tbuckley/cabot-search huggingface dataset:
Abstract 588: Preclinical evaluation of novel chimeric vesiculovirus mediated expression of proteolytic enzymes targeting two major stromal components of pancreatic ductal adenocarcinoma
Authors: Khandoker Usran Ferdous, Mulu Z. Tesfay, Camila C. Simoes, Aleksandra Cios, Bolni Marius Nagalo
Journal: Cancer Research (2024)

Abstract The vesiculovirus genus has recently garnered interest as an oncolytic virotherapy for pancreatic ductal adenocarcinoma (PDAC). A new synthetic chimeric vesiculovirus, VMG, demonstrated efficacy and safety against PDAC both in vitro and in vivo. The therapeutic effectiveness of virotherapies against PDAC is often hindered by immunosuppressive factors in the tumor environment, as well as the presence of hyaluronic acid (HA) and collagen (CN), which increase tumor stiffness and interstitial fluid pressure, leading to reduced drug/oncolytic virus and immune cell penetration into tumor. To address this, we engineered VMG viruses incorporating enzymes PH20, collagenase (CNase), and novel proteolytic enzyme SMC, the latter exhibits both PH20 and CNase-like activity. We characterized these modified viruses for their cytotoxicity and performance in vitro. Various PDAC cell lines displayed varied sensitivity to VMG vectors, yet they showed consistent oncolytic effects relative to the parent VMG-GFP virus. Our results revealed no compromise in viral replication or apoptosis-inducing ability after transgene insertion, which is evident as infectious viral progenies were produced to approximately similar level of magnitude of around 108 TCID50/ml in all the cell line tested. Additionally, the VMG-SMC and VMG-hPH20-CNase variants demonstrated notable enzyme activity. To enhance clinical relevance, we utilized an ex vivo live tumor platform, which indicated around 20% tumor cell death using VMG vectors compared to that of the control, signifying tumor viability and virus replicability 72 hours post-infection. Fluorescent imagery highlighted the viruses' ability to spread and express functional enzymes within tumors. In summary, VMG vectors expressing stroma-degrading proteolytic enzymes can effectively express PH20, CNase and SMC enzymes that degrade stromal barrier of HA and CN without interrupting the replicability, performance, and oncolytic characteristics of the VMG vectors. Future research should prioritize the safety of these vectors and their potential to augment neoantigen expression and immune cell infiltration in vivo, which are the hallmarks of antitumor efficacy. Citation Format: Khandoker Usran Ferdous, Mulu Z. Tesfay, Camila C. Simoes, Aleksandra Cios, Bolni Marius Nagalo. Preclinical evaluation of novel chimeric vesiculovirus mediated expression of proteolytic enzymes targeting two major stromal components of pancreatic ductal adenocarcinoma [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 588.
Abstract 1557: Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4
Authors: Yin Liu, Margaret R. Smith, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Gregory L. Kucera, Lance D. Miller, Wencheng Li, Michael D. Chan, Michael Farris, Dawen Zhao, Fei Xing
Journal: Cancer Research (2024)

Abstract Metastatic disease is the main cause of cancer death, and the brain is one of the major sites of breast tumor metastasis. The median survival of breast cancer patients who developed brain metastases (BrM) is less than a year even with the advanced treatment such as stereotactic radiosurgery (SRS). Regardless of high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. Previously, we found that loss of lncRNA XIST robustly promote metastasis and specially brain metastasis in breast cancer. However, the underlying molecular mechanism was not fully understood. In following study, we found that loss of XIST has significantly altered lipid metabolism of breast cancer cells specifically increasing lipid droplet amount and PUFA incorporation. Instead of de novo syntheses, XISTlow cancer cells acquire fatty acid by uptake from exogenous. We found that one X-linked gene, Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) which are highly upregulated after loss of XIST is responsible for the altered lipid metabolism. ACSL4 activated the free polyunsaturated fatty acids (PUFAs) and lead to increased incorporation of PUFAs into phospholipids. On one hand, elevated ACLS4 expression leads to relative low PPAR pathway activation by decreasing the cellular free PUFA level which directly binds and activate PPAR. PPAR pathway is known to inhibit the expression of inflammatory cytokines which are important for cancer cells to establish brain metastasis. On the other hand, elevated ACSL4 expression enable cancer cells to metabolize the abundant PUFAs in the brain environment, thereby gaining survival advantage. However, increased PUFA incorporation into lipids especially phospholipids produce excess lipid ROS and sensitize cells to ferroptosis inducer such as RSL3. Our study has find out that brain microenvironment not only supports the outgrowth of XIST low cells by providing PUFAs for maintaining their metastatic properties but also sensitizes those cells to ferroptosis inducers, a potential therapy for treating this devastating disease. Citation Format: Yin Liu, Margaret R. Smith, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Gregory L. Kucera, Lance D. Miller, Wencheng Li, Michael D. Chan, Michael Farris, Dawen Zhao, Fei Xing. Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4 [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 1557.
Abstract 6517: ALDOC as an indicator of HMGB1 blockade combined with checkpoint inhibitor based immunotherapy in GBM patients
Authors: Yi-Fang Yang, Ming-Hsien Chan, Chi-Long Chen, Michael Hsiao, Yu-Chan Chang
Journal: Cancer Research (2024)

Abstract Aldolase is an enzyme that takes part in glycolysis by catalyzing a six-carbon intermediate to yield two three-carbon products, requiring ATP. The aldolase family comprises three members, namely ALDOA, ALDOB, and brain-specific ALDOC. Low-grade gliomas and glioblastoma (GBM) are characterized by shared genetic events, including chromosome 1p/19q codeletion, EGFR amplification, and ATRX loss of function, in which ALDOC plays a role. Additionally, ALDOC is responsive to IDH1 mutations. If patients display IDH1 mutations, it is expected that ALDOC performance will be relatively higher. This finding suggests a more favorable prognosis. The ALDOC promoter region's function is impeded by hypermethylation, which declines as glioma progresses. The regulatory mechanisms and implications remain unclear. We established a multi-omics profile and identified several crucial mechanisms activated upon the loss of ALDOC expression. Among these mechanisms, we found HMGB1 to have a key role in linking the immune response, tumor microenvironment, and epigenetic modifications. We compared the proteomic and secretomic platforms in an ALDOC overexpression/knockdown model, which showed abundant HMGB1 expression following ALDOC inhibition. Importantly, there is an inverse correlation between ALDOC expression and HMGB1 protein levels. Additionally, our findings reveal that upregulation of ALDOC promotes its translocation to the nucleus, thereby enhancing its binding affinity with HMGB1. This, in turn, enables extracellular release of HMGB1 in GBM, which triggers signaling via receptors for advanced glycation end-products (RAGE) and several cytokines. Moreover, HMGB1 remodels the immune microenvironment and upregulates multiple immune checkpoint molecules, including PD-L1, PD-L2, B7-H3, and MHCs. Not all GBM models exhibited significant effects when combined with immune checkpoint blockade using HMGB1 blockade. However, ALDOC knockout mice demonstrated poorer survival and treatment efficacy, suggesting that ALDOC may be crucial for a personalized immunotherapy strategy. Citation Format: Yi-Fang Yang, Ming-Hsien Chan, Chi-Long Chen, Michael Hsiao, Yu-Chan Chang. ALDOC as an indicator of HMGB1 blockade combined with checkpoint inhibitor based immunotherapy in GBM patients [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 6517.
Abstract 5062: Evaluation of genetic mutations in non-small cell lung cancer patients
Authors: Miles Rothstein, Phillip Broughton, Ella Markalunas, Avery Funkhouser, Lorie Allen, Julie Martin, W. Jeffery Edenfield, Anna V. Blenda
Journal: Cancer Research (2024)

Abstract Lung cancers represent the second most common cancer and Non-Small Cell Lung Cancer (NSCLC) constitutes 80-85% of all lung cancers. Genes within several cellular pathways have been previously evaluated for their clinical impact in NSCLC. In this investigation, we evaluate genetic mutations found in 50 cancer-critical genes implicated in the signaling pathways RTK/RAS/MAP, TGFβ, PI3K, Wnt, GPCR, p53, JAK/STAT, Notch, and the cell cycle pathway. Some of these mutations have not yet been described or have not been described in NSCLC. The intent of our study is to evaluate these mutations and allow further research into their impact, specifically highlighting mutations that are involved in clinically important pathways. We evaluated mutations found in 59 NSCLC patients at the Prisma Health Cancer Institute. These mutations are part of 2,800 COSMIC (Catalogue of Somatic Mutations in Cancer) hotspot mutations in 50 cancer-critical genes. Each mutation was investigated further using the ClinVar database to identify whether it had been described in NSCLC or other cancers/conditions, its genetic consequence, pathogenesis, possible variations, and origin. A total of 73 unique mutations in 59 NSCLC patients were evaluated. Of the 73 mutations, 17 had not been described at all, 40 had been described in other cancers/conditions, and 16 had been previously described in NSCLC. The known mutations’ effects in other cancers/conditions were categorized as pathogenic, likely pathogenic, likely benign, benign, or uncertain. Novel mutations were found in genes that provide a druggable target, help predict treatment response, are under investigation for their ability to predict treatment response or confer additional clinical utility. Medical management of cancer has benefitted greatly from studies of genetic mutations. Most mutations identified in our patient population had not been described in NSCLC, and a smaller number of those had not been described at all. Further elucidation of these mutations may lead to additional discoveries relevant to NSCLC prognostication and treatment. Citation Format: Miles Rothstein, Phillip Broughton, Ella Markalunas, Avery Funkhouser, Lorie Allen, Julie Martin, W. Jeffery Edenfield, Anna V. Blenda. Evaluation of genetic mutations in non-small cell lung cancer patients [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 5062.
Abstract 3612: Preclinical &amp; clinical activity of autologous mRNA engineered chimeric antigen receptor monocytes for targeted cancer immunotherapy
Authors: Yuxiao Wang, Michele Gerber, Michael Gorgievski, Josephine D'Alessandro, Neha Diwanji, Ronald Vale, Siddhartha Mukherjee, Daniel Getts
Journal: Cancer Research (2024)

Abstract Introduction: The tumor microenvironment (TME) is a dynamic and multifaceted system that comprises largely myeloid lineage immune cells including neutrophils, macrophages, dendritic cells and monocytes. When activated, these cells are can effectively infiltrate TME and orchestrate anti-tumor immune response. Reprogramming myeloid cells by arming them with a tumor specific chimeric antigen receptor (CAR) presents an attractive strategy to overcome current limitations in solid tumor treatment. In this study, we present the isolation and mRNA-based engineering of monocytes with chimeric antigen receptors (CARs), followed by their in vivo application for cancer treatment in rodent models and in human T cell lymphoma patients. Results: Engineered monocytes demonstrated the abilities to infiltrate the TME, undergo activation, and differentiate into macrophages and dendritic cells. Upon CAR activation, these reprogrammed myeloid cells utilized both direct and indirect mechanisms to eliminate tumor cells. This included direct tumor cell killing through phagocytosis and TNF-associated mechanisms. Furthermore, engineered monocytes exhibited the capacity to recruit natural killer (NK) cells and T cells to the TME. In the case of T cells, these engineered myeloid cells facilitated the presentation of neoantigens to T cells and stimulate an adaptive immune response. In patients with T cell lymphoma, treatment with engineered monocytes expressing a CAR targeting CD5 exhibited a favorable safety profile and was associated with TME remodeling, expansion of novel T cell clones, and promising survival outcomes. Conclusions: These findings underscore the potential of reprogrammed myeloid cells as a novel avenue for cancer immunotherapy, offering hope for improved treatments and outcomes in the fight against cancer. Citation Format: Yuxiao Wang, Michele Gerber, Michael Gorgievski, Josephine D'Alessandro, Neha Diwanji, Ronald Vale, Siddhartha Mukherjee, Daniel Getts. Preclinical &amp; clinical activity of autologous mRNA engineered chimeric antigen receptor monocytes for targeted 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 3612.
Abstract 566: The anticancer effects of polyisoprenylated cysteinyl amide inhibitors involves interaction with the KRAS chaperone calmodulin
Authors: Kweku Ofosu-Asante, Jassy Mary Lazarte, Amarender Burra, Nazarius S. Lamango
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is the third leading cause of cancer-related deaths with a 5-year survival rate of less than 10%. Approximately 90% of reported cases are driven by KRAS mutations. The mutant KRAS acquires its functional localization through interactions with chaperone proteins via its polybasic polyisoprenylated tail. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) mimic this region possibly disrupting the polyisoprenylation-dependent interactions with chaperone proteins. Here, we determine the effect of newly developed PCAIs that were designed to be more water-soluble on cell viability, 3D spheroid invasion, spheroid degeneration and F-actin filaments on MIA PaCa-2 and PANC-1 cells. Of the seven new PCAIs analogs tested, NSL-AB-51 and NSL-AB-45 were the most potent, with EC50 values of 2.5 and 5.6 µM against MIA PaCa-2, and 1.7 and 4.5 µM against PANC-1 cells, respectively. At 5 and 10 µM, NSL-AB-51 decreased the invasion area of 3D spheroids by 98 and 99%, respectively. MIA PaCa-2 spheroids degenerated by 61% after 72 h treatment with 10 µM NSL-AB-51. Treatment with 1.0 μM NSL-AB-51 caused cell rounding and reduction of mean cell areas by 69% and F-actin filaments by 96%. Moreover, to identify the pharmacological target of the PCAIs, NSL-AB-45 was coupled to an epoxy-activated Sepharose resin for affinity trapping of PCAIs-interacting proteins. Affinity-analysis of supernatants and detergent membrane extracts from MIA PaCa-2 and PANC-1 cells revealed single Coomassie band of about 17 kDa that was identified as calmodulin by western blotting analysis. The calmodulin-PCAIs affinity interaction was found to be strongest in the presence of calcium and weakest in the presence of EDTA. These findings reveal that calmodulin is the likely target of PCAIs. Since calmodulin is the chaperone protein responsible for KRAS trafficking and localization to the inner surface of the plasma membrane, this finding strongly suggests, at least in part, an anticancer role for the PCAIs that involve disruption of KRAS functions. Citation Format: Kweku Ofosu-Asante, Jassy Mary Lazarte, Amarender Burra, Nazarius S. Lamango. The anticancer effects of polyisoprenylated cysteinyl amide inhibitors involves interaction with the KRAS chaperone calmodulin [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 566.
Abstract 7311: Lipid soluble vitamin B1 derivatives, benfotiamine and fursultiamine, prevent breast cancer cells growth
Authors: Caroline Ciaciuch O'Neill, Aveline P. Langmead, Kota V. Ramana
Journal: Cancer Research (2024)

Abstract Breast cancer is the leading cause of cancer death in women in the US and the second leading cancer after skin cancer in women worldwide. According to the CDC, women from 45-84 years of age are most at risk, with approximately 30% of deaths in this group being from cancer. Increased free radical formation, and oxidative and inflammatory responses have been shown to be major contributing factors for the progression of breast cancer. Several antioxidants and vitamins have been tested for their efficacy in preventing breast cancer. However, the role of vitamin B1 derivatives in the prevention of breast cancer is not known. Therefore, we hypothesize that with potent anti-oxidative and anti-inflammatory actions, lipid-soluble derivatives of vitamin B1 (thiamine), such as benfotiamine and fursultiamine, could prevent breast cancer growth and spread. We have treated human breast cancer cells such as MCF-7 and T-4D1 and mouse breast cancer cells 4T1 with vitamin B1 derivatives and examined the cancer cells growth. Our results indicate that treatment of various breast cancer cells with benfotiamine and fursultiamine prevents the proliferation of cancer cells in a dose-dependent manner. Further, both benfotiamine and fursultiamine by regulating the activation of caspase-3 and cleavage of PARP protein could prevent breast cancer cells growth. Benfotiamine and fursultiamine also regulates generation of reactive oxygen species in breast cancer cells. Further, vitamin B1 derivatives regulate the expression of various anti-apoptotic, pro-apoptotic, survival and inflammatory factors in both human and mouse breast cancer cells. We next planned to examine the effect of vitamin B1 derivatives on breast cancer growth in vivo using athymic nude mouse models. In conclusion, our in vitro results suggest that vitamin B1 derivatives, benfotiamine and fursultiamine, by promoting the apoptotic pathways prevent breast cancer cells growth and could be further developed as chemopreventive drugs. Citation Format: Caroline Ciaciuch O'Neill, Aveline P. Langmead, Kota V. Ramana. Lipid soluble vitamin B1 derivatives, benfotiamine and fursultiamine, prevent breast cancer cells growth [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 7311.
Abstract 4974: Development of an ovarian cancer diagnosis score using electronic health records
Authors: Minh Tung Phung, Karen McLean, Gillian E. Hanley, Celeste Leigh Pearce
Journal: Cancer Research (2024)

Abstract Background: Diagnosis of invasive epithelial ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) is often delayed, worsening both survival and quality of life for ovarian cancer patients. Diagnosis is delayed in ovarian cancer both because there is no effective screening method and because the symptoms commonly associated with ovarian cancer (i.e., abdominal/pelvic pain, bloating, loss of appetite, urinary symptoms) are non-specific to the disease. It would be beneficial to develop a flag in the electronic health record (EHR) when a patient’s healthcare utilization indicates further investigation for possible ovarian cancer is warranted. Thus, we used EHR data to develop a diagnosis score that identifies people who should be further assessed for potential ovarian cancer. Methods: EHR data from 211,123 female patients, including 135 ovarian cancer patients, at the University of Michigan Medical System during 2012-2023 were analyzed. Time-varying Cox proportional hazard models were fit to identify the association between ovarian cancer and the diagnostic codes recorded for healthcare visits in the EHR, including the temporal sequence of the diagnostic codes. The beta coefficients for the diagnosis codes from the Cox models were summed to create a weighted diagnosis score for each patient. The weighted diagnosis score was tested for association with ovarian cancer in the same population. Results: A total of 79 diagnostic codes were statistically significantly associated with ovarian cancer after applying a Bonferroni correction (p&amp;lt;9x10-5). The temporal sequence of the diagnoses was not associated with ovarian cancer. There were 11 pairs of diagnosis codes that were correlated (correlation coefficient &amp;gt;0.25); the diagnosis code with the higher p-value was excluded from further consideration. The remaining 68 codes were used to construct the diagnosis score. There was a statistically significant trend of increasing rate of ovarian cancer per quartile of the diagnosis score (hazard ratio=3.75, 95% confidence interval 3.50-4.03). Conclusion: A score for ovarian cancer diagnosis was developed based on 68 diagnostic codes in the EHR. The next step is to validate the diagnosis score in an external dataset. This validation is underway using administrative data from British Columbia, Canada. Citation Format: Minh Tung Phung, Karen McLean, Gillian E. Hanley, Celeste Leigh Pearce. Development of an ovarian cancer diagnosis score using electronic health records [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 4974.