for screening and characterization of neoantigen-specific TCRs [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 16.
Abstract 4697: Surface localization of enolase-1 (ENO-1) as an attractive theranostic target in docetaxel-resistant neuroendocrine-like prostate cancer cells
Authors: Krystal Rubi Santiago Torres, Carlos A. Casiano, Frankis Almaguel, Alfonso Duran, Kristen Whitley
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) is American men's second most common cancer. Although taxane-based chemotherapy is the last line of defense for Metastatic Castration Resistant Prostate Cancer (mCRPC), it invariably fails due to chemoresistance. The protein-specific membrane antigen (PSMA) has been an effective target for the imaging and therapy of mCRPC. Although PSMA radioligand therapy (PSMA-RLT) is a theranostics option for men with advanced PCa, about 30% have a limited response due to neuroendocrine-like PCa (NEPC), which lacks PSMA expression. Enolase (ENO) is a promising theranostic alternative due to its cell surface localization in many human tumors. We observed that chemosensitive PCa cell lines expressing NEPC markers express both ENO-1 and ENO-2; however, docetaxel-resistant NEPC-like cells only express ENO-1 and have a metabolic vulnerability due to the loss of ENO-2. We hypothesize that ENO-1 is expressed on the surface of NEPC-like cell lines and can be targeted with small molecule inhibitors (SMIs) that could potentially be used as theranostics agents. Additionally, we have observed changes in the expression and localization of ENO-1 in NEPC-like cell lines under different glucose concentrations. Our data show that under high glucose conditions, found on metabolically active metastatic tumors, ENO-1 is highly expressed on the cell surface, making it a promising candidate target for theranostics. However, low glucose conditions inhibit the activity of the c-MYC oncogene resulting in ENO-1 downregulation and upregulation of MBP1, the small splice variant of ENO1 that blocks the transcriptional activity of c-MYC. Our efforts to confirm ENO-1 surface expression on NEPC-like cell lines entailed using confocal microscopy, cell fractionation analysis followed by Western blotting, and Flow cytometric cell surface staining. We also evaluated the cytotoxicity of SMIs designed to target ENO-1 in chemoresistant NEPC-like cell lines using MTT viability assays, clonogenic assays, and Hoffman Modulation microscopy imaging. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel theranostics target. Citation Format: Krystal Rubi Santiago Torres, Carlos A. Casiano, Frankis Almaguel, Alfonso Duran, Kristen Whitley. Surface localization of enolase-1 (ENO-1) as an attractive theranostic target in docetaxel-resistant neuroendocrine-like prostate 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 4697.
Abstract 1601: The role of complement in pancreatic cancer cachexia
Authors: Andrew C. D'Lugos, Chandler Callaway, Sarah M. Judge, Andrew R. Judge
Journal: Cancer Research (2024)

Abstract Cancer cachexia is a multifactorial condition characterized by skeletal muscle atrophy and dysfunction that impairs longevity and quality of life for the vast majority of cancer patients. Recently, we discovered through unbiased proteomic analyses that the complement system is activated in the skeletal muscle of cachectic pancreatic cancer patients. Therefore, the purpose of this study was to investigate the role of complement in pancreatic cancer cachexia. To accomplish this, we obtained genetically modified, C57Bl6/J congenic mice lacking the central regulator of complement, C3 (C3−/− mice). Wild-type (C57Bl6/J, WT, n=12) and C3−/− mice (n=11) (male, 12 weeks old) received orthotopic injections of mouse pancreatic cancer cells (KPC) into the pancreas, and as non-cancer controls, WT (n=8) and C3−/− (n=4) mice received injections of PBS into the pancreas. Mice were monitored daily and euthanized at IACUC-mandated tumor endpoint (body condition score ≤ 2; range: 14-15 days). In-vivo diaphragm function was assessed immediately prior to euthanasia via M-mode ultrasound. Skeletal muscles (soleus, SOL; tibialis anterior, TA; diaphragm, DIA) were harvested and ex-vivo contractile function was assessed on strips of costal diaphragm. Diaphragmatic excursion and respiratory rate were reduced with KPC tumor burden in WT mice, but preserved in C3−/− mice. Deletion of C3 did not influence the KPC-induced reduction of body mass or KPC tumor growth. Atrophy of limb muscle mass (SOL, TA) and fiber size (TA) during KPC tumor burden was attenuated in C3−/− mice. Maximal specific force of DIA was greater in C3−/− versus WT KPC-bearing mice. KPC tumor burden increased collagen content in the DIA of WT mice, but not C3−/− mice. Diaphragm fiber size was reduced in WT KPC-bearing mice, but preserved in C3−/− mice. KPC tumor burden induced significant increases in immune cell (CD45+) infiltration and fibroadipogenic progenitor cell (PDGFRa+) abundance in the DIA of WT tumor-bearing mice, but to a lesser extent in C3−/− mice. These findings suggest complement activation is causative in pancreatic cancer-induced skeletal muscle wasting and dysfunction. Inhibition of complement during cancer cachexia may possess therapeutic potential for the preservation of skeletal muscle mass and function. Citation Format: Andrew C. D'Lugos, Chandler Callaway, Sarah M. Judge, Andrew R. Judge. The role of complement in pancreatic cancer cachexia [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 1601.
Abstract 3834: Plasmablastic lymphoma provisional prognostic score
Authors: Philip A. Haddad, Jaren Lerner
Journal: Cancer Research (2024)

Abstract Background Plasmablastic Lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin's lymphoma. It tends to be associated with immunosuppressive clinical contexts, such as HIV infection and immunosuppressive therapies for autoimmune disorders and organ transplants. However, due to the rarity of the disease, which needs to be better understood, varied treatment approaches have been implemented, and no optimal data or guidelines for managing PBL are available. Therefore, we conducted this study to develop a provisional PBL prognostic score (PBLPS) for this rare disease. Methods We used our constructed PBL database, which contains retrospective data on 300 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, blood counts, coexisting comorbidities, disease immunohistochemical and molecular phenotype, types of treatment, and survival outcomes. Of the 300 cases, 291 had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). We included factors that statistically impacted OS and scored them by the impact of their hazard ratios. Results The median OS of the cohort was 25 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: LDH&amp;gt;500 (p=0.04), CD4&amp;lt;100 (p=0.006), bone marrow (BM) involvement (p&amp;lt;0.0001), EBER-negative (p=0.01), HHV8+ (p=0.02), and involvement of liver (p=0.003), lungs/pleura (p&amp;lt;0.0001), and upper GI tract (p=0.001). A prognostic model was devised using these variables to identify different levels of risk. Involvement of BM and involvement of any of the worse prognosis organs (liver, lung/pleura, and/or upper GI tract) were each assigned a score of 2 when present. CD4&amp;lt;100, EBER-negative, and LDH&amp;gt;500 were assigned 1 point each as they had the lowest hazard ratios of all the other variables. In this exploratory cohort, we assigned low risk a score of 0, intermediate risk a score of 1-2, and high risk a score of 3-7. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of NR, 15, and 4 months, respectively (p&amp;lt;0.0001). Conclusion This PBLPS is a promising new tool for risk-stratifying patients with PBL. However, it still requires prospective validation. Citation Format: Philip A. Haddad, Jaren Lerner. Plasmablastic lymphoma provisional prognostic score [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 3834.