tbuckley/cabot-search huggingface dataset:
Abstract 4721: Cell death induction via CB2 receptor and TRPV receptor in cannabichromene (CBC) treated human pancreatic cancer cells
Authors: Yu-Na Hwang, Keun-Cheol Kim
Journal: Cancer Research (2024)

Abstract Cannabichromene (CBC: C21H3O2, M.W.: 314.46g) is one of the most abundant nonpsychotropic phytocannabinoids extracted from Hemp species (Cannabis sativa), and can extract using either a hexane/florisil extraction method. Phytocannabinoids contain Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and other compounds. CBC can cause strong anti-inflammatory effects in animal models of edema through non-CB receptor mechanisms, but there is little pharmacological study in cancer disease models. In this study, we investigated the molecular mechanism on anti-cancer activity of CBC treatment in human pancreatic cancer cells. MTT assay was performed to determine concentrations for inducing pharmacological effects of CBC in human pancreatic cancer cells. FACS and Annexin V/PI staining analysis showed the increase dead cells by CBC treatment, and Western blot analysis also showed the changes in expression of cell death related proteins by CBC. Moreover, CBC treatment increased expression of CB2 receptor and TRPV receptor, but the anti-cancer effect was restored by double inhibition with SR144528 for CB2 receptor and capsazepine for TRPV receptor, respectively. mRNA-seq analysis showed that 1206 genes were upregulated and 1145 genes were down-regulated by CBC treatment, indicating that some of ferroptosis related genes (HMOX1, CHAC1, GPX4 and NFE2L2) were regulated by CBC treatment. qPCR analysis showed that those genes are increased by CBC treatment in time dependent manner. It was also confirmed that HMOX1 protein expression was increased using Western blot analysis. Therefore, we suggest that CBC induces multiple cell death mechanism including ferroptosis via CB2 receptor and TRPV receptor in human pancreatic cancer cells. Citation Format: Yu-Na Hwang, Keun-Cheol Kim. Cell death induction via CB2 receptor and TRPV receptor in cannabichromene (CBC) treated human 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 4721.
Abstract 6147: Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers
Authors: Shisi He, James Perry, Shengchao Li, Braxton D. Mitchell, Yuji Zhang, Shuo Chen, Laura Beane-Freeman, Kathryn Hughes Barry, Sonja I. Berndt
Journal: Cancer Research (2024)

Abstract Objectives: Genetic susceptibility is thought to contribute to the development of multiple primary cancers (MPC), often called secondary cancers. Although rare variants contribute to risk, these only account for a small fraction of MPC cases. The contribution of common variants to risk is unknown. Methods: To identify common genetic variants associated with the risk of MPC, we conducted a trans-ancestry meta-analysis of genome-wide association studies (GWAS), including 7,360 MPC cases and 138,684 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and UK Biobank (UKBB). Association analyses were performed separately by genetic ancestry, genotype platform, and study, adjusting for age, sex, and principal components, and the results were meta-analyzed together using a fixed effects model. Genome-wide SNP heritability was estimated using GCTA. Pathway and functional enrichment analyses were conducted to gain insights into potential biological mechanisms underlying discovered loci. Results: We identified one novel locus at chromosome 3q26.2 (LRRC34, rs7621631) that was associated with MPC risk (P=1.16x10-8). Variants in this region have been previously associated with telomere length, suggesting a possible underlying mechanism. In sex-stratified analyses, we identified an additional locus at chromosome 12q24.33 (intergenic, rs10466868) associated with MPC in men (P= 7.76x10-8), but not women. Although the risk associated with these two discovered loci was small, the genome-wide SNP heritability was estimated to be 12%, suggesting that there are likely more common variants to be discovered for MPC risk. Conclusions: Our study demonstrates that common genetic variation contributes to the risk of multiple primary cancers and suggests additional loci are likely to be identified with larger studies. Citation Format: Shisi He, James Perry, Shengchao Li, Braxton D. Mitchell, Yuji Zhang, Shuo Chen, Laura Beane-Freeman, Kathryn Hughes Barry, Sonja I. Berndt. Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers [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 6147.
Abstract 4955: An analytic pipeline of neoantigen selection for both MHC-I and MHC-II pathways
Authors: Ko-Han Lee, Timothy Sears, Andrea Castro, Maurizio Zanetti, Hannah Carter
Journal: Cancer Research (2024)

Abstract Background: Accurate neoantigen selection is pivotal for assessing mutation burden and optimizing cancer vaccine formulation thereby playing a crucial role in cancer immunotherapy. The concurrent activation of CD4+ and CD8+ T cells engenders a robust immune response, which is key to effective treatment. However, currently analytic tools predominantly focus on the MHC-I pathway, typically relying on metrics such as gene expression level and MHC-binding affinity of mutated peptides. To address this gap, our study presents a comprehensive pipeline that encompasses both MHC-I and MHC-II pathways and integrates three critical dimensions of immune response: neoantigen abundance, presentation, and immunogenicity. Methods: We estimated mutated peptide abundance by analyzing genomic allelic frequency, transcriptomic allelic frequency, and RNA expression level. Antigen presentation was assessed using the patient harmonic binding rank (PHBR, a composite binding score for all potential MHC-peptide pairs) and MHC diversity (the variety of MHC alleles involved in peptide binding), with additional consideration for the loss of heterozygosity of MHC-I alleles, potentially indicative of immune escape. For immunogenicity, we factored in agretopicity (comparison of MHC-binding affinity between mutated and wild-type peptides), foreignness (similarity to immunogenic foreign antigens), and dissimilarity (sequence disparity with self-peptides, reflecting T cell negative selection process). Results: Implementing our pipeline on a dataset from Parkhurst et al. (2019), we analyzed immune reactivity in relation to 11,537 somatic mutations from 75 gastrointestinal cancer patients. Key metrics—RNA expression, transcriptomic allelic frequencies, PHBR, and MHC diversity—demonstrated significant correlations with both CD4+ and CD8+ activity (p&amp;lt;0.05). Notably, genomic allelic frequency was a significant factor in CD8+ reactivity, whereas agretopicity was crucial for CD4+ reactivity. Conclusion: Our pipeline elucidates the necessity for implementing both MHC-I and MHC-II pathway analyses to effectively select neoantigen candidates for CD8+ and CD4+ T cells respectively. The study confirms that abundance and antigen presentation metrics are robust indicators of neoantigen immunogenicity, supporting their use as potential markers in crafting more effective cancer vaccines. The findings highlight the critical role of this dual-pathway selection approach in generating a comprehensive immune response through neoantigen vaccination. Citation Format: Ko-Han Lee, Timothy Sears, Andrea Castro, Maurizio Zanetti, Hannah Carter. An analytic pipeline of neoantigen selection for both MHC-I and MHC-II pathways [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 4955.
Abstract 644: PKC-iota specific inhibitor ICA-1S causes the degradation of mutant p53 in ovarian cancer cell lines
Authors: Mahfuza Marzan, Nuzhat Nowshin Oishee, Abigail Olatunji, Mildred Acevedo-Duncan
Journal: Cancer Research (2024)

Abstract Ovarian cancer is the most lethal malignant disease of female. Treatment options for ovarian cancer are mostly the use of chemotherapeutics, surgery, or radiotherapy. However, due to resistance to drugs, relapse occurs and thus 5 years survival rate is only 47%. The tumor suppressor protein p53 works as a transcription factor to transcribe several proteins such as p21, p16 and PUMA that lead to halt cell cycle and also induce apoptosis when there is a damage in DNA. Mutation in several regions of p53 (mutp53) is quite common in cancers and can lead to the accumulation of p53 with loss of functions or sometimes gain of oncogenic functions. Thus there is a search for drugs that can degrade the mut53 and can restore the functions of normal p53. In this research, it was observed that the treatment of ovarian cancer cell lines (ES-2, HEY and OVCAR3) with atypical protein kinase C-iota (aPKCɩ) specific inhibitors ICA-1S can cause the degradation of mutp53 (53.6%, N=6 trials). Treatment with ICA-1S also lowered the level of phosphorylated p53 (ser15, 87%, N=3 trials). However, the level of MDM2 protein (murine double minute 2), a known p53 E3 ligase was not significantly (98%, N=2 trials) affected by ICA-1S in ES-2 cell line with mut p53 as well as p21 was also not affected. However level of PUMA was decreased both in ES-2 and HEY cell lines. Immunoprecipitation (IP) with aPKCɩ specific beads showed the aPKCɩ is associated with p53, though reverse IP with p53 beads was not able to show the association. Application of proteasome inhibitor MG-132 at a single dose of 0.5µM could not completely inhibit the degradation of mut53 and WTp53 in ICA-1S treated ES-2 cell line and HEY cell line, respectively, indicating the drug may be affecting the transcription of p53 as well. It is therefore postulated that aPKCɩ can phosphorylate p53, stabilizing it and may be affecting the transcription of p53 as well in those cell lines. Further research (kinase activity assay, immunoprecipitation, immunofluorescence) is going on to reveal the mode of this degradation. Citation Format: Mahfuza Marzan, Nuzhat Nowshin Oishee, Abigail Olatunji, Mildred Acevedo-Duncan. PKC-iota specific inhibitor ICA-1S causes the degradation of mutant p53 in ovarian cancer cell lines [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 644.
Abstract 674: Novel anti-cancer small molecule targeting the protein regulator of cytokinesis pathway
Authors: Amnon Peled, Michal Abraham, Hanna Wald, Rakefet Rosenfeld, Orly Eizenberg, Arnon Aharon
Journal: Cancer Research (2024)

Abstract Aberrant migration and proliferation of cancer cells are the hallmark of metastatic tumors. Protein Regulator of Cytokinesis 1 (PRC1) is a scaffold protein that regulates metabolic pathways of cancer cell proliferation, survival, and metastasis. BKT300 is a small molecule (MW 399.33, C22H25NO6), that selectively inhibits the migration and survival of hematological and solid cancer cells. BKT300 inhibits, at high affinity, both actin and microtubule formation and organization leading to G2/M cell cycle arrest, mitotic catastrophe, and apoptosis through the caspase 3 pathway. These effects are selective to cancer cells and were not observed on normal cells. BKT300 was found to arrest PRC1 in a phosphorylated form at position T481, down regulates the expression of CDC25C and up regulate p21. Suppression of PRC1 using SiRNA ablation inhibited BKT300 induced apoptosis on several tumor cell lines and inhibited the effect of BKT300 on G2M cell cycle arrest. Furthermore, using Biacore SPR, microscale thermophoresis (MST), and ELISA assays we were able to demonstrate the direct binding of BKT300 to PRC1. Beyond its single agent activity, BKT300 was shown to synergize with standard of care (SoC) treatments, including anti PD-1 immunotherapy, BCL-2 inhibitor (Ventoclax), topoisomerase I inhibitor (Irinotecan) topoisomerase II inhibitor (Doxorubicin), anti-metabolite Fluorouracil (5-FU) and alkylating agent (Temozolomide). BKT300 has a remarkable safety profile when administered at high doses to mice rats, minipigs and non-human primates. Treatment with BKT300 showed almost no effects on hematopoiesis and biochemistry in doses far higher than the affective ones. The in-vivo activity of BKT300 was demonstrated in multiple Xenograft, Syngeneic and PDX models in mice. In-vivo treatment with BKT300 resulted in preventive (small tumors) as well as therapeutic (large tumors) activity in triple negative breast cancer (TNBC) xenograft, MDA-MB-453 and MDA-MB-468 models leading to over then 70%-90% reduction in tumor size following one to two treatments cycles. Similar results were obtained using PDX models derived from patients with Colon, Ovarian and Pancreatic cancer. BKT300 is a novel, first in class, targeted anti-cancer treatment that inhibits the activity of the scaffold protein PRC1. BKT300 is expected to provide a new treatment option to, the high unmet medical need of, advanced difficult to treat cancers, specifically ones that overexpress PRC1 and CDC25C. Citation Format: Amnon Peled, Michal Abraham, Hanna Wald, Rakefet Rosenfeld, Orly Eizenberg, Arnon Aharon. Novel anti-cancer small molecule targeting the protein regulator of cytokinesis pathway [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 674.
Abstract 5082: Novel TSHR CAR T therapy for targeting oncocytic carcinoma
Authors: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew Pawlush, Claudia Manriquez-Roman, Elizabeth L. Siegler, Robert C. Smallridge, Abba Zubair, Han W. Tun, Saad S. Kenderian, John A. Copland
Journal: Cancer Research (2024)

Abstract Oncocytic carcinoma (Hurthle cell carcinoma) has the highest incidence of metastasis among the differentiated thyroid cancers. Metastatic disease is reported at the initial diagnosis in 10-20% of patients and 34% overall. Thyroid-stimulating hormone receptor (TSHR) expression is limited to the thyroid gland. It is abundantly expressed on thyroid tumor cells, making TSHR a compelling target for advanced thyroid cancer diagnostics and therapeutics. We developed a potent anticancer strategy for treating oncocytic carcinoma using a novel thyroid hormone stimulating receptor (TSHR)- targeted (chimeric antigen receptor) CAR T cell therapy. TSHR CAR T was generated by transducing T cells derived from healthy donors. In vitro effector functions (cytotoxicity, proliferation, degranulation) were tested in TSHR+ tumor models, and subsequent in vivo studies using NSG mice were performed to assess anti-tumor activity efficacy. We observed strong anti-tumor activity against metastatic oncocytic carcinoma cell line XCT.UC1 using the TSHR CAR T therapy in vivo. Re-challenging treated mice with XCT.UC1 cells reactivated TSHR CART cells with enhanced proliferation and complete suppression of tumor growth of the newly injected tumor cells. Our work represents a promising strategy to improve treatment outcomes of patients with metastatic oncocytic carcinoma that may provide a durable response. Citation Format: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew Pawlush, Claudia Manriquez-Roman, Elizabeth L. Siegler, Robert C. Smallridge, Abba Zubair, Han W. Tun, Saad S. Kenderian, John A. Copland. Novel TSHR CAR T therapy for targeting oncocytic 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 5082.
Abstract 2752: ICA1 promotes prostate cancer progression and metastasis via AR down-regulation
Authors: Fuhao Wang, Yu He, Xin Huang, Ming Chang, Xiao Zhang, Xiaoyi Li, Xinyu Ye, Yi Lu
Journal: Cancer Research (2024)

Abstract Cancer metastasis, one of the main characteristics in malignancy, contributes to high mortality in cancer patients. Prostate cancer (PCa) is the most common cancer among men and the second leading cause of cancer-related death in Europe and the United States. In China, its incidence has been dramatically increased over past years. However, the mechanism of PCa progression and metastasis remains unclear. The androgen receptor (AR) has been demonstrated to play an important role in PCa progression and metastasis. We have previously established mouse models of PCa bone metastasis and PCa lung metastasis. We have obtained cell clones with bone-specific or lung-specific metastatic capability. By transcriptomic analysis of highly metastatic cell clones and their parental cells, we found a gene group including islet cell autoantigen 1 (ICA1) that are highly expressed in both metastatic cell clones. We further compared these results with RNA array data in clinical samples. Data comparison and correlation analysis showed that ICA1 was negatively correlated with AR expression. Survival analysis of PCa and lung cancer patients showed higher expression of ICA1 but with shorter overall survival. Down-regulation of ICA1 expression in highly metastatic tumor cells significantly inhibited cell growth, colony formation, migration, and invasion. ICA1 overexpression in parental RM1 cells apparently increased cell growth, migration, and metastasis. Interestingly, down-regulation of ICA1 also significantly activated AMPK/mTOR signaling pathway. These findings are anticipated to shed light on the novel pathogenic mechanism underlying PCa and propose a compelling theoretical basis for the application of ICA1 in PCa. This work supported by the NSFC projects (81972420, 81972766, 82173336), as well as grants from the Science and Technology Project of Shenzhen (JCYJ20210324104214040, JCYJ20190809161811237).Keywords: prostate cancer, metastasis, ICA1, androgen receptor Citation Format: Fuhao Wang, Yu He, Xin Huang, Ming Chang, Xiao Zhang, Xiaoyi Li, Xinyu Ye, Yi Lu. ICA1 promotes prostate cancer progression and metastasis via AR down-regulation [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 2752.
Abstract 7489: Peripheral blood liquid biopsy for the screening of lung cancer
Authors: Jiyoun Seo, Stephanie N. Shishido, Jeremy Mason, Carmen Ruiz Velasco, Andrew Chen, Dominic Rothwell, Phil Crosbie, James Hicks, Caroline Dive, Peter Kuhn
Journal: Cancer Research (2024)

Abstract Lung cancer is the second most common type of cancer in both men and women and the leading cause of cancer-related mortality. Unfortunately, most patients have advanced stages (stage III or IV) at the time of diagnosis and the only U.S. Preventive Services Task Force-recommended screening test, Low Dose CT scan (LDCT), has a high false-positive rate. Therefore, there is an urgent need for the early detection of lung cancer with better discrimination between individuals with lung cancer and those without. In this study, we demonstrate the capability of a non-enrichment-based liquid biopsy workflow, the High Definition Single Cell Assay (HDSCA) to be used as a complementary tool to the current screening methodology. The HDSCA workflow can detect circulating cells of epithelial, mesenchymal, endothelial, and hematological origin, as well as acellular events such as oncosomes. This allows the investigation of the broad spectrum of circulating rare events for the potential identification of biomarkers associated with lung cancer. We investigated 52 peripheral blood samples collected from the second annual screening round of Manchester’s 'Lung Health Check' pilot of a community-based lung cancer screening cohort. Of these, 7 were subsequently diagnosed with non-small cell lung cancer, 2 with small cell lung cancer, and 43 were deemed at high risk of developing lung cancer. We additionally investigated 60 peripheral blood samples from individuals with no known pathology to use as controls. Within the screening cohort, a number of single rare analytes were found to have statistically significant differences between the lung cancer, high-risk cohort, and normal blood donor samples, which can potentially be biomarkers used to differentiate the cohorts. We also built a multi-analyte patient-level classification model utilizing the rare cellular and acellular events that stratified lung cancer patients from the normal donor individuals and high-risk cohort with high accuracy. Our results demonstrate the potential of liquid biopsy as a complementary screening approach for lung cancer. Citation Format: Jiyoun Seo, Stephanie N. Shishido, Jeremy Mason, Carmen Ruiz Velasco, Andrew Chen, Dominic Rothwell, Phil Crosbie, James Hicks, Caroline Dive, Peter Kuhn. Peripheral blood liquid biopsy for the screening of 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 7489.