tbuckley/cabot-search huggingface dataset:
Abstract LB-121: ACK in BRAF inhibitor resistance
Authors: Zhenyu Ji, Hensin Tsao, Mikula Hannes, Jenny Njauw, Raj Kumar
Journal: Cancer Research (2017)

Abstract BRAF inhibition by the small-molecule drug vemurafenib or dabrafenib achieves enormous success in the treatment of melanoma. However, melanoma patients lose their responsiveness after 6 months of treatment. Activation of receptor tyrosine kinase (RTK) was found in vemurafenib resistant melanomas and considered as a critical factor contributing to vemurafenib resistance. We hypothesize that the quick relapse after BRAFi therapy is at least partly due to the off targets of these drugs. Using trans-cyclooctene(TCO) moiety conjugated vemurafenib to treat melanoma cells in culture, we were able to confirm that ACK is a bona-fide intracellular target of vemurafenib. ACK, a protein kinase that regulates turnover of EGFR and other RTKs, was then identified to be downregulated in melanoma cells after short term vemurafenib treatment. Furthermore, ACK protein was reduced in multiple vemurafenib resistant melanoma cells. To prove ACK downregulation plays a role in vemurafenib resistance development, we knocked down ACK by shRNA. We found that ACK reduction delays EGFR degradation speed and increases EGFR protein expression. Since EGFR overexpression has been demonstrated as one important driver of vemurafenib resistance, we expected ACK reduction by shRNA would lead to BRAFi resistance, which was then confirmed by viability assay. During the development of BRAFi resistance, MITF is lost, which is accompanied by overexpression of growth factors and cytokines. We proved that higher resistance to vemurafenib can be induced by combination of ACK reduction and addition of EGFR ligands and cytokines. Our data suggest that EGFR activation in vemurafenib resistant melanoma is mediated by a combination of ACK and MITF downregulation, which lead to RTK and growth factor/cytokine upregulation. ACK binding and downregulation by BRAFi might be the first step toward resistance and a loophole inherent in these compounds themselves. Thus, optimizing BRAFi to ensure more selectivity should be a critical step further to improve the long-term benefits of this class of drugs. Note: This abstract was not presented at the meeting. Citation Format: Zhenyu Ji, Hensin Tsao, Mikula Hannes, Jenny Njauw, Raj Kumar. ACK in BRAF inhibitor resistance [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 LB-121. doi:10.1158/1538-7445.AM2017-LB-121
Abstract 5537: Loss of ITM2A, a novel tumor suppressor of ovarian cancer through G2/M cell cycle arrest, is a poor prognostic factor of epithelial ovarian cancer
Authors: So Young Kim, Eun-Ju Lee, Min Ji Cho, Hyemin Rhee
Journal: Cancer Research (2017)

Abstract Integral membrane protein 2A (ITM2A) is a type 2 transmembrane protein of unknown function. The aim of this study was to investigate its expression pattern, clinical significance, and biological function in epithelial ovarian cancer. ITM2A expression in 35 normal, 20 adenoma, 11 borderline and 90 cancerous ovarian tissues was measured by immunohistochemistry. Clinicopathological parameters were obtained from medical records. Survival data was analyzed using Kaplan-Meier estimates and multivariate analysis using the Cox-regression method. Anti-tumor activities of ITM2A were explored by cell proliferation and colony formation assays, flow cytometry, Western blots and animal studies using ovarian cancer cell lines. Chemoresponsiveness was evaluated by measuring IC50 and confirmed by animal studies using an intraperitoneal orthotropic model. ITM2A was significantly downregulated in invasive carcinomas compared to normal, adenoma and borderline tumor tissues. ITM2A loss occurred in 45.6% (41 of 90) of invasive carcinomas and was significantly associated with FIGO stage, type II tumors, suboptimal debulking operation, recurrence and chemoresistance. ITM2A loss and higher FIGO stage were independent factors for poor prognosis. Expression of ITM2A inhibited growth and induced G2/M cell cycle arrest by attenuating cdc2, cyclin B1, cdc25c and p-cdc2 (Thr 161). In vitro and in vivo experiments showed that ITM2A expression significantly reduced the paclitaxel and carboplatin IC50 and tumor mass after paclitaxel treatment. ITM2A is a new biomarker of poor prognosis in ovarian cancer. It is a novel tumor suppressor that induces cell cycle arrest, acts as a chemosensitizer, and has therapeutic potential for ovarian cancer. Citation Format: So Young Kim, Eun-Ju Lee, Min Ji Cho, Hyemin Rhee. Loss of ITM2A, a novel tumor suppressor of ovarian cancer through G2/M cell cycle arrest, is a poor prognostic factor of epithelial ovarian 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 5537. doi:10.1158/1538-7445.AM2017-5537
Abstract 2836: Mitochondrial genomic backgrounds differentially affect nuclear DNA methylation and gene expression
Authors: Carolyn J. Vivian, Amanda E. Brinker, Stefan Graw, Devin C. Koestler, Christophe Legendre, Gerald C. Gooden, Bodour Salhia, Danny R. Welch
Journal: Cancer Research (2017)

Abstract Accumulating data implicate mitochondrial genetics and metabolism as contributors to metastatic efficiency. With only 13 proteins encoded by the mtDNA genome, the mechanism(s) by which the coordination of multiple genes involved in metastasis could occur is unclear. We hypothesized that mitochondrial DNA (mtDNA) polymorphisms would differentially regulate nuclear DNA (nDNA) methylation and gene expression. To test the hypotheses, we created Mitochondrial Nuclear Exchange (MNX) mice, by transferring an oocyte nucleus from strainx into an enucleated oocyte from strainy. The mice show that mammary tumor formation and metastasis are regulated by inherited mitochondrial polymorphisms (PMID: 26471915). Age-matched, male mouse brains were collected and pooled from four litter mates representing each of the wild-type and MNX mice (8 groups). Genome-wide nDNA methylation (Mouse methyl-Seq) and gene expression (RNA-Seq) were measured and results validated in independent replicate samples. Significant, selective and reproducible differential DNA methylation and gene expression were observed and validated between strains having identical nDNA, but different mtDNA. While the signal(s) from mitochondria altering methylation is not fully defined, the findings support the hypothesis and demonstrate how mitochondrial genetic alterations could be one of several quantitative trait loci involved in complex phenotypes, such as metastasis. The results also suggest that mtDNA polymorphisms could serve as predictive biomarkers for cancer aggressiveness. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res, Biomedical Research Training Program, Kansas Bioscience Authority, CA134981, P30-CA168524. Citation Format: Carolyn J. Vivian, Amanda E. Brinker, Stefan Graw, Devin C. Koestler, Christophe Legendre, Gerald C. Gooden, Bodour Salhia, Danny R. Welch. Mitochondrial genomic backgrounds differentially affect nuclear DNA methylation and gene expression [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 2836. doi:10.1158/1538-7445.AM2017-2836
Abstract 4342: Loss of MSLN impairs pancreatic cancer growth in the peritoneal cavity
Authors: Michael W. Rudloff, Danielle Arons, Salma El-Behaedi, Rakan Albalawy, Christine Alewine
Journal: Cancer Research (2017)

Abstract Mesothelin (MSLN) is a cell surface glycoprotein that is expressed in at least 85% of pancreatic adenocarcinoma but not on cells of the healthy pancreas nor in the parenchyma of other vital organs. Due to this differential expression, MSLN has been used as a target for various antibody based treatments and cancer vaccines. The physiologic role of MSLN is unknown. Previous reports have suggested that overexpression of MSLN may increase tumorigenicity and metastatic potential of pancreatic adenocarcinoma. To further define the role of MSLN in this disease, we deleted MSLN from the human pancreatic cancer cell line, KLM1, using CRISPR/Cas9 gene editing. Successful deletion of MSLN was confirmed via flow cytometry and immunoblotting. Furthermore, KLMΔMSLN cells were rendered invulnerable to the MSLN-targeted immunotoxin, RG7787, which depends on the presence of surface MSLN for cytotoxicity. In cell culture, KLMΔMSLN cells grew at the same rate as control cells. KLMΔMSLN formed subcutaneous tumors in nude mice with the same frequency as control cells and these tumors grew at the same rate. However, when nude mice were inoculated with KLMΔMSLN or control cells intraperitoneally, a marked decrease in tumor burden was observed in cells lacking MSLN. In summary, we have engineered a pancreatic cancer cell line that lacks MSLN and demonstrated that loss of MSLN impairs tumor growth and spread specifically within the peritoneal cavity. Further experiments are in progress to identify the factors contributing to this phenotype. Citation Format: Michael W. Rudloff, Danielle Arons, Salma El-Behaedi, Rakan Albalawy, Christine Alewine. Loss of MSLN impairs pancreatic cancer growth in the peritoneal cavity [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 4342. doi:10.1158/1538-7445.AM2017-4342
Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival
Authors: Lijie Zhai, Erik Ladomersky, Kristen L. Lauing, Meijing Wu, Matthew Genet, Galina Gritsina, Balázs Győrffy, Priscilla K. Brastianos, David C. Binder, Jeffrey A. Sosman, Francis J. Giles, Charles D. James, Craig Horbinski, Roger Stupp, Derek A. Wainwright
Journal: Clinical Cancer Research (2017)

Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.Experimental Design: Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD-scid, and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation.Results:In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P = 0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially engrafted human GBM revealed an IFNγ-associated T-cell-mediated increase of intratumoral IDO1Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T-cell-mediated effects against GBM should consider combinatorial approaches that coinhibit potential T-cell-mediated IDO1 enhancement during therapy. Clin Cancer Res; 23(21); 6650-60. ©2017 AACR.
Abstract 5911: Omentin drives metabolic shift in ovarian cancer cells in the omental tumor microenvironment
Authors: Chi Lam Au Yeung, Abhinav Achreja, Hongyun Zhao, Tsz-Lun Yeung, Rosemarie Schmandt, Daniel K. Yip, Karen H. Lu, Deepak Nagrath, Samuel C. Mok
Journal: Cancer Research (2017)

Abstract Advanced stage high grade serous ovarian cancer (HGSC) metastasizes preferentially to the omentum, which is a well-vascularized fold of peritoneal tissue and is a major site of adipose tissue accumulation. The mechanisms by which omental adipose tissue interact with ovarian cancer cells and promotes tumor growth and disease progression are not entirely clear. We previously showed that a novel adipokine called omentin (Intestinal Lactoferrin Receptor ITLN1) produced by the omental adipose tissue was significantly down-regulated in patients with HGSC compared with those in BMI matched healthy individuals, and omentin suppressed ovarian cancer cell growth only in the presence of adipocytes in vitro. Since we and others demonstrated that omentin induced insulin-dependent glucose uptake exclusively in adipocytes, we therefore hypothesized that omentin may suppress ovarian cancer growth via driving metabolic shift in ovarian cancer cells in the omental microenvironment. Using a cancer cell/adipocyte-co-culture model, we demonstrated that omentin reduced both glucose uptake and lactate secretion in ovarian cancer cells when they were co-cultured with adipocytes but not with other stromal cell types, suggesting that omentin-induced glucose uptake in adipocytes may deplete the surrounding glucose that fuels the glucose-addicted ovarian cancer cells in the omental microenvironment and thus drive metabolic shift in ovarian cancer cells. To delineate the underlying mechanism by which omentin induced glucose uptake in adipocytes, expression levels of the adipocyte-specific glucose transporter GLUT4 induced by omentin in adipocytes and the effect of GLUT4 silencing in adipocytes using GLUT4 specific siRNAs on ovarian cancer growth were examined. The results showed that omentin up-regulated GLUT4 in adipocytes and GLUT4 silencing in adipocytes abrogated the effects of omentin on glucose uptake in adipocytes and ovarian cancer cell growth in the co-culture model. Taken together, this study shows that omentin plays an important role in driving metabolic shift in ovarian cancer cells in the omental microenvironment. Therapeutic strategies based on up-regulating omentin in ovarian cancer patients may inhibit ovarian cancer progression and improve patient survival rates. Note: This abstract was not presented at the meeting. Citation Format: Chi Lam Au Yeung, Abhinav Achreja, Hongyun Zhao, Tsz-Lun Yeung, Rosemarie Schmandt, Daniel K. Yip, Karen H. Lu, Deepak Nagrath, Samuel C. Mok. Omentin drives metabolic shift in ovarian cancer cells in the omental tumor microenvironment [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 5911. doi:10.1158/1538-7445.AM2017-5911
Abstract 371: Developing small molecule therapeutics to target AKT signaling in non-small cell lung cancer
Authors: Balaji Chandrasekaran, Deeksha Pal, Venkatesh Kolluru, Srinivasa R. Ramisetti, Arun K. Sharma, Murali Ankem, Chendil Damodaran
Journal: Cancer Research (2017)

Abstract Lung cancer remains a leading public health problem which is evidenced by its increasing death rate. Platinum-based chemotherapy is the first-line of treatment for patients in advanced stages of non-small cell lung cancer (NSCLC), however the success rates are not quite impressive. Hence, developing individualized treatment strategies for metastatic lung cancer gains momentum, such as Tyrosine kinase inhibitors erlotinib and gefitinib, or ALK inhibitors ceritinib and alectinib are commonly used in the clinic. Recent reports suggest that pAKT(ser473) is highly expressed in NSCLC and higher nuclear expression of pAKT correlated with poor prognosis and an independent prognostic marker for survival. Our lab is interested to develop novel small molecules which specifically inhibit AKT signaling in NSCLC. Structure-activity relationship (SAR) studies in our laboratory have recently ideintifed one such compound, AKS-407, that effectively inhibited cell growth at nanomolar concentration in NSCLC cell lines (A549 and H460; 250nM). Molecular studies revealed AKS-407 inhibited AKT signaling by down regulating pAKT(ser473) expression and downstream events including NFκB activation, BCl-2 expression in both the cell lines. As signaling through AKT regulates epithelial-mesenchymal transition (EMT) in NSCLC, we determined the effect of AKS-407 on EMT phenotype on NSCLC cells. Treatment of AKS-407 inhibited the mesenchymal markers includes snail, MMP9, N-cadherin, β-catenin and vimentin expression that resulted in blocking invasion and migration of A549 and H-460 cells. These results suggest AKS-407 to be a promising small molecule targeting AKT signaling pathway which remains an important target for the development of effective treatment of metastatic NSCLC. Validating in-vivo efficacy of this potential drug candidate would further support our overall goal of the study. Citation Format: Balaji Chandrasekaran, Deeksha Pal, Venkatesh Kolluru, Srinivasa R. Ramisetti, Arun K. Sharma, Murali Ankem, Chendil Damodaran. Developing small molecule therapeutics to target AKT signaling 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 371. doi:10.1158/1538-7445.AM2017-371
Abstract 3529: Investigating the in vivo role of the EHF transcription factor in intestinal epithelial differentiation
Authors: Camilla M. Reehorst, Ian Y. Luk, Rebecca Nightingale, Mercedes Davalos-Salas, Amardeep S. Dhillon, John M. Mariadason
Journal: Cancer Research (2017)

Abstract Objective: Poor tumor differentiation status is associated with worse patient outcome in colorectal cancer. However, the molecular basis for loss of differentiation in colon cancer is not well understood. We have found that the transcription factor Ets homologous factor (EHF) is highly expressed in the normal human and mouse colonic epithelium and is down-regulated in poorly-differentiated colorectal cancer cell lines. The aim of this study was to investigate the role of EHF in regulating normal colonic epithelial cell differentiation in vivo. Methods: A novel mouse model was generated in which the Ets DNA binding domain (exon 8) of EHF was flanked by loxP sites (EHFlox/lox). To inactive EHF in the intestinal epithelium, EHFlox/lox mice were crossed to Villin-CreERT2 mice and recombination induced by tamoxifen treatment. Tamoxifen and vehicle treated mice were monitored weekly for up to one year. At each endpoint, tissue was collected and the effect of EHF deletion on intestinal cell proliferation and differentiation assessed by qRT-PCR and immunohistochemistry. Results: Targeted inactivation of EHF in the small intestinal and colonic epithelium following tamoxifen treatment was confirmed at the DNA and RNA level. EHF inactivation in the intestinal epithelium had minimal effect on survival, weight gain and overall health of the animals. Furthermore, loss of EHF did not markedly affect cell proliferation or the overall architecture of the intestinal epithelium. Finally, EHF inactivation also had minimal effect on markers of absorptive, enteroendocrine or Paneth cell differentiation but did reduce the number of goblet cells in the colonic epithelium. Conclusion: EHF does not play a major role in regulating cell proliferation in the mouse intestine but may play a role in regulating goblet cell differentiation. The role of EHF in intestinal tumourigenesis and response to stress are currently being investigated. Citation Format: Camilla M. Reehorst, Ian Y. Luk, Rebecca Nightingale, Mercedes Davalos-Salas, Amardeep S. Dhillon, John M. Mariadason. Investigating the in vivo role of the EHF transcription factor in intestinal epithelial differentiation [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 3529. doi:10.1158/1538-7445.AM2017-3529
Archetypes of AML Defined Using Whole Exome Sequencing and Clinical Characteristics in a Diverse Group of Patients
Authors: Christopher B. Benton, Koichi Takahashi, Prithviraj Bose, Feng Wang, Hsiang-Chun Chen, Xiaofeng Zheng, Jianhua Zhang, Xuemei Wang, Xiaoping Su, Guillermo Montalban-Bravo, Ghayas C. Issa, Naval Daver, Elias J. Jabbour, Courtney D DiNardo, Carlos E Bueso-Ramos, Keyur Patel, Steven M. Kornblau, Marina Konopleva, Gautam Borthakur, Tapan M. Kadia, Jorge E. Cortes, Farhad Ravandi, Michael Andreeff, Guillermo Garcia-Manero, Andrew Futreal, Hagop M. Kantarjian
Journal: Blood (2016)
Abstract 5412: Expression and inhibition of monocarboxylate transporters in canine osteosarcoma
Authors: Heather L. Gardner, Joelle M. Fenger, Vincent P. Sandanayaka, Cheryl A. London
Journal: Cancer Research (2017)

Abstract Background: A distinguishing feature of cancer cells is their ability to undergo aerobic glycolysis, even in the presence of oxygen. This process generates lactic acid, which must be removed from the cell in order to maintain proliferation and survival. Monocarboxylate transporters (MCTs) move lactic acid across the plasma membrane, providing a mechanism for tumor cells to meet their bioenergetic needs during glycolysis in a variety of limiting microenvironments. The objective of this work is to determine the biologic effects of modulating cellular metabolism through inhibition of MCT1 and MCT4 in canine osteosarcoma (OS), a well-established spontaneous large animal model of the human disease. Methods: MCT1 and MCT4 expression was assessed in canine OS cell lines using qRT-PCR and western blotting. Immunohistochemistry and qRT-PCR were performed to determine relative MCT1 and MCT4 expression in primary canine OS tissues. The effects of small molecule inhibitors (NGY066 and NGY008) and shRNA approaches targeting MCT1 and MCT4 on proliferation and survival of canine OS were examined using the CyQUANT Cell Proliferation and Caspase-3/7 assays, respectively. The impact of MCT1/4 inhibition on cellular oxygen consumption was evaluated using the Seahorse Cell Mito Stress Test. Lastly, potential synergistic effects of combining metformin and doxorubicin with MCT1/4 inhibition in canine OS cell lines were investigated using the CyQUANT Assay. Results: We found that while both MCT1 and MCT4 are expressed in canine OS lines and tissues, MCT1 is expressed at higher levels relative to MCT4 in the cell lines. Small molecule inhibitors directed against MCT1 and MCT4 did not significantly inhibit cell proliferation or induce apoptosis even in the presence of limiting cell culture conditions. Maximal respiratory capacity was not increased in canine OS cell lines following inhibition of MCT1 and MCT4 function. However, synergistic anti-proliferative activity was observed when OS cells were treated with doxorubicin or metformin in the presence of MCT1 and MCT4 inhibitors. Conclusions: MCT1 and MCT4 are expressed in canine OS, and therefore represent a good model to evaluate the therapeutic potential of manipulating lactic acid transport. Importantly, drug combinations with synergistic activity may be necessary to realize the full potential of MCT1/4 inhibition. Citation Format: Heather L. Gardner, Joelle M. Fenger, Vincent P. Sandanayaka, Cheryl A. London. Expression and inhibition of monocarboxylate transporters in canine osteosarcoma [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 5412. doi:10.1158/1538-7445.AM2017-5412