tbuckley/cabot-search huggingface dataset:
Abstract 2347: MicroRNA mediated CDK4/6 inhibitor resistance via extracellular signaling
Authors: Liam Cornell, Geoffrey I. Shapiro
Journal: Cancer Research (2017)

Abstract Multiple potent and highly selective inhibitors of the cell cycle kinases - CDK4 and CDK6 are in development. One such inhibitor, palbociclib, was recently approved for use in combination with letrozole for the treatment of estrogen receptor positive (ER+) breast cancer. Cyclin D-dependent kinase activity is a driving factor for ER+ breast carcinogenesis, irrespective of CCND1 amplification, making CDK4/6 inhibition a promising approach for this breast cancer subset. However, as with all cancer treatments, resistance will be a major issue limiting the efficacy of this approach. To date, mechanisms of palbociclib resistance have not been extensively investigated. Through interrogation of the generated CDK4/6 inhibition resistant cells we discovered overexpression of CDK6, specifically, mediates resistance. CDK6 depletion reversed resistance and overexpression caused resistance, whereas the same was not true when CDK4 or D cyclin protein levels were manipulated. Interestingly, when generating and analyzing resistant cell populations, we observed a “bystander effect”, by which resistance was transmissible between cells. The “resistant bystander” cells display all characteristics of the drug exposure induced resistant cells, however became resistant in just 48 hours as oppose to 14 weeks. Analysis of conditioned medium revealed that the transmission of resistance is dependent on exosomes, but not protein or DNA. We identified a specific miRNA, present in the exosomes of resistant cells, by microarray which caused resistance when excreted. Additionally, overexpression and inhibition of the miRNA confirmed that it is responsible for causing resistance. miRNA overexpressing cells exhibited the same phenotype as drug induced resistant cells, and furthermore, could cause resistance in neighboring cell populations by exosome mediated signaling. Using Biotin labelled miRNA-mRNA pulldown followed by RNA-seq, we identified the TGFβ pathway as the miRNA target. Downregulation of the TGFβ caused a decrease in the CDK inhibitors, p15 and p21, resulting in an increased CDK6 protein level and palbociclib resistance. We subsequently confirmed these data in patient samples by comparing before treatment and post relapse biopsies. These findings highlight a novel mechanism of conferred drug resistance as well as new insights into acquired CDK4/6 inhibitor resistance. Citation Format: Liam Cornell, Geoffrey I. Shapiro. MicroRNA mediated CDK4/6 inhibitor resistance via extracellular signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2347. doi:10.1158/1538-7445.AM2017-2347
Abstract 4285: Impact of subsidies on cancer genetic testing uptake in Singapore
Authors: Shao Tzu Li, Jeanette Yuen, Ke Zhou, JOANNE NGEOW
Journal: Cancer Research (2017)

Abstract Purpose: Previous reports cite high costs of clinical cancer genetic testing as main barriers to patient’s willingness to test. We report findings of a pilot study that evaluates how different subsidy schemes impact genetic testing uptake and total cost of cancer management. Methods:We included all patients who attended the Cancer Genetics Service at the National Cancer Centre Singapore ( January 2014-May 2016). Two subsidy schemes, the blanket scheme (100% subsidy to all eligible patients), and the varied scheme (patients received 50%-100% subsidy dependent on financial status) were compared. We estimated total spending on cancer management from government’s perspective using a decision model. Results: 445 patients were included. Contrasting against the blanket scheme, the varied scheme observed a higher attendance of patients (34 vs 8 patients per month), of which a higher proportion underwent genetic testing (5% vs 38%), while lowering subsidy spending per person (S$1098 vs S$1161). The varied scheme may potentially save cost by reducing unnecessary cancer surveillance when first-degree relatives uptake rate is above 36%. Findings :Provision of subsidy leads to a considerable increase in genetic testing uptake rate. From the government’s perspective, subsidising genetic testing may potentially reduce total costs on cancer management. Understanding and overcoming barriers for cascade testing in first degree relatives can improve cost-savings. Citation Format: Shao Tzu Li, Jeanette Yuen, Ke Zhou, JOANNE NGEOW. Impact of subsidies on cancer genetic testing uptake in Singapore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4285. doi:10.1158/1538-7445.AM2017-4285
Abstract 585: Chromosome 9p24.1 deletions as a determinant of tumor immune surveillance and immune checkpoint blockade therapy in non-small cell lung cancer
Authors: Tao Shen, Jie Wu
Journal: Cancer Research (2017)

Abstract Anti-PD-1/PD-L1 immune checkpoint blockade therapy requires the presence of PD-L1/PD-L2 and MHC class I antigens on the tumor cell surface. We previously found JAK1 truncating mutations in endometrial cancer cells that impairs JAK1/JAK2-STAT1-IRF1-mediated signaling pathway, which regulates MHC class I antigen presentation. To determine the potential role and genetic defects in the IFN-γ-IRF1 pathway in non-small cell lung cancer (NSCLC), we analyzed the Cancer Genome Atlas (TCGA) data. Expression of IRF1 correlated with cytolytic activity markers GZMA and PRF1. Loss-of-function (LOF) genetic alterations in the IFN-γ-IRF1 pathway genes were found in 64 cases (6.3%) among 1016 patients. These genetic defects occurred prevalently in the JAK2 gene (33 cases) and often through deletions (29 cases) of chromosome 9p24.1. JAK2 gene deletions were frequently associated with deletions of CD274 and PDCD1LG2 genes that encode PD-L1 and PD-L2, respectively, whereas CD274 and PDCD1LG2 deletions were always accompanied by JAK2 deletions. Chromosome 9p is frequently deleted in NSCLC. This has been attributed to CDKN2A/CDKN2B and PTPRD tumor suppressor genes located at the chromosome 9p21.3-9p24.1. Interestingly, JAK2, CD274, and PDCD1LG2 genes are co-localized at chromosome 9p24.1 near the CDKN2A/CDKN2B and PTPRD genes. JAK2, CD274, and PDCD1LG2 deletion often but not always coincided with CDKN2A/CDKN2B and PTPRD deletions. IFN-γ induced IRF1 expression and cell surface HLA-ABC levels in A549 cells that contain wildtype JAK2 but not in H1573 cells that had a truncating JAK2. Deletion of JAK2 or inhibition of JAK2 kinase activity in A549 cells resulted in loss of IFN-γ-regulated IRF1 and cell surface HLA-ABC, whereas expression of exogenous JAK2 in H1573 cells restored IFN-γ responses. These findings reveal a previously unrecognized significance of chromosome 9p deletion in NSCLC and point to chromosome 9p24.1 as a determinant of immune checkpoint therapy. Citation Format: Tao Shen, Jie Wu. Chromosome 9p24.1 deletions as a determinant of tumor immune surveillance and immune checkpoint blockade therapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 585. doi:10.1158/1538-7445.AM2017-585
Abstract 4137: Second generation alpha-helical stapled peptides efficiently reduce lymphoma cell viabilityby inhibiting LUBAC and NF-κB activity
Authors: Francisco A. Aguilar-Alonso, Amanda L. Whiting, Erin Marshall, Federico Bernal
Journal: Cancer Research (2017)

Abstract The linear ubiquitin chain assembly complex (LUBAC) is the only known linear ubiquitin ligase whose function is dependent on the interaction of three proteins: HOIL, HOIP and SHARPIN. The activity of this ubiquitin ligase has been linked to a malignant phenotype associated with the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (ABC-DLBCL) through constitutive activation of the NF-κB pathway. A first generation of stapled peptides designed to inhibit LUBAC by intracellular disruption of the complex have been shown to reduce cell viability and NF-κB activity in ABC-DLBCL cells modestly. We have developed a second generation of stapled peptides based on the alpha-helical interaction interface of HOIP to enhance their ability to reduce LUBAC formation and, consequently, NF-κB activity as well as ABC-DLBCL cell viability. Live cell imaging showed that some of the second generation HOIP stapled peptides are cell permeable. Biochemical assays revealed that these peptides compromised cell viability, disrupted LUBAC complex formation and inhibited the NF-κB canonical pathway in ABC-DLBCL cell lines. Many of these new peptides were far more potent than any of the previously generated compounds that target the HOIL-HOIP binding interface. These findings support the hypothesis that these second generation peptides may be a useful tool as coadjuvants or therapeutic agents for the treatment of ABC-DLBCL. Citation Format: Francisco A. Aguilar-Alonso, Amanda L. Whiting, Erin Marshall, Federico Bernal. Second generation alpha-helical stapled peptides efficiently reduce lymphoma cell viabilityby inhibiting LUBAC and NF-κB activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4137. doi:10.1158/1538-7445.AM2017-4137
Abstract 2569: BCL6 promotes glioma and serves as a novel therapeutic target
Authors: Liang Xu, Ye CHEN, Marina Dutra-Clarke, Anand Mayakonda, Masaharu Hazawa, Steve E. Savinoff, Ngan Doan, Jonathan W. Said, William H. Yong, Henry Yang, Ling-Wen Ding, Yan-Yi Jiang, Jeffrey W. Tyner, Jianhong Ching, Jean-Paul Kovalik, Markus Müschen, Joshua J. Breunig, De-Chen Lin, Phillip Koeffler
Journal: Cancer Research (2017)

Abstract ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma multiforme (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell proliferation and is overexpressed in GBM samples. Using a somatic transgenic mouse model, Bcl6 confers the proliferative and invasive stimuli to glioma cells in vivo. Moreover, we discover AXL as a novel downstream target of BCL6. Through AXL, BCL6 enhances both MEK-ERK and S6K-RPS6 axes. Pharmacological inhibition of BCL6 activity effectively blocks GBM growth and inhibits AXL expression. Together, these findings uncover a novel glioma-promoting role of BCL6, and provide the rationale of targeting BCL6 as a potential therapeutic approach. Citation Format: Liang Xu, Ye CHEN, Marina Dutra-Clarke, Anand Mayakonda, Masaharu Hazawa, Steve E. Savinoff, Ngan Doan, Jonathan W. Said, William H. Yong, Henry Yang, Ling-Wen Ding, Yan-Yi Jiang, Jeffrey W. Tyner, Jianhong Ching, Jean-Paul Kovalik, Markus Müschen, Joshua J. Breunig, De-Chen Lin, Phillip Koeffler. BCL6 promotes glioma and serves as a novel therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2569. doi:10.1158/1538-7445.AM2017-2569
Abstract 3868: The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic pontine glioma
Authors: Huizi Guo, Sepehr Akhtarkhavari, Charles G. Eberhart, Harpreet Kaur, Eric H. Raabe
Journal: Cancer Research (2017)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable, invasive and aggressive pediatric brain tumor. Identifying molecular markers that regulate tumor growth and invasion are needed for developing efficient treatment strategies. LIN28B is a stem cell factor expressed during normal fetal development and re-expressed in cancer cells. We had previously shown that LIN28A, another family member of LIN28 proteins, regulates invasion and tumorigenicity in adult high grade gliomas. We observed increased LIN28B expression in patient-derived DIPG neurosphere cell lines using western blotting. We hypothesized that LIN28B promotes proliferation and prevents apoptosis in DIPG. Using two different lentiviral transduced short hairpin RNAs (shRNA), we suppressed LIN28B protein levels in DIPG neurospheres, as confirmed by western blotting. DIPG neurospheres that have been treated with LIN28B shRNA showed reduced proliferation as measured by BrdU incorporation (P&amp;lt;0.01) and increased apoptosis as measured by cleaved caspase-3 (CC-3) expression (P&amp;lt;0.01). To determine the molecular mechanism of LIN28B-mediated phenotypes in DIPG, we studied the canonical downstream effector of LIN28B called HMGA2, which is a DNA-binding protein that functions as a transcriptional regulator. Using western blotting, we found decreased HMGA2 protein levels in DIPG neurospheres infected with LIN28B shRNA. Taken together, our results suggest that LIN28B is important for promoting DIPG cell proliferation and preventing apoptotic cell death. Additionally, we also found that LIN28B regulates HMGA2 expression in DIPG neurospheres. Future studies will focus on expanding our understanding of the molecular mechanisms of LIN28B-regulated malignancy in DIPG. Citation Format: Huizi Guo, Sepehr Akhtarkhavari, Charles G. Eberhart, Harpreet Kaur, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2017-3868
Abstract 4778: Telomere DNA damage promotes mammary gland fibrosis and estrogen receptor-positive breast cancer
Authors: Jianchun Wu, David L. Crowe
Journal: Cancer Research (2017)

Abstract Human breast luminal progenitor cells exhibit telomere DNA damage, which is associated with mammographic density and increased cancer risk. Telomeric repeat factor 2 (TRF2) protects telomeres from DNA damage response and its expression is reduced in human ductal carcinoma in situ and breast cancers. To determine the relationships between telomere DNA damage, mammary gland biology, and cancer risk we genetically deleted TRF2 expression in the mouse mammary gland. TRF2 conditional null mutant mice also were bred with tumor prone MMTV-Wnt1 animals. Telomere DNA damage response was determined by localization of 53BP1 at telomeres and activation of ATM/Chk2/p53 signaling by western blot. Mammary gland and tumor histopathology were determined by hematoxylin and eosin staining. Cell proliferation and ER+ differentiation was determined by immunohistochemistry. Tumor derived CD24+/CD49f+ mammary stem cells and CD61+ luminal progenitor cells were transplanted to mammary fat pads of immunodeficient mice. Alternative lengthening of telomeres was determined by PML localization at telomeres, chromosome orientation-fluorescence in situ hybridization, and telomere circular DNA amplification. Tumor bearing mice were injected with 15 mg raloxifene to determine mammary tumor anti-estrogen sensitivity. Mammary glands lacking TRF2 expression exhibited increased telomere DNA damage response, histopathological and functional degeneration, and prominent ductal fibrosis. TRF2 deficient mammary tumors exhibited rapid onset and increased proliferation. Tumor derived LP cells failed to form tumors following transplantation. The MSC population was highly tumorigenic and maintained telomeres via the ALT mechanism. Telomere DNA damage response in mammary tumors resulted in p53 dependent ER+ cellular differentiation and sensitivity to anti-estrogen therapy. Telomere DNA damage correlated with estrogen receptor expression in human breast cancer. We concluded that telomere DNA damage resulted in mammary gland fibrosis, reduced tumor latency, ER+ differentiation, and sensitivity to anti-estrogen therapy. Citation Format: Jianchun Wu, David L. Crowe. Telomere DNA damage promotes mammary gland fibrosis and estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2017-4778
Abstract 2871: Non-invasive monitoring of the efficacy of anticancer therapeutic agent in lung orthotopic xenograft models of NSCLC using Bio-Luminescence Imaging (BLI)
Authors: Sanchareeka Dey, Sarada Preeta Kalainayakan, Poorva Ghosh, Li Zhang
Journal: Cancer Research (2017)

Abstract Non-Small Cell Lung Cancer (NSCLC) patients have a poor rate of survival owing to diagnosis at a later stage. This necessitates development of novel therapeutic strategies that limit rapid progression of NSCLC and imaging techniques that monitor such changes in vivo. There has been a significant growth of bioluminescence imaging applications in small laboratory animal models in recent years, owing to its high sensitivity, efficiency, and non-invasive nature. Our lab has previously demonstrated that a therapeutic agent that disrupts mitochondrial respiration effectively hampers proliferation of NSCLC cell lines in vitro. With an effort to investigate the potential of this therapeutic agent in clinical settings, we used a lung orthotopic xenograft mouse model along with bioluminescence imaging (BLI) to continuously monitor the efficacy of the drug in vivo. Briefly, we implanted NSCLC cell line transduced with lentiviral particles carrying luciferase sequence, in the left lung of 6-8 weeks old female NOD/SCID mice to generate lung orthotopic xenografts. The therapeutic agent was administered intravenously over several weeks. Tumor growth was then compared between the untreated versus the treated mice, non-invasively through bioluminescence imaging (Perkin Elmer’s IVIS Lumina III Imager). On sacrificing the mice, the lungs were harvested, formalin fixed and paraffin embedded for Immunohistochemistry. Our BLI data show that in the mice treated with the therapeutic agent, tumors are localized to the left lung (site of implantation) as opposed to the control mice where the tumors metastasized to the right lung. The BLI data indicates significant decrease in radiance (total flux in photons per second) in mice subjected to treatment when compared to control mice. We show that the therapeutic agent significantly inhibits progression and metastasis of human NSCLC cell line orthotopically injected in the lungs of NOD/SCID mice. The results suggest that it might be potent anti-cancer drug as it is effective in a model that recapitulates the natural environment of lung tumorigenesis. Immunohistochemical studies are underway to discern the mechanistic details. Citation Format: Sanchareeka Dey, Sarada Preeta Kalainayakan, Poorva Ghosh, Li Zhang. Non-invasive monitoring of the efficacy of anticancer therapeutic agent in lung orthotopic xenograft models of NSCLC using Bio-Luminescence Imaging (BLI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2871. doi:10.1158/1538-7445.AM2017-2871
Abstract 5880: Acquired chemotherapeutic drug resistance in colorectal cancer is regulated by epithelial-to-mesenchymal transition and altered cellular pathways
Authors: Lahiru Gangoda, Nidhi Mathew, Michael Liem, Shiva Keertikumar, Ching-Seng Ang, John Mariadason, Suresh Mathivanan
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the western world. Chemotherapy is the mainstay in the treatment of metastasized CRC. However, cancer cells acquire resistance to treatment by various mechanisms resulting in treatment failure. Even though the molecular mechanisms regulating acquired drug resistance is critical to overcome chemoresistance, it is poorly understood. We developed a panel of seven CRC cells resistant to 5-FU. The parental and 5-FU resistant CRC cells were assayed for proteins known for their involvement in chemotherapeutic resistance. In addition, an unbiased quantitative proteomics and DNA methylation analysis was performed on the panel of seven parental and 5-FU resistant CRC cells. The integrated analysis revealed multiple mechanisms contributing to chemotherapeutic drug resistance including epithelial-to-mesenchymal transition (EMT), deregulation of apoptosis, increased survival autophagy and epigenetic modifications resulting in altered drug metabolite potency. Inhibitors of EMT and autophagy sensitized the 5-FU resistant CRC cells. Furthermore, CRIPSR based gene knockouts of these candidate genes (both up and downregulated) either sensitized the CRC cells or rendered them resistant to 5-FU. As a follow up, PDX mouse models were established and made resistant to 5-FU. Follow up quantitative proteomics and biochemical validations of 5-FU resistant PDX tissue lysates confirmed the role of EMT in acquired chemoresistance. Overall, this project unravelled multiple mechanisms by which CRC cells may become resistant to 5-FU. Importantly, some of these mechanisms are also conserved in many cancer types and hence targeting these mechanisms can overcome chemoresistance and increase patient survival rates. Citation Format: Lahiru Gangoda, Nidhi Mathew, Michael Liem, Shiva Keertikumar, Ching-Seng Ang, John Mariadason, Suresh Mathivanan. Acquired chemotherapeutic drug resistance in colorectal cancer is regulated by epithelial-to-mesenchymal transition and altered cellular pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5880. doi:10.1158/1538-7445.AM2017-5880