tbuckley/cabot-search huggingface dataset:
Abstract 5843: XBP1 regulates the expression of cell cycle associated genes in ERα positive breast cancer cells
Authors: David Barua, Afrin Sultana, Md Nahidul Islam, Ananya Gupta, Sanjeev Gupta
Journal: Cancer Research (2020)

Abstract Estrogen receptor α (ERα)-positive breast cancer is a heterogeneous disease with distinct molecular features. Over the time of treatment, endocrine resistance develops in these types of cancers which is major challenge in recent times and finding a better treatment options against these resistant cancers is urgent. Several studies have suggested the association of XBP1 in therapy resistance in ERα-positive breast cancers. Indeed, XBP1 physically interacts with ER and activates ER-dependent transcription in a ligand-independent manner. Moreover, overexpression of XBP1 in ERα-positive breast cancer cells confers estrogen independent growth and reduced sensitivity to anti-estrogen. Despite growing evidence about the involvement of XBP1 in ERα-positive breast cancer, molecular targets of XBP1 is poorly understood. The aim of current study is to identify the XBP1-regulated targets in ERα-positive breast cancer cells. XBP1 deficient sub-clones in MCF7 cells were generated by using CRISPR-CAS9 mediated gene knockout strategy. Cell viability and anti-estrogen sensitivity were determined by MTS assay, cell proliferation was evaluated by colony formation assay, cell death was determined by flow cytometry. XBP1-regulated genes were identified by analysing transcriptomic data from control and XBP1-knockdown T47D cells (GSE49955). Relative expression of genes were analysed by qPCR. RRM2 overexpression clones were generated by transfecting RRM2 vector using nucleofector. Deficiency of XBP1 in MCF7 cells showed decreased growth and proliferation as compared to control MCF7 cells. Deletion of XBP1 in MCF7 cells demonstrated compromised E2-mediated cell growth and reduced activation of E2-dependent genes. Moreover, XBP1 deficiency in MCF7 cells increases sensitivity towards anti-estrogens including tamoxifen and fulvestrant. Expression of cell cycle associated genes RRM2, CDC6 and TOP2A were found significantly reduced in all ERα-positive breast cancer cell lines with compromised function of XBP1. RRM2, CDC6 and TOP2A have been previously reported as direct targets of XBP1 in other cell types (i.e., muscle, pancreatic β-cell, and plasma cell) and helper T-cells. Furthermore, overexpression of RRM2 in XBP1 deficient MCF7 sub-clones rescued the cell growth and proliferation same as control MCF7 clones. Therefore, this study has revealed XBP1 regulated new targets in ERα-positive breast cancer cells which could be instrumental in providing new insights for better therapeutic potential in this context. Citation Format: David Barua, Afrin Sultana, Md Nahidul Islam, Ananya Gupta, Sanjeev Gupta. XBP1 regulates the expression of cell cycle associated genes in ERα positive breast 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 5843.
Abstract 4825: Super enhancer-associated lincRNA BCSL1 promotes the development of breast cancer
Authors: Xiaoqing Yuan, Li Peng, Jianing Chen, Xiuying Cui, Yujie Liu, Erwei Song
Journal: Cancer Research (2020)

Abstract Long Intergenic non-coding RNAs (lincRNAs) expressed in tissue-specificity model are involved in a variety of tumor biological processes. Super enhancers (SEs) have been shown to drive the expression of genes including lincRNAs that control cell identity and the development of cancer. However, the role of super-enhancer-driven lincRNAs in luminal type breast cancer (BC) is poorly understood. Here we identified a lincRNA, BCSL1, was uniquely up-regulated in BC tumor tissues and cell lines. ChIP-sequencing and Hi-C analysis manifested that BCSL1 was directly regulated by the luminal subtype specific SEs in BC cells. Nuclear plasma separation assay and FISH test showed that BCSL1 slightly more located in the cytoplasm than the nucleus of MCF7 cells. Knocking down of BCSL1 significantly inhibited the proliferation, colony formation and apoptosis of BC cells, and the cell cycle switching from G1 stage to S stage. Overexpression of BCSL1 significantly increased their proliferation, colony formation and apoptosis. Mechanistically, RNA pulldown, Mass spectrometry and RNA-sequencing indicated BCSL1 may be involved in the development of luminal BC by participating in apoptosis-related pathways.In summary, we identified a lincRNA, BCSL1, that is uniquely increased in breast cancer. Increased expression of BCSL1 promotes the proliferation, colony formation and apoptosis of luminal breast cancer cells. BCSL1 might be developed as a biomarker of luminal breast cancer patients. This work was supported by the National Natural Science Foundation of China (81803636 and 81972658), the Natural Science Foundation of Guangdong Province (2018A0303130329). Citation Format: Xiaoqing Yuan, Li Peng, Jianing Chen, Xiuying Cui, Yujie Liu, Erwei Song. Super enhancer-associated lincRNA BCSL1 promotes the development of breast 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 4825.
Abstract 6255: Augmented lung tumor infiltration of chemotherapeutics using synthetic antigen receptor- mesenchymal stem cells (SAR-MSCs)
Authors: Susheel Kumar Nethi, Drishti Sehgal, Jayanth Panyam, Swayam Prabha
Journal: Cancer Research (2020)

Abstract Targeted delivery can improve drug accumulation in tumor tissue and treatment outcomes. However, currently available options suffer from a lack of selectivity for tumor cells. Mesenchymal Stem cells (MSCs) can be engineered with chemotherapeutic-loaded polymeric nanoparticles (PNPs) for tumor-targeted delivery, owing to their characteristic tumor tropic properties. Although nano-engineered MSCs demonstrated significant anticancer activity in multiple ovarian cancer models, their non-specific accumulation in clearance organs such as lungs and liver remains a concern. Parallel to the concept of chimeric antigen receptor (CAR)-T cell therapy, we advance here a strategy of modifying MSCs with synthetic antigen receptors (SARs) that target specific antigens overexpressed on cancer cells. Our approach consists of stably incorporating recombinant protein G (PG) on the surface of MSCs, followed by binding of a full-length IgG to the PG handle. Because protein G binds to the Fc region of IgG, antigen-binding affinity of the antibody is conserved. Epidermal growth factor receptor (EGFR) has been reported to be overexpressed and implicated in the pathogenesis of several malignancies especially lung cancer. Cetuximab (Cmab) is an anti-EGFR monoclonal antibody used in the treatment of metastatic lung cancer. In the current study, SAR-MSCs were developed by coating the nano-engineered MSCs with palmitated PG, followed by incorporating Cmab on the cell surface. Flow cytometry and confocal microscopy were used to confirm the incorporation of fluorescently labeled PAPG handle on MSC surface. Similarly, the installation of fluorescently labeled antibody on PAPG-functionalized MSCs was confirmed by flow cytometry. Preliminary efficacy studies in a mouse orthotopic A549-luc human lung adenocarcinoma model demonstrated significantly (P&amp;lt;0.05) improved survival of mice treated with Cmab-modified nano-engineered MSCs compared to isotype IgG-modified nano-engineered MSCs control group. These results suggest that the SAR technology could further improve the effectiveness of MSCs as tumor targeted drug delivery vehicles. Citation Format: Susheel Kumar Nethi, Drishti Sehgal, Jayanth Panyam, Swayam Prabha. Augmented lung tumor infiltration of chemotherapeutics using synthetic antigen receptor- mesenchymal stem cells (SAR-MSCs) [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 6255.
Abstract 2861: Targeting cancer with antibody-drug conjugates: Promises and challenges
Authors: Alexis Dean, Julianne Twomey, Baolin Zhang
Journal: Cancer Research (2020)

Abstract Chemotherapy is inherently associated with side effects due to its poor selectivity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology promises to overcome barriers of classical chemotherapy by utilizing monoclonal antibodies to deliver potent payloads to selected target cancer cells. The antibody and cytotoxic payload are joined by a chemical linker resulting in an agent with the prospect of increased selectivity, anti-cancer activity, and improved systemic circulation. As of 2019, the US Food and Drug Administration (FDA) has approved five ADCs with cancer indications, including brentuximab vedotin for treatment of CD30-expressing lymphomas, trastuzumab emtansine for Her2-positive breast cancer, inotuzumab ozogamicin for CD22-positive acute lymphoblastic leukemia (ALL), gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia (AML), and polatuzumab vedotin for diffuse large B-cell lymphoma (DLBCL). Currently, there are about 80 ADCs under clinical development in nearly 130 clinical trials. Despite initial success, there are still many challenges in the development of ADCs with respect to their safety and efficacy profiles. In this study, we aim to survey the recent efforts in the design and development of ADCs. We have focused on site-specific conjugation methods for producing homogenous ADCs with consistent drug-antibody ratio (DAR) - a challenge often observed in conventional conjugation methods. This information is further discussed with respect to the ADC interaction with target cells to elicit cytotoxicity. The survey results will be presented, giving perspective on technical considerations for ADC design towards better correlation between preclinical and clinical results and overall safer and more efficacious products. Citation Format: Alexis Dean, Julianne Twomey, Baolin Zhang. Targeting cancer with antibody-drug conjugates: Promises and challenges [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 2861.
Abstract 666: A novel, highly selective PI3Kδ inhibitor for the treatment of solid malignancies that express high levels of target protein as assessed by immunohistochemistry
Authors: Amy R. MacQueen, Giuditta Viticchie, Karolina Niewola, Francesca Finotello, Ian Powley, Pritom Shah, Lars van der Veen, Michael Lahn, Zoe Johnson
Journal: Cancer Research (2020)

Abstract The inhibition of PI3Kδ preferentially targets regulatory T cells and myeloid derived suppressor cells, breaking tumour-induced immune tolerance and restoring anti-tumour immunity. Bioinformatics and protein expression studies have shown that PIK3CD/PI3Kδ is also highly expressed in certain solid malignancies. IOA-244 is a novel, highly selective PI3Kδ inhibitor, with the unique property of being ATP non-competitive. In addition to the effects of PI3Kδ inhibition on the balance of CD8+ T cells and T regulatory cells in the tumour microenvironment, we have recently demonstrated that IOA-244 effectively controls the growth of tumour cells with high levels of PI3Kδ in vivo in T-cell deficient hosts. Analysis of TCGA datasets shows that certain solid tumours express high levels of PIK3CD transcript, comparable to that of diffuse large B cell lymphoma. Of these indications, cutaneous and uveal melanoma are amongst the highest expressers. To support the clinical development of IOA-244, we demonstrate that patient-derived melanoma cells with a high expression of PIK3CD are susceptible to treatment with IOA-244 in a mouse patient-derived xenograft model. Furthermore, in vitro explant studies using clinical biopsy material demonstrates that PI3Kδ expression can be detected in tumour tissue and that IOA-244 has an anti-proliferative function when added to these samples. Based on these and other supporting data, IOA-244 has received clinical trial approval in Europe and phase I clinical testing is underway in solid tumours with an anticipated high Treg:CD8 ratio and/or high protein expression of PI3Kδ. Citation Format: Amy R. MacQueen, Giuditta Viticchie, Karolina Niewola, Francesca Finotello, Ian Powley, Pritom Shah, Lars van der Veen, Michael Lahn, Zoe Johnson. A novel, highly selective PI3Kδ inhibitor for the treatment of solid malignancies that express high levels of target protein as assessed by immunohistochemistry [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 666.
Abstract 2487: Mutation of the <i>STK11</i> gene predicts recurrence of breast cancer
Authors: Chih-Yang Wang, Yung-Chieh Chang, Yao-Lung Kuo, Kuo-Ting Lee, Pai-Sheng Chen, Chun Hei Antonio Cheung, Che-Hung Shen, Chih-Peng Chang, Ming-Derg Lai, Meng-Ru Shen, Hui-Ping Hsu
Journal: Cancer Research (2020)

Abstract Introduction: Breast cancer is the most common cancer in women, and some patients develop recurrence after standard therapy. Effective predictors are urgently needed to detect recurrence earlier. Methods: We conducted a comprehensive study via an experimental and bioinformatics approach to detect mutated genes in breast cancer. Twenty-seven breast cancer patients who developed recurrence within 24 months postoperatively and 22 control cancer patients without recurrence were enrolled from National Cheng Kung University Hospital in Taiwan. Targeted deep sequencing was performed to assess the mutations among individuals with breast cancer using a panel of 143 cancer-associated genes. Bioinformatics and public databases were used to predict the protein functions of the mutated genes. Results: Mutations were identified in 49 breast cancer specimens, and the most frequently mutated genes were BRCA2, TP53, APC, ATM, BRCA1, NOTCH1, TET2, NF1, TSC2, PIK3CA, TSC1, PTEN, MSH2, PTCH1, PIK3R1, STK11, RB1, BAP1, CDH1 and FBXW7. Mutation of these genes was correlated with protein phosphorylation and autophosphorylation. Among these highly mutated genes, mutations of STK11 were associated with poor prognosis and increased recurrence of breast cancer. Knockdown of STK11 in triple negative breast cancer cell lines increases transcription of cytokines and modulates immune response. Conclusion: Our findings suggest that mutation of STK11 is correlated with early recurrence of breast cancer patients and it will become a powerful prognostic marker for recurrence of breast cancer. Suppression of STK11 signaling by gene mutation may contribute to immune escape. Citation Format: Chih-Yang Wang, Yung-Chieh Chang, Yao-Lung Kuo, Kuo-Ting Lee, Pai-Sheng Chen, Chun Hei Antonio Cheung, Che-Hung Shen, Chih-Peng Chang, Ming-Derg Lai, Meng-Ru Shen, Hui-Ping Hsu. Mutation of the STK11 gene predicts recurrence of breast 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 2487.
Abstract 728: Early assessment of treatment effect in small cell lung cancer (SCLC) via ctDNA analysis
Authors: John Jiang, Christine Ju, Corinna Woestmann, Aarthi Balasubramanyam, Liu Xi, Stephanie J. Yaung, Sandeep Gattam, Bernd Hinzmann, Michael Thomas, Felix Lasitschka, Michael Meister, Marc Schneider, Felix Herth, Thomas Muley, Birgit Wehnl, John Palma
Journal: Cancer Research (2020)

Abstract INTRODUCTION: Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. A ctDNA-based method for disease monitoring for small cell lung cancer (SCLC) would be beneficial to disease management. By employing plasma taken during early treatment cycles and NGS, we tested whether early response assessed by ctDNA level could predict treatment effect. METHODS: Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (for Research Use Only, not for use in diagnostic procedures), ctDNA levels were assessed in post-treatment plasma samples based on variants identified at baseline. Mutant allele concentration or mutant molecules per milliliter-of-plasma (MMPM) was utilized to quantify ctDNA over all variants of all sequenced genomic regions. Samples collected from an observational German Lung Cancer Multi-Marker Study were analyzed retrospectively. In a cohort of 69 stage IV SCLC subjects, the association of survival with ctDNA-based monitoring classifier was evaluated in the first available post-treatment plasma sample after starting chemotherapy (median number of days after start of treatment = 25) by Kaplan-Meier methods and Cox proportional hazards model. RESULTS: The analysis demonstrated that subjects with mean MMPM less than the lower quartile (14.3) had longer progression free survival (PFS) compared to that of subjects with mean MMPM greater than or equal to the lower quartile (log-rank P = 0.0095; HR [95% CI] = 0.48 [0.27, 0.84]). The same classifier was applied for overall survival analysis, and subjects with mean MMPM less than the lower quartile had longer overall survival (OS) compared to that of subjects with mean MMPM greater than or equal to the lower quartile (log-rank P = 0.0095; HR [95% CI] = 0.46 [0.26, 0.84]). CONCLUSIONS: Changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects that either respond or fail to respond to therapy earlier than current standard of care methods such as computed tomography (CT) scan. Hypotheses will be validated in a separate cohort. Future prospective studies to confirm these results are needed. Citation Format: John Jiang, Christine Ju, Corinna Woestmann, Aarthi Balasubramanyam, Liu Xi, Stephanie J. Yaung, Sandeep Gattam, Bernd Hinzmann, Michael Thomas, Felix Lasitschka, Michael Meister, Marc Schneider, Felix Herth, Thomas Muley, Birgit Wehnl, John Palma. Early assessment of treatment effect in small cell lung cancer (SCLC) via ctDNA analysis [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 728.
Abstract 2299: Sarcoma as second cancer in pediatric cancer survivors: Large population analysis
Authors: Monish Ram Makena, Thinh H. Nguyen, Siddhartha Yavvari, Maninder Kaur, Teresia Pham, Eduardo Urias, Narendra Panapitiya, Mohamad M. Al-Rahawan
Journal: Cancer Research (2020)

Abstract Introduction: As the prognosis of a pediatric cancer continues to improve, the burden of long term therapy effects, including subsequent malignant neoplasm (SMN), in survivors is an increasing epidemiologic concern. The mortality rate from cancer in the pediatric population decreased from 6.5 per 100,000 in 1970 to 2.3 in 2015, indicating more chance of SMNs. Sarcoma as a SMN in pediatrics has important clinical significance and has been extensively reported globally. We quantified the percentage of sarcoma as second cancer and determined the primary cancer distribution for patients with sarcoma as second cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) database, which includes 28% of the U.S population and data from 18 state cancer registries (SEER-18), was probed for the overall incidence of SMN in pediatric cancer survivors and the incidence of sarcoma as the SMN specifically. Results: Our SEER database analysis found that out of 75,665 cases of primary pediatric malignancies, 1218 (1.61%) developed SMN. The second most common SMN was sarcoma, accounting for 14.37% of them in pediatric population. The breakdown of sarcoma into sub groups showed that osteosarcoma, fibrosarcoma, and rhabdomyosarcoma are the most common second sarcomas seen in pediatric cancer survivors. Finally, we looked at the distribution of primary cancer in pediatric cancer survivors who developed sarcoma as a SMN. We found that retinoblastoma, lymphoid leukemia, and Hodgkin lymphomas were the most common types of primary cancer. Similar results were reported among different racial groups around the world, which show a universal trend of sarcomas as second cancers in pediatric cancer survivors. Conclusion: By analyzing the SEER database, we corroborated previous findings, suggesting that about 14% of SMN after a childhood cancer is encompassed by sarcoma. The exact etiology of cancer, be it primary predisposition or secondary to exposures, is uncertain. Radiation and chemotherapies used in patients with pediatric cancers can be carcinogenic. Our study highlights the need for development of novel non-DNA damaging or alternate antineoplastic therapies to avoid the long-term potential of development of SMN. Citation Format: Monish Ram Makena, Thinh H. Nguyen, Siddhartha Yavvari, Maninder Kaur, Teresia Pham, Eduardo Urias, Narendra Panapitiya, Mohamad M. Al-Rahawan. Sarcoma as second cancer in pediatric cancer survivors: Large population analysis [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 2299.
Abstract 1502: Cell state mapping reveals a role for a stress program in melanoma
Authors: Maayan Baron, Mohita Tagore, Miranda Hunter, Isabella S. Kim, Reuben Moncada, Yun Yan, Nathaniel R. Campbell, Richard M. White, Itai Yanai
Journal: Cancer Research (2020)

Abstract Transcriptional profiling has revealed a diverse range of cell states in cancer, but the function of these various states remains elusive. Using a combination of zebrafish melanoma modeling and human validation, we have identified a conserved stress-like state that confers intrinsic drug resistance and is associated with poor patient survival. Single cell sequencing of a series of transgenic zebrafish melanoma tumors revealed 3 distinct cell states that correspond to a neural crest, melanocyte or stress-like state. The existence of these 3 states was confirmed using spatial transcriptomics, a method that does not require tissue dissociation or cell sorting. The stress-like state expresses genes such as fos, hsp70 and ubb, proteins which are all required for adaptation to diverse cellular stresses. A transgenic reporter of the stress like state demonstrates that it has higher tumor seeding capabilities compared to non-stressed cells, and confers intrinsic resistance to MEK inhibitors, a commonly used melanoma therapeutic. The stress program can be induced by extrinsic processes such as heat shock, and confers resistance to MEK inhibitors in both zebrafish and human melanomas. Our study identifies a population of stress-like cells that are present from the time of tumor initiation, suggesting that the transcriptional seeds of therapeutic failure are established during the earliest steps of tumorigenesis. Citation Format: Maayan Baron, Mohita Tagore, Miranda Hunter, Isabella S. Kim, Reuben Moncada, Yun Yan, Nathaniel R. Campbell, Richard M. White, Itai Yanai. Cell state mapping reveals a role for a stress program in melanoma [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 1502.