tbuckley/cabot-search huggingface dataset:
Abstract 3012: ONC201 induces apoptosis in gastric adenocarcinoma and exhibits synergy with rhTRAIL
Authors: Cassanda Susan Parker, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2020)

Abstract Gastric adenocarcinoma is highly lethal with a 5-year survival of only 31.5%, largely due to late presentation of disease and ineffective chemotherapy options. ONC201 is a first-in-class small molecule anti-cancer therapy that induces cell death in many different types of malignant tumors via a multitude of mechanisms including up-regulation of TNF-related apoptosis-inducing ligand (TRAIL) by Foxo3a and death receptor 5 (DR5) via activation of the integrated stress response. We investigated the efficacy of ONC201 in inducing cell death in gastric adenocarcinoma cells as monotherapy and in combination with recombinant human TRAIL (rhTRAIL). AGS (caspase 8 and PIK3CA mutant, HER2 amplified) and SNU-16 (p53 mutant) gastric adenocarcinoma cell lines were treated with ONC201 and rhTRAIL and viability assays were performed to determine cell line sensitivities. Both cell lines were then treated with combination therapy based on sensitivities and viability assays were performed in order to determine combination indices. Cell death was verified with sub-G1 analysis via flow cytometry and protein expression was established via western blotting. SNU-16 cells were sensitive to ONC201, while AGS cells were shown to be resistant to monotherapy. Both cell lines were sensitive to rhTRAIL and exhibited synergy when treated in combination with ONC201, resulting in combination indices of less than 0.5 at doses that did not induce cell death in fibroblasts. The proportion of cells in sub-G1 phase of the cell cycle increased in a dose-dependent manner with combination treatment. PARP cleavage increased in a dose-dependent manner after combination therapy, indicating apoptosis and ATF4 and CHOP expression also increased with increasing doses of combination therapy, indicating activation of the integrated stress response. These results suggest that ONC201 may be an effective therapeutic agent for gastric adenocarcinoma in combination with rhTRAIL by inducing apoptosis via the integrated stress response. We are currently expanding the in vitro model to include additional cell lines SNU-1(Ras mutant, microsatellite instability) and SNU-5 (p53 and CDH1 mutant). We are further exploring the role of ONC201 in priming cells via up-regulation of DR5 receptors such that they have increased sensitivity to rhTRAIL when pretreated with ONC201 as a potential source for the established synergy in gastric adenocarcinoma cells. We will also apply this study regimen to an organoid and in vivo model. Citation Format: Cassanda Susan Parker, Lanlan Zhou, Wafik S. El-Deiry. ONC201 induces apoptosis in gastric adenocarcinoma and exhibits synergy with rhTRAIL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3012.
Abstract 4934: DCBLD2 mediated cisplatin-induced epithelial-to-mesenchymal transition and metastasis in non-small cell lung cancer
Authors: Xiaosu Chen, Yajing Lv, Chongbiao Huang, Rong Xiang
Journal: Cancer Research (2020)

Abstract In clinical practice, we observed that many patients with solid tumors were diagnosed with early metastasis after chemotherapy, consistent with a large number of preclinical and clinical repots. However, the mechanism how chemotherapy induced tumor metastasis was seldomly reported. In this work, we found that cisplatin promoted epithelial-to-mesenchymal transition (EMT), cell motility and metastasis in non-small cell lung cancer (NSCLC). Moreover, we validated DCBLD2 was a key mediator in cisplatin-induced metastasis in NSCLC through an in vivo, genome-scale CRISPR/Cas9 activation screening. DCBLD2 was abnormally high-expressed in patients with NSCLC, in accordance with the analysis of TCGA database. The expression level of DCBLD2 was negatively correlated with the prognosis of NSCLC patients. Mechanically, DCBLD2 promoted EMT, cell migration in NSCLC cells and metastasis in a mouse xenograft models by binding to cytoskeletal proteins. In addition, we found that cisplatin played an essential role in promoting DCBLD2 expression. The ERK signaling pathway could be activated by cisplatin with phosphorylated, leading to the transcription factor FOS binding to the promoter region of DCBLD2, upregulating the expression of DCBLD2. In conclude, DCBLD2 was a contextual determinant of chemotherapy and metastatic in NSCLC and a potential target for anti-metastasis drugs. Citation Format: Xiaosu Chen, Yajing Lv, Chongbiao Huang, Rong Xiang. DCBLD2 mediated cisplatin-induced epithelial-to-mesenchymal transition and metastasis in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4934.
High-density lipoproHigh-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization studytein characteristics and coronary artery disease: a Mendelian randomization study
Authors: A Prats Uribe, S Sayols-Baixeras, A Fernández-Sanlés, I Subirana, R Carreras-Torres, G Vilahur, F Civeira, J Marrugat, M Fitó, Á Hernáez, R Elosua
Journal: Metabolism (2020)
Abstract 4342: Histological variants and sites of presentation of malignant melanoma in a resource poor setting: A histopathological review
Authors: Kasimu Umar Adoke, Mohammed Faruk, Yawale Iliyasu, Saad Aliyu Ahmed
Journal: Cancer Research (2020)

Abstract Background: Melanoma is a malignant tumour that arises from melanocytic cells. The incidence is increasing worldwide in white population where fair skin people receive excessive sun exposure. Although relatively uncommon in Africa-Americans, recent trends shows increase incidence in Africa- Americans. Data on the incidence and biology of melanoma are few in Africa. This study review the variants and sites of melanoma in a resource poor setting in Nigeria with some immunohistochemical stains performed. Method: All cases of melanoma diagnosed in the Department of Pathology in a tertiary hospital in Nigeria over a three year period (2016-2018) were retrieved. Patient's information including site and age were also retrieved from their case notes. Immunohistochemistry using two antibodies S-100, HMB-45 was done. Results: A total 38 cases were seen during the study period with a male female ratio of 1:1.1. The age range was 5-80 years with a mean age of 48.8±18.1. The most common site for melanoma is the foot 19(50%), followed by the uvea 7(18.4%), skin and inguinal lymph node 4(10.5%), anorectal and conjunctiva had 2(5.3%). The commonest histological variant of melanoma was acral lentigenous melanoma 19(50%), Superficial spreading melanoma 4(10.5%), nodular melanoma 3(7.9%) and desmoplastic melanoma 1(2.6%). Immunohistochemistry was used on three cases to rule out differentials. Conclusion: Malignant melanoma in our setting is in contrast with African-Americans and Caucasians population base on site and histological type, hence future studies on molecular pathways of melanoma in Africa needs to be explored to show similarity or difference and the possibility of targeted immunotherapy. Citation Format: Kasimu Umar Adoke, Mohammed Faruk, Yawale Iliyasu, Saad Aliyu Ahmed. Histological variants and sites of presentation of malignant melanoma in a resource poor setting: A histopathological review [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4342.
Abstract 5869: Characterization and therapeutic implications of SMARCA4 mutations in cancer
Authors: Tharu M. Fernando, Robert Piskol, Russell Bainer, Ethan Sokol, Sally Trabucco, Qing Zhang, Huong Trinh, Sophia Maund, Marc Kschonsak, Subhra Chaudhuri, Tom Januario, Zora Modrusan, Robert L. Yauch
Journal: Cancer Research (2020)

Abstract Genomic studies performed in cancer patients have identified a high frequency of alterations in the core catalytic subunit of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex, SMARCA4. Cells with inactivating SMARCA4 mutations rely on its paralog, SMARCA2, making it an attractive therapeutic target. Here we report the results of genomic profiling of 131,668 cases from patients with solid tumors and identified 8,588 cases with one or more SMARCA4 alterations. We observed a high prevalence of homozygous SMARCA4 truncating and non-truncating mutations in certain tumor types, notably non-small cell lung cancer (NSCLC) and cancers of unknown primary. We found that homozygous SMARCA4 mutations in NSCLC were mutually exclusive with other mutations in mSWI/SNF and oncogenic drivers, including KRAS and EGFR. A retrospective study of NSCLC patients who were treated in the Flatiron Health network (&amp;gt;265 oncology practices in the U.S.) and underwent FoundationOne® or FoundationOne CDx® tumor sequencing as part of routine care revealed that real-world patients with homozygous truncating SMARCA4 mutations had significantly reduced overall survival. The large sample size of our cohort also elucidated novel hotspot missense mutations within the helicase domain of SMARCA4. Functional modeling of these mutations using biochemical and cell-based (ATAC-seq) assays demonstrated that all evaluated mutations have significantly reduced nucleosome remodeling activity upon in vitro reconstitution in SMARCA4-deficient cells. We also addressed whether SMARCA4 missense mutations could rescue the cell growth defects and loss in chromatin accessibility induced upon SMARCA2 loss. Interestingly, we observe that a few missense mutants were able to either partially or fully rescue growth, suggesting hypomorphic activity under the selective pressure of SMARCA2 loss. Overall, these studies highlight NSCLC patients with homozygous truncating SMARCA4 mutations as a novel population with an unmet need who may benefit from SMARCA2-targeted therapy and underscore that careful selection criteria must be employed to identify patients with inactivating, homozygous SMARCA4 missense mutations. Citation Format: Tharu M. Fernando, Robert Piskol, Russell Bainer, Ethan Sokol, Sally Trabucco, Qing Zhang, Huong Trinh, Sophia Maund, Marc Kschonsak, Subhra Chaudhuri, Tom Januario, Zora Modrusan, Robert L. Yauch. Characterization and therapeutic implications of SMARCA4 mutations in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5869.
Abstract 3632: Genomic profiling in circulating tumor DNA from Chinese advanced gastric adenocarcinomas patients
Authors: ZHE ZHANG, Hui Chen, Yifan Zhou, Bei Zhang, Yuezong Bai, Lieping Guo
Journal: Cancer Research (2020)

Abstract Background and Objective: Circulating tumor DNA (ctDNA) is considered to be an ideal sample for advanced unresectable cancer patients to perform gene sequencing to guide clinical therapy, which might help to avoid tumor heterogeneous, especially in gastric adenocarcinomas (GACs). However, the ctDNA genomic profiling of Chinese advanced GACs is still missing. Methods: Blood samples were obtained from 122 advanced GACs patients. Target sequencing were performed on ctDNA using a validated commercial 150-gene-panel NCC-GP150, which includes 100 microsatellite loci. Blood tumor mutation burden (bTMB) and blood microsatellite instability (bMSI) were calculated according to the NGS results. Statistical analysis was performed by the Mann-Whitney U test and Fisher exact test using GraphPad Prism. Results: In 122 patients, 47 (38.5%) were female and 75 (61.5%) were male, with the median age of 61 (range 24 to 84). A total of 660 somatic variations were identified in 118 genes as indicated by a maximum somatic allele frequency (MSAF) of &amp;gt;0.3%. One hundred and two (83.6%) patients carried at least one somatic variation and 84 (68.9%) patients had at least on pathogenic or likely pathogenic variations. The median pathogenic or likely pathogenic variations was 2.5 per patient in our cohort. The most frequent altered genes were TP53 (36.9%), LRP1B (18%), MYC (14.8%), RBM10 (13.9%), ERBB2 (13.9%), KRAS (12.3%), AR (11.5%) and FAT1 (10.7%). From the perspective of signaling pathway, the variations occurred frequently in RTK-Ras-MAPK pathway (53.3%), cell cycle pathway (52.5%), DNA damage repair (DDR) pathway (22.1%), Wnt pathway (18.9%), PI3K/AKT pathway (16.4%), and TGF-β pathway (2.5%). The median bTMB was 3 (mean 5.27, range 0 to 52); and 8 (7.8%) patients had high bMSI. The bMSI-H patients had significantly higher bTMB than bMSS patients (22 vs 3, p&amp;lt;0.0001) and patients harboring DDR pathway gene variations had significantly higher bTMB than wildtype subgroups (6 vs 3, p=0.0004). Conclusions: Our study revealed a comprehensive genomic profiling of advanced Chinese GACs patients. And the relationship between the genomic profiling and target-therapy as well as immunotherapy will be studied in an enlarged group of GACs patients. Citation Format: ZHE ZHANG, Hui Chen, Yifan Zhou, Bei Zhang, Yuezong Bai, Lieping Guo. Genomic profiling in circulating tumor DNA from Chinese advanced gastric adenocarcinomas patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3632.
Abstract 4791: Metabolic switch from glycolysis to oxidative phosphorylation (ox-phos) provides survival advantage to anti-androgen-treated prostate cancer cells and make them vulnerable to mitochondrial metabolism inhibitors IACS-010759 and CB-839
Authors: Hirak S. Basu, Nathaniel Wilganowski, Samantha Robertson, Sumankalai Ramachandran, Amado Zurita-Saavedra, Mark Titus, Evan Cohen, James Reuben, George Wilding
Journal: Cancer Research (2020)

Abstract Background: Most cancer cells depend more on glycolysis for their energy need compared with their normal counterparts incubated under identical condition. In addition to glycolysis, tumor cells also engage mitochondrial ox-phos to support growth. Here, we show that PCa cells surviving under anti-androgen enzalutamide (ENZA) treatment switch from glycolysis to ox-phos for their energy need and are more vulnerable to mitochondria-targeted metabolic inhibitors. We have also standardized a high-resolution quantitative fluorescence microscopic method to detect this metabolic switch in patient circulating tumor cells (CTCs). Methods: Seahorse assay has been used to compare mitochondrial metabolism in ENZA treated anti-androgen-sensitive LNCaP and -resistant C4-2 and PCa2b cells. The Seahorse data were supported by mass spectroscopic analysis of corresponding metabolites and metabolic fluxes. An ex vivo fluorescence staining for the CTC mitochondria with high ox-phos followed by high-resolution quantitative microscopic image analysis method has been standardized to follow such changes in cultured cells and patient CTCs. Results: Seahorse, mass spectroscopy and high-resolution microscopy of mitochondrial ox-phos showed that ENZA significantly decreases glycolysis and increases ox-phos in all surviving PCa cells within 24h of treatment. These cells are more vulnerable to treatment with mitochondrial ox-phos inhibitor IACS-010759 and a glutaminase inhibitor CB-839. High-resolution microscopic analysis of CTCs has thus far been performed in 18 patient blood samples. Six out of the 18 patients developed resistance to anti-androgen therapy within 0-6 months of sample collection. CTCs from all six patients showed a relatively higher average fluorescence due to high mitochondrial ox-phos as compared with the rest of the patients. Discussion: The data presented here may lead to informed combination therapy for selected PCa patients developing resistance to anti-androgen therapy for better clinical outcome. Citation Format: Hirak S. Basu, Nathaniel Wilganowski, Samantha Robertson, Sumankalai Ramachandran, Amado Zurita-Saavedra, Mark Titus, Evan Cohen, James Reuben, George Wilding. Metabolic switch from glycolysis to oxidative phosphorylation (ox-phos) provides survival advantage to anti-androgen-treated prostate cancer cells and make them vulnerable to mitochondrial metabolism inhibitors IACS-010759 and CB-839 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4791.
Abstract 1150: Targeting PI3K inhibits ER-mammary tumor initiation and early dissemination
Authors: Yuan Zhang, Jingyang Wang, Yi Xiao, Victoria Seewaldt, Dihua Yu
Journal: Cancer Research (2020)

Abstract Despite recent advances in cancer treatment, including targeted therapies and immunotherapies, many women still die of breast cancer. To ultimately reduce breast cancer death, it is of urgent need to develop more effective prevention and early intervention strategies. Although tamoxifen and aromatase inhibitors decrease incidences of estrogen receptor positive (ER+) breast cancer, there is no effective agent for prevention of ER negative (ER-) breast cancer. In this study, we identified that PI3K pathway is significantly activated in premalignant ER- breast lesions compared to paired normal tissue from breast cancer patients. We therefore tested whether blocking PI3K pathway by genetic knockdown or using a clinically applicable PI3K inhibitor (GDC0941) can inhibit ER- tumor initiation and progression. Indeed, both genetic knockdown of PI3K and low dose GDC0941 intervention reversed the disorganized three-dimensional growth of semi-transformed human ER- mammary epithelial cells in vitro. More importantly, low dose GDC0941 treatment significantly delayed the tumor initiation in MMTV-neu mouse model which develops ER-HER2+ mammary tumors. Notably, low dose GDC0941 treatment did not show discernable adverse effects, including no significant changes in body weight and liver functions, no immuno-toxicity. Since PI3K activation is crucial for early disseminated tumor cells, we collected bone marrow from treated mice versus vehicle control group, and examined the impact of GDC0941 treatment on early dissemination of tumor cells into the bone marrow. Excitingly, we found that administration of low dose GDC0941 significantly decreased CD45-ErBb2+/CK8/18+ early disseminated mammary tumor cells into the bone marrow, indicating that low dose PI3K inhibitor not only delayed primary tumor initiation but also prevented tumor cell early dissemination in the bone marrow. Taken together, these data support the notion that using low dose targeting drug to block PI3K pathway is safe and promising for ER- breast cancer prevention. Citation Format: Yuan Zhang, Jingyang Wang, Yi Xiao, Victoria Seewaldt, Dihua Yu. Targeting PI3K inhibits ER-mammary tumor initiation and early dissemination [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1150.
Abstract 5180: Nuclear receptor tyrosine kinase c-MET restrains efficacy of PARP inhibitor in pancreatic cancer cells
Authors: Yuan Gao, Mei-Kuang Chen, Dihua Yu, Mien-Chie Hung
Journal: Cancer Research (2020)

Abstract Pancreatic tumors commonly have intra-tumor hypoxia and high reactive oxygen species (ROS) production and have become the fourth leading cause of death in the United States. Although ROS leads to oxidation of macromolecules such as DNA, protein, and lipids, pancreatic cancer cells are capable of surviving from the ROS-induced stress at relatively high tolerable levels. Therefore, identifying potential molecular mechanisms for pancreatic cancer cells to overcome ROS-induced cellular stress is important for develop therapeutic strategies in treating pancreatic cancer patients. While poly (ADP-ribose) polymerase 1 (PARP1) is a key protein for repairing ROS-induced DNA damages, we intended to include PARP inhibitors in targeted therapy strategy. Recent clinical trial showed that PARP inhibitor benefits pancreatic patients with BRCA mutation. However, our goal is to expand PARP inhibitor targeted therapy to pancreatic cancer patients without BRCA mutation with PARP inhibitor using strategies of combining kinase inhibitors as we demonstrated in breast cancer in our previous publications. Here, we used hydrogen peroxide (H2O2) as ROS stimuli and demonstrated that H2O2 induces nuclear transport of the receptor tyrosine kinase c-MET in AsPC-1 and BxPC-3 pancreatic cancer cells. We further showed that nuclear-located c-MET interacts with PARP1, and the interaction can be partially interrupted by crizotinib, a kinase inhibitor targeting c-MET. Moreover, combination of crizotinib and PARP inhibitor, olaparib, has synergistic anti-tumor effect in eliminating pancreatic cancer cells. Our data suggest that the intra-tumor hypoxia micro-environment of pancreatic cancer may promote nuclear localization of c-MET, which results in resistance to PARP inhibitor therapy. We further proposed a new therapeutic strategy of combining c-MET inhibitors and PARP inhibitors for advanced pancreatic cancer patients. Citation Format: Yuan Gao, Mei-Kuang Chen, Dihua Yu, Mien-Chie Hung. Nuclear receptor tyrosine kinase c-MET restrains efficacy of PARP inhibitor in pancreatic cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5180.