tbuckley/cabot-search huggingface dataset:
Abstract 5876: ALDH3A1 as a predictive marker for gemcitabine treatment in pancreatic cancer
Authors: Jin Su Kim, Ji Young Keum, Chan Hee Park, Seungmin Bang
Journal: Cancer Research (2024)

Abstract Background: Pancreatic cancer is one of the incurable cancer. The currently preferred chemotherapy regimens, including gemcitabine, do not extend patient survival by more than a year, and studies on drug resistance mechanisms or biomarkers for the drug sensitivity are very limited. Aldehyde dehydrogenase (ALDH) is a family of enzymes that play an essential role in cell survival and protection. In cancer cells, it is thought that overexpression of the ALDHs confers a survival advantage to the cells, which is associated with a poor prognosis. In this study, we analyzed the drug sensitivity between ALDH3A1 expression and gemcitabine in PDAC cells. Method: In this study, we investigated the relationship between ALDH3A1 expression and gemcitabine sensitivity using 8 pancreatic cancer cell line. We observed changes in the pattern of ALDH3A1 expression in established gemcitabine resistance pancreatic cancer cell line. Following this, we functionally inhibited ALDH3A1 to determine its impact on gemcitabine sensitivity using shRNA method. To elucidate the molecular mechanisms related with ALDH3A1, we performed multi-omics analysis such as transcriptomics and proteomics. Results: As a results, there was a negative correlation between ALDH3A1 expression (Protein &amp; mRNA) and gemcitabine resistance 8 pancreatic cancer cell lines. However, in established gemcitabine resistance BxPC3 cells compared to control cells, gemcitabine resistance increased more than 1000 fold while the protein expression was decreased. In these results correlated with inhibition of ALDH3A1 expression using shALDH3A1 experiments both change ALDH3A1 expression and gemcitabine resistance. In biological phenotype experiments, cell proliferation and migration increased in the ALDH3A1 inhibition groups. When using combination treatment of gemcitabine and CB29, a known ALDH3A1 inhibitor, drug resistance increased by more than 2,000 fold in the combination treatment groups. In RNAseq analysis, Adherens junction, Ras signaling, Axon guidance, and JAK-STAT signaling pathway related genes were up regulated in shALDH3A1 treatment group compared control. Conclusion: In this study, we demonstrated the negative correlation between ALDH3A1 and gemcitabine resistant in pancreatic cancer cell lines and suggesting that it may serves as a predictive marker for gemcitabine treatment in pancreatic cancer patients. Keywords: Pancreatic ductal adenocarcinoma (PDAC), Aldehyde dehydrogenase 3 family member A1 (ALDH3A1), Gemcitabine sensitivity. Citation Format: Jin Su Kim, Ji Young Keum, Chan Hee Park, Seungmin Bang. ALDH3A1 as a predictive marker for gemcitabine treatment in pancreatic 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 5876.
Abstract 4738: Overcoming therapy resistance in rhabdomyosarcoma by targeting the PI3K-MAPK pathway
Authors: Yadong Wang, Eleanor Chen
Journal: Cancer Research (2024)

Abstract Rhabdomyosarcoma (RMS) is a devastating pediatric cancer. There has not been any significant change in the treatment options for the last 4 decades, especially for relapsed or advanced disease. There is an urgent need to identify alternative treatment options to improve survival outcomes of RMS patients. RMS is comprised of two major subtypes as defined by the presence or absence of PAX3/PAX7-FOXO1 gene fusion. Fusion-negative RMS (FN RMS) is characterized by alterations in the RAS-PI3K-MAPK pathway in &amp;gt;90% of the cases. However, the role of the PI3K-MAPK pathway in therapy resistance and disease relapse remains poorly characterized. We have generated two FN-RMS lines, RD and SMS-CTR, with resistance to the standard-of-care chemotherapeutic agent, vincristine, through long-term culturing in incrementally increased concentrations of the drug. By RNA sequencing, vincristine-resistant RD and SMS-CTR cells demonstrated increased expression of genes in the RAS-PI3K-MAPK pathway compared to the parental lines. We hypothesize that increased activity of the PI3K-MAPK pathway contributes to therapy resistance in FN RMS. To test the hypothesis, we first showed that targeted disruption of PIK3CA by shRNA inhibited the cell growth of vincristine-resistant FN RMS cells. The same cells also showed increased sensitivity to the MEK inhibitor, trametinib, as well as the PIK3Cα inhibitor, alpelisib, compared to the parental cells. We then showed that zebrafish FN-RMS tumors treated with the combination of vincristine and alpelisib significantly inhibited tumor growth compared to the treatment with each agent alone. Through integrative analysis of RNA sequencing and ATAC-seq data, we identified MYOD1 and NFATC2 as among the top candidate upstream regulators. Targeted disruption of either MYOD1 or NFATC2 by CRISPR/Cas9 reduced cell growth of vincristine-resistant FN RMS cells and altered expression of the genes in the PI3K-MAPK pathway, implicating MYOD1 and NFATC2 in driving abnormal activity of this pathway. To assess the relevance of our findings in the clinical settings, we showed that selective components in the PI3K-MAPK pathways are up-regulated in 3 matched primary-recurrence/metastasis paraffinized tissue samples of human FN RMS by the NanoString GeoMx Digital Spatial Profiler (DSP) platform. Our findings indicate that targeting the PI3K-MAPK pathway is a promising targeted therapy option for overcoming therapy resistance in RMS. Citation Format: Yadong Wang, Eleanor Chen. Overcoming therapy resistance in rhabdomyosarcoma by targeting the PI3K-MAPK 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 4738.
Abstract 6754: A microneedle array patch chemo-immunotherapy for cutaneous squamous cell carcinoma
Authors: Yufan Yang, Haotong Zhang, Cara D. Carey, Jiying Zhang, Stephen C. Balmert, Emrullah Korkmaz, Louis D. Falo
Journal: Cancer Research (2024)

Abstract Cutaneous squamous cell carcinoma (cSCC) is the second most common human malignancy worldwide. Current therapies, including surgical excision, are associated with significant morbidities and considerable expense. Multiple efforts are now underway to develop novel therapies that are effective, durable, safe, cost-effective, and patient-friendly. Here, we report ongoing efforts to develop a localized dissolvable microneedle array patch (MAP) based therapy for cSCC. Our approach is based on the hypothesis that the delivery of an immunogenic cell death (ICD) inducing chemotherapeutic agent to the tumor microenvironment (TME) of accessible cSCCs could kill tumor cells as a source of antigen and induce a proinflammatory TME to generate a potent patient-specific anti-tumor immune response. Specifically, we evaluated MAP therapy using a UV-induced preclinical cSCC mouse model. We applied MAPs delivering the potent ICD-inducing chemotherapeutic agent, doxorubicin (DOX) to UV-induced tumors. MAPs efficiently delivered DOX to the tumor microenvironment. Compared to traditional needle injection, MAP delivery resulted in sustained high levels of DOX in the TME with minimally systemic exposure. Cell death was evident in MAP-DOX-treated tumors, and treatment resulted in tumor regression, increased survival, and long-term immune protection. Further, we found that tumor regression was associated with an early proinflammatory neutrophilic infiltrate. Taken together, our results suggest that MAP delivery of doxorubicin may be a promising approach to cSCC treatment. and that proinflammatory neutrophils are likely an important component of the early infiltrate that leads to tumor regression. Citation Format: Yufan Yang, Haotong Zhang, Cara D. Carey, Jiying Zhang, Stephen C. Balmert, Emrullah Korkmaz, Louis D. Falo. A microneedle array patch chemo-immunotherapy for cutaneous squamous cell 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 6754.
Abstract 6240: Mutation impact on mRNA versus protein expression across human cancers
Authors: Yuqi Liu, Abdulkadir Elmas, Kuan-lin Huang
Journal: Cancer Research (2024)

Abstract Cancer mutations are often assumed to alter proteins, thus promoting tumorigenesis. However, how mutations affect protein expression has rarely been systematically investigated. We conduct a comprehensive analysis of mutation impacts on mRNA- and protein-level expressions of 953 cancer cases with paired genomics and global proteomic profiling across six cancer types. Protein-level impacts are validated for 47.2% of the somatic expression quantitative trait loci (seQTLs), including mutations from likely “long-tail” driver genes. Devising a statistical pipeline for identifying somatic protein-specific QTLs (spsQTLs), we reveal several gene mutations, including NF1 and MAP2K4 truncations and TP53 missenses showing disproportional influence on protein abundance not readily explained by transcriptomics. Cross-validating with data from massively parallel assays of variant effects (MAVE), TP53 missenses associated with high tumor TP53 proteins were experimentally confirmed as functional. Our study demonstrates the importance of considering protein-level expression to validate mutation impacts and identify functional genes and mutations. Citation Format: Yuqi Liu, Abdulkadir Elmas, Kuan-lin Huang. Mutation impact on mRNA versus protein expression across human 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 6240.
Abstract 6244: MultiTME: A Bayesian method for integration and analysis of multimodal, multi-patient spatial profiling data
Authors: Haoran Zhang, Jeff Quinn, Liron Yoffe, Vivek Mittal, Wesley Tansey
Journal: Cancer Research (2024)

Abstract The role of the tumor microenvironment (TME) in cancer evolution and progression is complex and multi-faceted. Multiple cellular phenotypes and patterns of cell-cell communication have been implicated as drivers of drug resistance and metastasis. The spatial architecture of the TME is emerging as particularly important in characterizing the trajectory of tumor growth and response to therapy. Accordingly, there has been a rapid rise in technologies to spatially profile the TME. Each technology focuses on a different modality (e.g. transcriptomics, proteomics, metabolomics) and operates at a different granularity, from coarse-grained tissue spots aggregating dozens of cells to fine-grained subcellular resolution. There is currently no computational method capable of drawing unified inferences across modalities. We introduce MultiTME, a single, holistic generative model for jointly modeling multimodal data across multiple samples in a cohort. MultiTME addresses these challenges through a two-dimensional integration of both samples and multimodal data. MultiTME incorporates a cohort of tissue samples, enabling the joint modeling of different samples within a single analytical framework. This integration allows for a comprehensive analysis of the spatial distribution of cell types across multiple samples, enhancing the understanding of TME variability and the identification of robust biomarkers. MultiTME also integrates multimodal data with varying resolutions, such as Spatial Transcriptomics (ST), single-cell RNA sequencing (scRNA-seq), and Imaging Mass Cytometry (IMC), and provides a multi-layered understanding of the TME. This integration enables the modeling of TME at a finer scale and the discovery of cell types and subtypes that are not distinguishable using single-modal approaches. It also provides concurrent expression profiles across different modalities, leading to the identification of novel biomarkers. We demonstrate MultiTME's efficiency and scalability with a dataset of coupled ST, scRNA-seq, and IMC from a cohort of 8 lung cancer patients. MultiTME's capability to handle both intra-cohort and inter-modality variability offers a panoramic view of TME and helps identify biomarkers and therapeutic targets for cancer screening and treatment. MultiTME is open source. Citation Format: Haoran Zhang, Jeff Quinn, Liron Yoffe, Vivek Mittal, Wesley Tansey. MultiTME: A Bayesian method for integration and analysis of multimodal, multi-patient spatial profiling data [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 6244.
Abstract 4035: Lipid-based nanoparticle combination immunotherapy with sitravatinib for the systemic treatment of high-risk neuroblastoma
Authors: Miranda Diaz-Infante, Griffin Kane, Christina Lusi, Meghan Brassil, Kim Wigglesworth, Christian Alarcon, Jason Shohet, Prabhani Atukorale
Journal: Cancer Research (2024)

Abstract We seek to develop a systemic, innate immunomodulatory nanoparticle therapy that combines synergistically with sitravatinib for the treatment of high-risk neuroblastoma, where metastasis is the largest hurdle for current treatment modalities. Here, we utilize a unique lipid-based nanoparticle (LNP) system comprised of co-encapsulated agonists of the Stimulator of Interferon Genes (STING) and Toll-like Receptor 4 (TLR4) pathways (immuno-NPs) that can be safely administered in the systemic blood circulation for delivery to the tumor microenvironment (TME) and uptake by perivascular innate antigen-presenting cells (APCs). STING/TLR4 agonists together promote the synergistic production of Type I interferon β (IFNβ), a key activator of anti-tumor immunity from the TME itself. Here, we also focus on sitravatinib, an investigational drug shown to inhibit receptor tyrosine kinases such as discoidin domain receptor 2 (DDR2), which can inhibit the sustained remodeling of collagen around primary tumors. The inhibition of such is vital to treatment as sustained collagen remodeling can facilitate the metastasis of cancer cells via epithelial-mesenchymal transition (EMT). We hypothesize that the downstream effects of sitravatinib treatment will augment tumor clearance and increase the therapeutic efficacy of immuno-NPs with respect to recruiting APCs. Our early pilot studies in humanized mice bearing orthotopic SH-5YSY tumors show that immuno-NPs are effective at tumor clearance. We found that mice inoculated subcutaneously with syngeneic 9464D-GD2 tumors showed decreased tumor growth when treated with our novel combination therapy in comparison to monotherapy controls. In both humanized and syngeneic tumor models, our ongoing mechanistic studies involve quantification of EMT in primary tumors, systemic nanoparticle deposition at metastatic sites, and the mechanistic impact of combination therapy on IFNβ-promoted elimination of metastasis. Here, we have proposed and tested an immunotherapy with great promise for treating neuroblastoma. However, the impact of nanoparticle-based immunotherapy reaches far beyond neuroblastoma: it has the potential to be a platform for the development of immunotherapies specific to other highly metastatic cancer types. Citation Format: Miranda Diaz-Infante, Griffin Kane, Christina Lusi, Meghan Brassil, Kim Wigglesworth, Christian Alarcon, Jason Shohet, Prabhani Atukorale. Lipid-based nanoparticle combination immunotherapy with sitravatinib for the systemic treatment of high-risk neuroblastoma [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 4035.
Abstract 2119: Translational research to facilitate development of novel therapeutic combinations of letrozole for the treatment of glioblastoma
Authors: Aniruddha Sunil Karve, Bhavesh Babulal Gabani, Sidharth Nitin Gadgil, Shravani Parag Kulkarni, Gary A. Gudelsky, Pankaj B. Desai
Journal: Cancer Research (2024)

Abstract Letrozole (LTZ), a third-generation aromatase inhibitor, appears to be a promising novel therapeutic for the treatment of glioblastoma (GBM). It synergistically enhances the efficacy of the DNA alkylating agent temozolomide, one of the few approved chemotherapeutics for GBM, against patient-derived GBM cells. RNA-seq analysis of tumor from recurrent GBM patients treated with LTZ prior to surgery in a “window of opportunity” phase 0/1 dose escalation clinical trial revealed that LTZ downregulates genes encoding for DNA-damage repair proteins (BRCA2) in a dose dependent manner. Our central hypothesis for this project is that combination of LTZ with targeted therapeutic agents that promote DNA damage results in synergistic effects against GBM. The objective of this study is to evaluate the effects of poly-ADP ribose polymerase (PARP) inhibitors in combination with LTZ against patient-derived GBM cells. Our secondary aim for this project is to delineate the blood-brain barrier (BBB) permeability of PARP inhibitors. Employing patient-derived G43, G75 and JHH-136 GBM lines we assessed the influence of PARP inhibitors (olaparib, pamiparib, veliparib and niraparib) in combination with LTZ on cell viability and neurosphere growth. We then utilized male CD-IGS rats (n=6; body wt., 250g) to assess plasma and brain extracellular fluid (ECF) pharmacokinetics (PK) of PARP inhibitors using cerebral microdialysis. The IC50 values for PARP inhibitors in these assays ranged from 0.06 to 11.31 µM. Treatment in combination with LTZ (0.05 µM), a non-cytotoxic concentration of LTZ in these lines, significantly decreased the IC50 values for PARP inhibitors (0.012 to 0.51 µM). Combination Index analysis indicated that this combination was strongly synergistic. Furthermore, the plasma and brain ECF PK analyses suggested that PARP inhibitors such as pamiparib and niraparib exhibit facile transport across the BBB barrier as reflected in Kp,uu,brain (ratio of AUCecf/AUCplasma, unbound) values of 0.98 and 0.45, respectively. Overall, these results provide a strong foundation for pursuing further development of combination therapy of GBM with LTZ and PARP inhibitors. A careful assessment of the clinical efficacy and safety profile of these agents will further guide shortlisting combination of LTZ for pre-clinical and clinical development. Citation Format: Aniruddha Sunil Karve, Bhavesh Babulal Gabani, Sidharth Nitin Gadgil, Shravani Parag Kulkarni, Gary A. Gudelsky, Pankaj B. Desai. Translational research to facilitate development of novel therapeutic combinations of letrozole for the treatment of 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 2119.
Abstract 4676: 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a novel paclitaxel chemosensitizer to inhibit growth in Taxol non-resistant and Taxol resistant cancers
Authors: Ka Ming Cheng, Gui yun Wu, Kowk Kuen Cheung, Xiao-Ling Shen, Ying-Jie Hu, Ki Lui
Journal: Cancer Research (2024)

Abstract 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a single molecule isolated from a traditional Chinese Medicinal herb Marsdenia tenacissima (MT). Recently, our group has isolated a few single molecules from the MT herb, they have shown significant anti-tumor activity in vitro and MT2 has the highest potential among all. We have performed MTT viability assay and clonogenic assay to demonstrate that MT2-alone is non-cytotoxic, but the cytotoxicity of the paclitaxel+MT2 combination treatment was more significant than that of paclitaxel, a microtubule stabilizing chemotherapeutic agent. The underlying mechanism of such growth inhibition is contributed by the down-regulation of the pro-survival signaling and up-regulation of the apoptotic signaling such as an increase in cleaved caspase 3 and decrease in anti-apoptotic Bcl-2 proteins when cancer cells are co-treated with MT2+paclitaxel. More importantly, intraperitoneal administration of the combination treatment 5 times of MT2+paclitaxel (30mg/kg, 8mg/kg) has a more significant anti-tumor effect than the paclitaxel-alone (8mg/kg) or MT2-alone (30mg/kg) treatments using the wild-type hepatic HepG2 xenograft model in nude mice. Besides the wild-type HepG2 cancer cells, we have further demonstrated that MT2 is able to resensitize paclitaxel-resistant HepG2 cancer cells by inhibiting the activity of p-glycoprotein (Pgp), a key drug efflux transporter in chemotherapy resistance cancer cells. Also, the combination treatment has shown a significant anti-tumor effect in HepG2/DOX Pgp-overexpressed xenograft in nude mice. Taken together, MT2 is a novel chemosensitiser in combination use with paclitaxel to treat cancer. It enhances cancer apoptosis by suppressing the anti-apoptotic and survival signaling pathways in cancer cells. Citation Format: Ka Ming Cheng, Gui yun Wu, Kowk Kuen Cheung, Xiao-Ling Shen, Ying-Jie Hu, Ki Lui. 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a novel paclitaxel chemosensitizer to inhibit growth in Taxol non-resistant and Taxol resistant 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 4676.