tbuckley/cabot-search huggingface dataset:
Abstract 4184: Genetic and pharmacological disruption of survivin suppressed primary and metastatic tumor growth by attenuating TGFB pathway in ovarian cancer
Authors: Junming Yue
Journal: Cancer Research (2020)

Abstract Introduction: Survivin, a member of the inhibitor of apoptosis family, is upregulated in multiple cancers including ovarian cancer, but is rarely detectable in normal tissues. Therefore, it is a potential drug target. However, targeting survivin is still challenge and small molecule inhibitors failed in clinical trials. It's very important to understand how survivin contributes to tumor development. In this study, we investigated the role of survivin in ovarian cancer using ovarian cancer cell lines in vitro and mouse models in vivo and examined how survivin contributes to ovarian primary ovarian tumor growth and metastasis by examining epithelial to mesenchymal transition (EMT). Methods: To define the role of survivin in EMT in ovarian cancer cells, we established survivin knockout cell lines using lentiviral CRISPR/Cas9 nickase and pharmacologically inhibited survivin with a novel inhibitor MX106. We examined EMT markers, migration and invasion assays in survivin disrupted ovarian cancer cells using Transwell plates. We also assessed primary ovarian tumor growth and metastasis in an orthotopic ovarian cancer mouse models through intrabursal injecting survivin KO cell line and also treatment using MX106. Findings: We found that disruption of survivin expression inhibited EMT by attenuating the TGFβ pathway in ovarian cancer cells. Cell proliferation, migration, and invasion were significantly inhibited in survivin knockout or MX106 treatment in SKOV3 and OVCAR3 cell lines compared to control cells. Inhibition of survivin sensitized cell responses to paclitaxel treatment and overcame chemoresistance in vitro. Lentiviral CRISPR/Cas9 mediated survivin knockout or MX106 treatment efficiently inhibited primary ovarian tumor growth and metastasis in orthotopic ovarian cancer mouse models. Conclusions: Our data demonstrate that inhibition of survivin using either genetic knockout or a novel inhibitor MX106 suppresses primary ovarian tumor growth and metastasis by attenuating TGFβ pathway. MX106, as a novel survivin inhibitor effectively overcame chemoresistance compared to commercial YM155, which provides a novel approach for ovarian cancer therapy. Citation Format: Junming Yue. Genetic and pharmacological disruption of survivin suppressed primary and metastatic tumor growth by attenuating TGFB pathway in ovarian 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 4184.
NCCN Guidelines Insights: Kidney Cancer, Version 1.2021
Authors: Robert J. Motzer, Eric Jonasch, Shawna Boyle, Maria I. Carlo, Brandon Manley, Neeraj Agarwal, Ajjai Alva, Katy Beckermann, Toni K. Choueiri, Brian A. Costello, Ithaar H. Derweesh, Arpita Desai, Saby George, John L. Gore, Naomi Haas, Steven L. Hancock, Christos Kyriakopoulos, Elaine T. Lam, Clayton Lau, Bryan Lewis, David C. Madoff, Brittany McCreery, M. Dror Michaelson, Amir Mortazavi, Lakshminarayanan Nandagopal, Phillip M. Pierorazio, Elizabeth R. Plimack, Lee Ponsky, Sundhar Ramalingam, Brian Shuch, Zachary L. Smith, Bradley Somer, Jeffrey Sosman, Mary A. Dwyer, Angela D. Motter
Journal: Journal of the National Comprehensive Cancer Network (2020)

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.
Abstract 4984: Where do the T lymphocytes go in prostate cancer: Correlation with CD103, CD39 expression and clinical pathological parameters
Authors: Beatriz Walter, Billel Gasmi, Xu Naizen, Vladimir Valera, Peter Pinto, Maria J. Merino
Journal: Cancer Research (2020)

Abstract Introduction: Many solid tumors such as prostate cancer have shown limited response to immunotherapy treatment. Whether this is due to absence of tumor specific antigens or poor immune infiltrate, the exact mechanism is not well understood. Our study evaluates the presence and spatial distribution in benign versus malignant tissue of CD4+ and CD8+ cells in whole mounted radical prostatectomies samples and characterized the subset of intraepithelial CD103+ and CD39+ cells, which have been previously shown to harbor more cancer specific T-cells. Materials and Methods: Sixteen cases of whole mounted radical prostatectomy samples were used to asses CD4, CD8, CD103 (all abcam) and CD39 (Sigma) expression by IHC. Location of positive cells within epithelium and stroma in tumor and benign prostatic tissue was evaluated. The results were confirmed using QuPath Software, for positive detection of immune cells by color deconvolution and threshold adjustments. Results: The CD4 and CD8 staining demonstrated that most of the immune cells were present in the stroma but not within the malignant glands. The whole prostate sections (mean size 51.4 × 44mm) generated around 1650 ROI's per/case. All the ROI's were included in the analysis. CD4+ and CD8+ were evaluated in whole gland vs tumor area. No significant difference = of CD4+ and CD8+ cell density was seen between whole prostate area and tumor areas (CD4+ 2.9 vs 1.9%) and (CD8+ 1.3 vs 1.2%). The density of CD4+ and CD8+ cells in tumors vs benign gland was approximately the same (means 0.93 for both). For the CD103+ analysis, the positive cells were rarely found in the tumor epithelium in comparison with the benign glands (mean 1.09 vs 5.41; representing 2 vs 9.3% of the total lymphocytes). The CD39 stain showed positive cells mostly at the benign epithelium. No correlation was found between our results and Gleason grade, stage or prognosis. Conclusion: Our study suggests the possibility that in solid cancers such as prostate cancer, immune cells may not be able to reach appropriately the malignant epithelium with only a small subset of T cells reaching their target. This may have important clinical implication for the success of the immune therapy in this group of patients. Further studies are being performed to deeply characterized the tumor infiltrating cell population. Citation Format: Beatriz Walter, Billel Gasmi, Xu Naizen, Vladimir Valera, Peter Pinto, Maria J. Merino. Where do the T lymphocytes go in prostate cancer: Correlation with CD103, CD39 expression and clinical pathological parameters [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 4984.
Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial
Authors: Robert M. Kacmarek, Jesús Villar, Dácil Parrilla, Francisco Alba, Rosario Solano, Songqiao Liu, Raquel Montiel, Jesús Rico-Feijoo, Anxela Vidal, Carlos Ferrando, Isabel Murcia, Ruth Corpas, Elena González-Higueras, Qin Sun, César E. Pinedo, David Pestaña, Domingo Martínez, César Aldecoa, José M. Añón, Marina Soro, Jesús M. González-Martín, Cristina Fernández, Rosa L. Fernández, Isabel Murcia, Carlos Ferrando, José Ferreres, Anxela Vidal, José M. Añón, Juan A. Soler, Raquel Montiel, Francisco Alba, José Rubio, David Pestaña, Jesús Blanco, César Aldecoa, Nela Hernández, Domingo Martínez, Elena González, M. Mar Cruz, Songqiao Liu, Jesús Villar, Robert M. Kacmarek
Journal: Intensive Care Medicine (2020)
Abstract 4682: Influence of PI3K/AKT pathway on imatinib mesylate treatment outcome in chronic myeloid leukemia patients
Authors: Swathi Banapuram, Manjula Gorre, Raghunadha Rao Digumarti, Vishnupriya Satti, Komaraiah Palle, Sandhya Annamaneni
Journal: Cancer Research (2020)

Abstract Chronic myeloid leukemia (CML) is a common myeloproliferative disorder characterized by cytogenetic abnormality [t(9;22)(q34;q11)] that generates BCR-ABL oncogene with aberrant tyrosine kinase activity, the driver event in CML origin. Tyrosine kinase inhibitors (TKIs) are remarkably effective; yet, treatment failure is common in some cases due to the accumulation of mutations in BCR-ABL itself and other genes causing drug resistance/relapse, which indicates that BCR-ABL inhibition alone may not be sufficient to combat CML. The PI3K/Akt/mTOR signaling pathway downstream of BCR-ABL has been proven to be an important survival mechanism in leukemias. In vitro studies demonstrated that targeting this pathway could be a viable strategy, but needs further validation in CML patients. In this study, we examined the critical PI3K/AKT/mTOR pathway genes (PIK3CA, PTEN, AKT1, SHIP1, mTOR, and FOXO3A) in CML patients (n=51) using qPCR method at diagnosis and after treatment, and analyzed with respect to BCR-ABL status, and JAK2, STAT5, and STAT3 levels. Interestingly, significant upregulation of AKT1 (p=0.012) and PIK3CA (p=0.026) and downregulation of PTEN (P=0.06) and SHIP1 (p=0.039) was observed in samples at diagnosis compared to their post imatinib treated. Remarkably, these elevated AKT1 and PI3KCA transcript levels were significantly associated with increased BCR-ABL and JAK2 transcript levels, but not STAT3 and STAT5 suggesting PI3K pathway as a prominent target in CML. However, with respect to the clinical phase and imatinib response, none of the genes showed significant differences except for PTEN, which was significantly downregulated in advanced phase (p&amp;lt;0.042) and in cases with poor imatinib response. Overall, these results indicate a critical role for PI3K pathway in CML and its maintenance. Citation Format: Swathi Banapuram, Manjula Gorre, Raghunadha Rao Digumarti, Vishnupriya Satti, Komaraiah Palle, Sandhya Annamaneni. Influence of PI3K/AKT pathway on imatinib mesylate treatment outcome in chronic myeloid leukemia 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 4682.
Abstract 2100: Deep learning can predict microsatellite instability from histology in colorectal cancer across different ethnic groups
Authors: Isaiah S. Pressman, Hongming Xu, Jeonghyun Kang, Yoon Jin Cha, Sung Hak Lee, Tae Hyun Hwang
Journal: Cancer Research (2020)

Abstract Microsatellite instability (MSI) is known to be an important genomic marker for prediction of a patient's response to immune checkpoint inhibitors across various types of cancer. Conventional methods to measure DNA mismatch repair (MMR) status are pCR-based panel sequencing or immunohistochemical staining based methods. Recently, deep learning has been proposed as an efficient diagnostic tool in this regard, as it can learn to predict MSI directly from H&amp;E stained slides. However, it is thought that deep learning may not generalize effectively beyond the ethnicities present in the training dataset. Therefore, we investigated the impact of ethnic differences on deep learning performance at MSI classification across a range of model architectures and hyperparameters. A total of 360 WSIs from a subset of the TCGA colorectal cancer (TCGA set) and another 170 WSIs from Gangnam Severance Hospital (Yonsei University College of Medicine, Seoul, Republic of Korea, Gangnam set) were included in this study. 360 H&amp;E stained WSIs from TCGA set were divided into a set of square tiles of size 256x256um (0.5um/pixel) and then color normalized using Macenko normalization. Those tiles were divided into two classes - MSI-H and MSS (Microsatellite stable) based on the patient's MSI status. We trained various models on those tiles using a range of hyperparameters including model architecture, number of trainable layers, learning rate, and learning rate scheduling. The performance of this model was measured using the AUROC in the TCGA set (internal validation) and Gangnam set (external validation). Our results for ResNet18 - a popular convolutional network architecture - on TCGA and Gangnam test datasets are around 0.79 and 0.76 respectively, with a standard deviation on Gangnam of 0.03. Given good hyperparameters and model architecture, the model's performance on the Gangnam test data was within one standard deviation of its performance on the TCGA test data, despite the fact that said model was trained using only the TCGA data containing few asian patients. The lack of a significant performance difference challenges the notion that there are morphological differences in colorectal cancers between patients of Caucasian and Asian ethnicities that would prevent a deep learning system from generalizing effectively. Citation Format: Isaiah S. Pressman, Hongming Xu, Jeonghyun Kang, Yoon Jin Cha, Sung Hak Lee, Tae Hyun Hwang. Deep learning can predict microsatellite instability from histology in colorectal cancer across different ethnic groups [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 2100.
Abstract 5049: Development of huPBMC-NCG mice to study xenogenic graft versus host disease (GVHD)
Authors: Cunxiang Ju, Hongyan Sun, Dingyu Wang, Shiying Guo, Mingkun Zhang, Hainan Wu, Shuai Li, Chao Ju, Jing Zhao, Xiang Gao
Journal: Cancer Research (2020)

Abstract Graft versus host disease (GVHD) is a severe complication of allogeneic stem cell transplantation for leukemia treatment. NCG mice lacking functional murine T, B, NK cells as well as decreasing functional macrophage and dendritic cells could be used as recipients of human peripheral blood mononuclear cells (huPBMC) for the studies of human GVHD. In this study, huPBMC-NCG mice were developed by the engraftment of huPBMC into unconditioned or irradiated NCG mice. The engraftment kinetics, irradiation effect, and preclinical treatment were explored in these mice. After huPBMC engraftment, NCG mice developed GVHD symptoms, including body weight loss, fur loss, reduced activity, hunched posture and severe ruffling, and eventually led to mortality. We also observed human T cell trafficking to target organs including gut, heart, liver, skin, and lung by flow cytometry and immunohistochemistry. Interestingly, irradiation could significantly accelerate the onset of GVHD following huPBMC engraftment. Meanwhile, irradiated huPBMC-NCG mice presented less variability in the kinetics of GVHD and the frequency of this disease in comparison with unconditioned counterparts, thus providing a more stable model for human GVHD studies. For preclinical studies, we found immunomodulatory drugs including Abatacept (CTLA4-Ig) targeting APC cells or anti-Ly6G antibody targeting neutrophils could alleviate GVHD-associated symptoms along with improving overall survival of huPBMC-NCG mice. Taken together, this study established stable huPBMC-NCG mice to mimic the onset and development of human GVHD, which was helpful for the development of therapeutic intervention. Citation Format: Cunxiang Ju, Hongyan Sun, Dingyu Wang, Shiying Guo, Mingkun Zhang, Hainan Wu, Shuai Li, Chao Ju, Jing Zhao, Xiang Gao. Development of huPBMC-NCG mice to study xenogenic graft versus host disease (GVHD) [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 5049.
Abstract 2220: Non-clinical tumor models reveal broad combination potential of ICOS agonist antibodies
Authors: Jeremy D. Waight, Meixia Bi, David Kilian, Christopher Hopson, Shu-Yun Zhang, Sara Brett, Sapna Yadavilli, Tianqian Zhang, Hong Shi, Kenneth W. Hance, Marc Ballas, Axel Hoos
Journal: Cancer Research (2020)

Abstract Unprecedented rates of durable clinical responses have been observed for antibody-based therapeutics targeting immune checkpoint proteins such as cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1). Nonetheless, a significant number of patients fail to respond, highlighting the need for alternative and complementary immunotherapeutic interventions for cancer. Inducible T-cell costimulator (ICOS/CD278) is a CD28 superfamily receptor that is predominantly expressed on effector and cytotoxic T cells shortly after T cell receptor (TCR) activation. In addition to promotion of T cell and B cell collaboration, ICOS signaling (via ICOS ligand [ICOSL] or antibody-based crosslinking) has been shown to improve T cell antitumor activity, survival, durable tumor rejection. To support the clinical development of GSK3359609 (a hIgG4 ICOS agonist antibody) several in vivo combination studies were conducted using a tool anti-mouse ICOS agonist antibody (clone 7E.17G9). Analogous with the Fc-based characteristics of a human IgG4 antibody, the anti-mouse ICOS tool antibody exhibited significant antitumor activity when grafted on a murine IgG1 (or Fc-reduced) backbone. Using an in vivo models of breast cancer (EMT6, BALB/c), the murinized ICOS tool antibody demonstrated potent antitumor activity alone (tumor growth inhibition [TGI] of 40-60%) in combination with immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4 (TGI of 100% and 90%, respectively). Antitumor activity was associated with increased total T cell infiltration into the tumor, a higher tumor CD8/Treg cell ratio, and broad increases in T cell activation markers (e.g. CD25, CD69, Granzyme B, perforin, and PD-1). The cancer immunity cycle posits that multiple points of intervention exist for cancer immunotherapy, many of which should be considered in order to identify complementary therapeutic strategies. With this in mind, and consistent with ICI, antitumor activity was observed in combination with innate immune modulators (e.g. TLR4 agonist) and chemo/cytotoxic (e.g. carboplatin and paclitaxel) therapies in different syngeneic tumor models. Altogether these data underscore the broad utility of ICOS agonist antibodies as a reliable combination partner for cancer immunotherapy. Citation Format: Jeremy D. Waight, Meixia Bi, David Kilian, Christopher Hopson, Shu-Yun Zhang, Sara Brett, Sapna Yadavilli, Tianqian Zhang, Hong Shi, Kenneth W. Hance, Marc Ballas, Axel Hoos. Non-clinical tumor models reveal broad combination potential of ICOS agonist antibodies [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 2220.
Abstract 3099: Ultra-deep next-generation sequencing of selected single genes for detecting circulating tumor DNA in lung cancer patients
Authors: Anine Larsen Ottestad, Elisabeth F. Emdal, Sissel G. Wahl, Bjørn Henning Grønberg, Hong Yan Dai
Journal: Cancer Research (2020)

Abstract Purpose Circulating tumor DNA (ctDNA) can potentially be used to monitor cancer treatment response. In this study, we developed and used a sensitive and selective ultra-deep next-generation sequencing (NGS) approach for detection of ctDNA in lung cancer patients. Method Most studies use fixed gene panels for detection of ctDNA by NGS. Deep sequencing of large target regions is expensive and generates a myriad of variants, which are difficult to interpret. For the purpose of using ctDNA for monitoring, we try to overcome these challenges by sequencing only selected regions where mutations were previously found in the tumor. This method is more sensitive and cost-efficient. In this study, we included about 80 lung cancer patients. Tumor DNA was sequenced with a large gene panel and somatic mutations were identified in each tumor. We then defined the target region according to the tumor mutations and selected primers for constructing NGS libraries. Since the coverage region is small it enables ultra-deep sequencing of several samples simultaneously. We evaluated the lower limit of detection for this method by sequencing a series of artificially constructed samples with known mutant allele frequencies (MAFs). DNA from peripheral blood leucocytes was sequenced in parallel with plasma DNA to exclude variants from clonal hematopoiesis. Preliminary results Using 40 ng as input DNA, which contains approximately 12,000 haploid genomes, we detected mutations down to 0.02% MAF. This corresponds to about 6 mutated copies per mL plasma. Currently, we are applying this method on patient plasma DNA samples. Conclusion We have developed a sensitive method for ctDNA detection, and we will present the results of the lung cancer patient samples. Citation Format: Anine Larsen Ottestad, Elisabeth F. Emdal, Sissel G. Wahl, Bjørn Henning Grønberg, Hong Yan Dai. Ultra-deep next-generation sequencing of selected single genes for detecting circulating tumor DNA in lung cancer 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 3099.