tbuckley/cabot-search huggingface dataset:
Abstract 3222: Acute and long-term responses to treatment with the HDAC inhibitor quisinostat in preclinical models of glioblastoma
Authors: Keely Orndorff, James McNamara, Mariya Stavnichuk, Costanza Lo Cascio, Connor White, Ernesto Luna Melendez, Gozde Uzunalli, Nader Sanai, Shwetal Mehta
Journal: Cancer Research (2024)

Abstract Introduction: High expression of histone deacetylases (HDACs), particularly HDAC1, is strongly associated with poor prognosis for glioblastoma (GBM) patients. Quisinostat is a second-generation, class I-II selective HDAC inhibitor with high specificity for HDAC1 and potent anti-tumor activity. Here, we evaluated GBM PDX tissues and glioma stem cells (GSCs) for cellular, transcriptomic and phenotypic changes after acute and long-term treatment with quisinostat. Methods: Multiple GBM PDX models and PDX-derived GSCs were treated with quisinostat, radiation, or a combination of quisinostat and radiation. Tissue and cells were processed for RNA-seq, qRT-PCR, and immunofluorescence assays to examine alterations in neuronal signaling, cell fate, DNA damage, and markers of stemness and differentiation. Results: Bulk RNA sequencing of tumor tissue revealed that chronic co-treatment with quisinostat and radiation led to increased cellular expression of neuronal signaling and neuronal development pathways compared to the untreated control group. Increase in expression of neuronal signaling genes was also observed upon in vitro treatment of GSCs with quisinostat. Immunocytochemistry and immunofluorescence staining confirmed changes in neuronal signaling and neuronal cell fate proteins after quisinostat treatment. Conclusions: Quisinostat treatment induces a shift in tumor cells towards a neuronal-like cell fate. Considering that GSCs have been shown to establish synaptic junctions with healthy neurons to evoke enhanced excitatory currents within glioma cells and contribute to treatment resistance, further investigation of this shift upon HDAC inhibition is crucial. Ongoing studies are aimed at evaluating the significance of these cellular and molecular changes resulting from quisinostat treatment and whether the quisinostat-induced cell fate changes can be exploited for future combination therapy for GBM. Citation Format: Keely Orndorff, James McNamara, Mariya Stavnichuk, Costanza Lo Cascio, Connor White, Ernesto Luna Melendez, Gozde Uzunalli, Nader Sanai, Shwetal Mehta. Acute and long-term responses to treatment with the HDAC inhibitor quisinostat in preclinical models 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 3222.
Abstract 3801: Spatially resolved laser-activated cell sorting (SLACS) for high throughput spatial cell sorting in tumor research
Authors: Sumin Lee, Amos Chungwon Lee
Journal: Cancer Research (2024)

Abstract Understanding of tumor heterogeneity and the microenvironment is a cornerstone in advancing cancer research and therapy. The Spatially resolved Laser-Activated Cell Sorter (SLACS) represents a novel approach in cancer research, allowing for high-throughput, precise cell isolation while preserving spatial information, which is crucial for studying tumor heterogeneity and the tumor microenvironment. The SLACS instrument utilizes laser-activated technology for selective isolation of cells from heterogeneous tissue samples, optimized for accuracy, speed, and minimal cell damage. This instrument has demonstrated effective isolation of specific cell types from complex tissue matrices, maintaining cell integrity and spatial information. Its high-throughput capacity significantly reduces sample processing time. This groundbreaking tool offers detailed exploration of tumor heterogeneity and the tumor microenvironment, providing valuable insights into cancer biology and potential therapeutic targets. Citation Format: Sumin Lee, Amos Chungwon Lee. Spatially resolved laser-activated cell sorting (SLACS) for high throughput spatial cell sorting in tumor research [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 3801.
Abstract 6905: A multi-targeted approach to evaluate therapeutic selection and efficacy in preclinical GBM models
Authors: Emily Eastwood, Bianca Carapia, Javier Rodriguez, Kristen Buck, Derrick Gorospe, Elizabeth Valencia, Bridget Corcoran, Raffaella Pippa, Yuan-Hung Chien, Warren Andrews, Long Do, Jonathan K. Nakashima, Jantzen Sperry
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is a devastating primary brain cancer with approximately 10,000 new US diagnoses annually. The current standard of care (SOC) for GBM includes surgical resection followed by radiation therapy (RT) and temozolomide (TMZ), however, there is near universal recurrence and development of resistance after treatment. Relapse in disease is tightly linked with dynamic changes in gene expression during tumor evolution, highlighting the need for stronger preclinical GBM models. Here, we report developing a pair of patient-derived xenograft (PDX) models from surgical resections obtained from initial GBM incidence in a patient (BarneyOI™ Cancer Model CRT00433) and subsequent recurrence following treatment (BarneyOI Cancer Model CRT00435) to study disease progression and novel treatment strategies. Recent studies have suggested the utilization of combination therapy approaches for GBM patients to address TMZ resistance. To this end, Certis has developed a personalized, AI-based approach to predict and test combination therapies in preclinical cancer models. Accuracy of the predicted sensitivities to treatment was evaluated in vivo using both subcutaneous (SC) and orthotopic (OT) mouse models. Luciferase-tagged CRT00433 and CRT00435 spheroid cell lines were transduced with firefly luciferase and implanted intracranially by stereotactic surgery for OT monitoring. Optical bioluminescence imaging (BLI) and murine-scale MRI from Aspect Imaging were used to assess therapeutic response of AI-predicted combination therapies and SOC treatment. Citation Format: Emily Eastwood, Bianca Carapia, Javier Rodriguez, Kristen Buck, Derrick Gorospe, Elizabeth Valencia, Bridget Corcoran, Raffaella Pippa, Yuan-Hung Chien, Warren Andrews, Long Do, Jonathan K. Nakashima, Jantzen Sperry. A multi-targeted approach to evaluate therapeutic selection and efficacy in preclinical GBM models [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 6905.
Abstract 3237: KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer
Authors: Jessica D. Johnson, Yihong Chen, Sridharan Jayamohan, Yi He, Diksha Jamwal, Neetesh Pandey, Edward Kost, Ratna K. Vadlamudi, Gangadhara R. Sareddy
Journal: Cancer Research (2024)

Abstract Background: Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase (KDM1A/LSD1) is highly overexpressed in OCa. However, whether KDM1A plays a role in chemoresistance and whether its inhibition enhances chemotherapy response in OCa is unknown. In this study, we explored the hypothesis that KDM1A inhibition will sensitize OCa cells to standard-of-care chemotherapy. Methods: Transduction of KDM1A-specific shRNA was used to generate KDM1A knockdown (KD) cells. Cell viability, colony formation, and apoptosis assays were used to determine the impact of KDM1A KD on sensitization of SKOV3, OVCAR8, and OVCAR5 OCa cells to cisplatin, carboplatin, and paclitaxel. The combination effect of KDM1A inhibitors (NCD38 and SP2509) and chemotherapy drugs was further determined. Mechanistic studies were conducted using RNA-sequencing, RT-qPCR, and Western blotting. In vivo efficacy ofKDM1A knockdown with or without chemotherapy was determined using OCa orthotopic xenograft models. Results: Analysis of TCGA datasets revealed that KDM1A expression is negatively correlated with OCa survival, and its expression is high in patients who do not respond to chemotherapy. Further, Western blotting results show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A-KD or KDM1A inhibition sensitized OCa cells to chemotherapy drugs in reducing cell viability, survival, and enhancing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistantA2780-CP70 cells to carboplatin treatment. RNA-seq studies revealed that KDM1A-KD and cisplatin-regulated genes showed negative correction with epithelial-mesenchymal transition (EMT) and positive correlation with apoptosis-related pathways. Importantly, KDM1A KD in combination with cisplatin significantly reduced the tumor growth in the orthotopic OCa xenograft model. Conclusion: These results suggest that the combination of KDM1A inhibitors with chemotherapy is a viable therapeutic approach for the treatment of OCa Citation Format: Jessica D. Johnson, Yihong Chen, Sridharan Jayamohan, Yi He, Diksha Jamwal, Neetesh Pandey, Edward Kost, Ratna K. Vadlamudi, Gangadhara R. Sareddy. KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian 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 3237.
Abstract 3796: Investigating unbiased whole transcriptome high-resolution spatial interactions within tumor masses
Authors: Marie M. Lee, Julie Wilhelmy, Thomas Ong, Wanxin Wang, Bertrand Yeung, Christina Chang, Christina Fan
Journal: Cancer Research (2024)

Abstract Tumor masses contain a diverse array of cell types, including both normal and tumor cells from different lineages, endothelial cells, and immune cells. Interactions among these cellular constituents and their spatial arrangements play a pivotal role in tumor development, progression, and metastasis. While single-cell analysis has provided valuable insights regarding the dissociated cellular composition of tumors, it falls short in elucidating the complex interplay of cell-cell interactions and spatial relationships that may drive tumor cellular behavior and gene expression. We used the Curio Seeker Spatial Mapping Kits to uncover those spatial relationships in human tumor samples. The method captured whole transcriptomes and preserved the spatial locations of tumor cells, infiltrating immune cells, and normal cells by self segregating gene expression signatures and unbiased clustering. Amongst other findings by using Curio Seeker, we identified areas of immune cell infiltrates that were devoid of tumor cells, signifying zones of potential anti-tumor response. The high spatial resolution, continuous gene expression maps from the Curio Seeker Spatial Mapping Kits reveal spatial interactions between different cellular populations that enable researchers to better understand how the interplay between tumor cell types and their cellular neighborhoods affect gene expression and tumor cell behavior. Citation Format: Marie M. Lee, Julie Wilhelmy, Thomas Ong, Wanxin Wang, Bertrand Yeung, Christina Chang, Christina Fan. Investigating unbiased whole transcriptome high-resolution spatial interactions within tumor masses [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 3796.
Abstract 6020: GPC3-targeted radiopharmaceutical therapy for neuroendocrine prostate cancer
Authors: Renee Clift, Fanching Lin, Katrina Salvador, Matt Guest, Daniel Kim, Guangzhou Han, Gary Li
Journal: Cancer Research (2024)

Abstract Introduction: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein with minimal expression in normal tissues. Besides hepatocellular carcinoma, upregulation of GPC3 protein has been observed in a significant subset of treatment-emergent neuroendocrine prostate cancer (NEPC), which accounts for to 30% of prostate cancer cases refractory to anti-androgen and other therapies. The differential expression of GPC3 between NEPC cells and normal tissues provides a theranostic opportunity for targeted radiopharmaceutical therapy (RPT). Methods: The novel RPT agent RYZ-GPC3 comprises a small macrocyclic peptide binder with high affinity to GPC3 linked with a tetraxetan moiety capable of chelating a variety of radioisotopes. The expression of GPC3 in NEPC cells was assessed by flow cytometry and immunohistochemistry (IHC). The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR) and radioligand binding assays. In vivo biodistribution of [177Lu]Lu-RYZ-GPC3 and anti-tumor therapy with [177Lu]Lu-RYZ-GPC3 or [225Ac]Ac-RYZ-GPC3 were performed in NEPC xenografts. Results: The novel agent is a highly potent and selective peptide binder to GPC3 of human, mouse and NHP origins, and is compatible with multiple radiometal isotopes. In vivo biodistribution study of [177Lu]Lu-RYZ-GPC3 in GPC3-positive NEPC xenografts showed sustained tumor uptake of 10.8, 12.6, 5.1, and 2.2 %ID/g at 2, 24, 72 and 168 hours post dose, respectively, with fast renal clearance. Minimal or no uptake was observed in other normal tissues. A single injection of [225Ac]Ac-RYZ-GPC3 (11.1 kBq) resulted in significant tumor growth inhibition (TGI 109%) with durable regression and prolonged survival. All treatments were well tolerated. Conclusion: Preclinical in vitro and in vivo data demonstrated the potential of the novel binder as a theranostic agent for the treatment of patients with GPC3+ NEPC. Citation Format: Renee Clift, Fanching Lin, Katrina Salvador, Matt Guest, Daniel Kim, Guangzhou Han, Gary Li. GPC3-targeted radiopharmaceutical therapy for neuroendocrine 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 6020.
Abstract 6014: PLK1-dependent phosphorylation of PRMT5 promotes DNA damage response in prostate cancer
Authors: Jia Peng, Yanquan Zhang, Jianlin Wang, Qianjin Li, Daheng He, Xinyi Wang, Xiongjian Rao, Meng Wu, Pingli Mo, Lei Wang, Sai Wu, Ruixin Wang, Jinghui Liu, Mansoureh Nouri, Izumi Tadahide, Xiaoqi Liu
Journal: Cancer Research (2024)

Abstract Prostate cancer stands out as the most frequently diagnosed cancer in men and is projected to be the second leading cause of cancer-related deaths among men in the US. Consequently, there is an urgent need for studies focusing on innovative therapeutic approaches. DNA Damage Response (DDR) is critical for cell survival, as it promotes genomic stability and reduces the risk of inheriting damage. DDR also promotes cancer cells' survival, making it a therapeutic target in cancer. PRMT5, an enzyme in the methyltransferase family, is frequently activated and overexpressed in various cancers, including prostate cancer. Furthermore, research has revealed that PRMT5 has been implicated in DDR in prostate cancer, and the regulation of PRMT5-dependent DDR is influenced by its phosphorylation. Polo-like kinase 1 (PLK1) is a serine/threonine kinase also reportedly involved in DDR in prostate cancer. Our preliminary study found that PRMT5 is positively correlated with PLK1 in prostate cancer based on the TCGA database. Nonetheless, the mechanism through which PRMT5 is regulated needs to be clarified. Here, we found that PLK1 phosphorylates PRMT5 at the S470 site, and this specific phosphorylation is required for maintaining the enzymatic activity of PRMT5. Moreover, Plk1-associated phosphorylation of PRMT5 subsequently promotes DNA damage repair, indicated by the decreasing level of γH2AX after DNA double-strand breaks (DSB). Our RNA-seq analyses of prostate cancer cells with wild-type or mutant S470 sites indicate that Plk1-associated phosphorylation on the S470 site exerts an influence on DNA replication and DDR pathways. These findings shed light on a novel perspective regarding the roles of PLK1-mediated PRMT5 phosphorylation in DDR, offering potential therapeutic strategies in prostate cancer. Citation Format: Jia Peng, Yanquan Zhang, Jianlin Wang, Qianjin Li, Daheng He, Xinyi Wang, Xiongjian Rao, Meng Wu, Pingli Mo, Lei Wang, Sai Wu, Ruixin Wang, Jinghui Liu, Mansoureh Nouri, Izumi Tadahide, Xiaoqi Liu. PLK1-dependent phosphorylation of PRMT5 promotes DNA damage response 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 6014.
Abstract 6741: Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer
Authors: Tao Yu, Kevin Van der Jeught, Haiqi Zhu, Zhuolong Zhou, Samantha Sharma, Sheng Liu, Ka Man So, Haniyeh Eyvani, Xiyu Wang, George E. Sandusky, Yunlong Liu, Mateusz Opyrchal, Sha Cao, Jun Wan, Chi Zhang, Xinna Zhang
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide, causing substantial mortality. The urgent need for effective treatments has driven research into immune checkpoint blockade (ICB) therapies, which have demonstrated significant clinical benefits across various cancer types. Despite the success of ICB therapies, a significant proportion of CRC patients exhibit resistance to treatment, prompting the identification of mechanisms that hinder therapy resistance or enhance treatment response. CRC cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. In this study, we found that colorectal tumors with high glutaminase (GLS) expression exhibit reduced T-cell infiltration and cytotoxicity, leading to poor clinical outcomes. To validate these findings, we applied the ovalbumin (OVA)/OT-I T cell-based cytotoxicity assay and the CRC patient-derived organoids (PDOs)/autologous T cell killing assay. Our results indicated that inhibition of GLS significantly enhanced T-cell cytotoxicity in vitro and ex vivo. Mechanistically, we elucidated that inhibition of GLS activated reactive oxygen species-related signaling pathways in tumor cells, thereby potentially increasing tumor immunogenicity by promoting antigen presentation. The combinational therapy of GLS inhibitor and ICB exhibited a superior tumor growth inhibitory effect in comparison with either of the monotherapies. These findings shed new light on clinical therapeutic strategies for CRC patients, offering a promising approach to enhance the efficacy of ICB therapy. Citation Format: Tao Yu, Kevin Van der Jeught, Haiqi Zhu, Zhuolong Zhou, Samantha Sharma, Sheng Liu, Ka Man So, Haniyeh Eyvani, Xiyu Wang, George E. Sandusky, Yunlong Liu, Mateusz Opyrchal, Sha Cao, Jun Wan, Chi Zhang, Xinna Zhang. Targeting glutamine metabolism potentiates antigen presentation in 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 6741.
Abstract 7597: Therapeutic potential of ketogenic diet as an adjuvant to lenvatinib treatment in hepatocellular carcinoma
Authors: Minghe Zhang, Terence Kin-Wah Lee, Stephanie Ma, Man Tong
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) has been a major public health concern worldwide for decades because of its high mortality rates and poor prognosis, which are attributable to frequent tumor relapse and limited treatment regimens. Lenvatinib is one of the tyrosine kinase inhibitors approved for first-line treatment of advanced HCC, but its efficacy remains modest. Growing evidence suggest that the unsatisfactory survival benefits of lenvatinib could be attributed to the acquired drug resistance developed in HCC patients. In this study, we aim to explore the intrinsic metabolic vulnerability which could be exploited to enhance the treatment efficacy of lenvatinib in HCC. Our previous study showed that loss of tyrosine catabolism accompanied with a reduced downstream ketone metabolite beta-hydroxybutyrate (BHB) supports HCC initiation. To explore the therapeutic value of BHB in potentiating lenvatinib treatment in HCC, tyrosine catabolism-suppressing HCC cells were treated with BHB. We found that BHB treatment suppressed cell proliferation, increased cellular reactive oxygen species and potentiated the efficacy of lenvatinib treatment. Similar tumor-suppressive effect was observed when BHB was administered in vivo in mice bearing HCC patient derived xenograft. Combination treatment of lenvatinib and ketogenic diet which induces BHB level could drastically attenuate tumor development in immunocompetent mice bearing hepatic tumors. This study presents a potentially translatable combination treatment regimen to potentiate the therapeutic efficacy of lenvatinib in advanced HCC. Citation Format: Minghe Zhang, Terence Kin-Wah Lee, Stephanie Ma, Man Tong. Therapeutic potential of ketogenic diet as an adjuvant to lenvatinib treatment in hepatocellular 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 7597.