tbuckley/cabot-search huggingface dataset:
Abstract 1149: Targeting Rad6B suppresses melanomagenesis
Authors: Ashapurna Sarma, Sarah Petit, Fangchao Liu, Pratima Nangia-Makker, Guangzhao Mao, Malathy Shekhar
Journal: Cancer Research (2017)

Abstract Active β-catenin signaling in melanoma is associated with aggressive disease. We have previously shown that Rad6B, an ubiquitin conjugating enzyme, is a positive regulator of β-catenin stability and transcriptional activity, and is itself a transcriptional target of β-catenin. This stabilization is mediated by Rad6B-induced K63-linked polyubiquitination of β-catenin that renders it insensitive to 26S proteasomal degradation. Immunohistochemical analysis of human cutaneous melanoma samples showed the first detectable expression of Rad6B in melanocyte hyperplasia and continued Rad6B and β-catenin overexpression in primary and metastatic melanomas. These data implicate a critical role for Rad6B in melanocyte transformation and a continuing role in melanoma progression. To analyze the role of Rad6B in melanomagenesis, we targeted Rad6B expression/activity in human M14 metastatic melanoma cells by using a Rad6-selective small molecule inhibitor SMI#9 and the CrispR/Cas9 gene editing system. Immunoblot analysis showed that compared to controls, M14 cells treated with SMI#9 showed decreased levels of β-catenin, and β-catenin driven transcriptional targets Rad6, vimentin, Mitf-M, and Melan A. Although Snail levels were not altered, SMI#9 treated cells showed increase in phosphorylated Snail. Immunocytochemical staining verified the western blot data and showed cytoplasmic relocalization of PCNA and Snail in SMI#9 treated cells which is consistent with increase in phosphorylated Snail. Concordant with the decrease in vimentin and unphosphorylated Snail levels, Rad6B-inhibited cells display poor capacity to migrate as compared to controls. Whereas Rad6B knockout cells were severely growth impaired, Rad6B edited clones showing partial expression (potentially from only one allele) similarly showed decreased levels of β-catenin, vimentin, and Mitf-M. Similar to Rad6B-inhibited cells, Rad6B edited cells were migration- and invasion-impaired. Whereas control cells produced robust tumors and overt lung metastases, the Rad6B gene edited cells were poorly tumorigenic. Rad6B gene edited clones showed complete loss of Melan A. Since Mitf-M is a transcriptional regulator of Melan A and a key player in melanocyte lineage specification, our data suggest that targeting Rad6B could potentially inhibit melanomagenesis by reprogramming melanoma cells. Supported by NIH CA178117 and 3Balls Racing. Citation Format: Ashapurna Sarma, Sarah Petit, Fangchao Liu, Pratima Nangia-Makker, Guangzhao Mao, Malathy Shekhar. Targeting Rad6B suppresses melanomagenesis [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 1149. doi:10.1158/1538-7445.AM2017-1149
Abstract 200: Long lasting inhibition of TGF-β receptor Type 1 inhibitor (TGF-β R1) for treatment of pancreatic cancer
Authors: Cristian Rodriguez-Aguayo, Emine Bayraktar, Haifa Shen, Gabriel Lopez-Berestein
Journal: Cancer Research (2017)

Abstract Pancreatic cancer stroma is a high component of total tumor volume and activators of fibro-genesis such as Transforming growth factor-β (TGF-β) are abundantly secreted by pancreatic stellate cells (PSCs) to the tumor microenvironment. Aberrant TGF-β signaling pathways are associated with many human diseases, including bone diseases, immune-suppression, fibrosis, cancer progression and metastasis. However, the precise mechanism of this phenomenon in pancreatic cancer remains unclear. In this study we hypothesized that inhibition of TGF-β Type I receptor kinase (TGF-β R1) in pancreatic cancer and stellate cells regulates proliferation and fibrosis through the regulation of TGF-β R1 signaling pathway in PC cells, resulting in decreased migration, and decreased proliferation. We analyzed a TGF-β R1 data set of PC patients from the Cancer Genome Atlas. Furthermore, the analysis of a panel of pancreatic cancer cell lines showed that TGFR-B1 at mRNA and protein levels were higher in PC cells when compared with human pancreatic duct epithelial (HPDE) normal cells. In vitro cell viability, growth, cell-cycle progression, migration, invasion and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following the inhibition of TGF-β R1 in pancreatic cancer and stellate cells. The experimental validation identifies TGFR-β1 associated with PC survival. Significant inhibition of cell growth, invasion, migration, angiogenesis and fibro-genesis. Furthermore, treatment with LY-DMPC:DMPG-MSV inhibited growth of CAPAN-II tumors. These findings identify TGFR-β1 as a potential therapeutic target in pancreatic cancers expressing high levels of this oncogenic protein. Note: This abstract was not presented at the meeting. Citation Format: Cristian Rodriguez-Aguayo, Emine Bayraktar, Haifa Shen, Gabriel Lopez-Berestein. Long lasting inhibition of TGF-β receptor Type 1 inhibitor (TGF-β R1) for treatment of pancreatic 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 200. doi:10.1158/1538-7445.AM2017-200
Abstract 4527: Estimating tumor cell dissemination rates through lymph and blood via computational modeling
Authors: Anne Marie Barrette, Benedicte Lenoir, Mihaela Skobe, Marc R. Birtwistle
Journal: Cancer Research (2017)

Abstract Metastasis is the primary cause of death from most cancer types, but the relative rates of tumor cell migration through lymphatic versus blood routes remains an open question. Here we combine data from a xenograft model of metastatic breast cancer with a computational model of tumor cell growth and dissemination to help answer this question. Orthotopic mouse xenografts using the triple negative breast cancer cell line MDA-MB-231 allowed for monitoring of metastatic cells within the primary tumor, bloodstream, lymph nodes, and lungs. Experiments resembling a pulse-chase method helped inform and parameterize the model to the rate of dissemination to the lymph nodes and lungs. Our ordinary differential equation model describes primary tumor growth as the balance between proliferation and death, with the proliferative fraction decreasing with tumor size, and the apoptotic or necrotic fraction increasing with tumor size. Intravasation to both lymph and blood rapidly increases early in tumor growth, followed by a decay to a low rate of tumor cell release well before the primary tumor grows to its saturating size. The mouse data guided our parameter estimations based on the assumptions that disseminated tumor cell death rate is greatest in the harsh environment of the blood and lowest in the more accommodating lymph node, and that metastatic cells seeding in the lymph nodes and lungs follow similar growth dynamics as the primary tumor only with far fewer total cells. We are currently performing sensitivity analysis to explore the range of relative rates of tumor cell dissemination that fit the in vivo data, and thus gain insight into tumor cell dynamics within the different compartments. These analyses will allow us to estimate what the relative contributions of blood versus lymphatic tumor cell dissemination are to overall metastatic burden, as well as suggest experiments that further constrain these estimates. Such combined experimental and modeling analysis lend insight into where one might detect pre-metastatic cells early in disease progression or suggest new targets for anti-metastasis drugs based on the dominant mode of dissemination. Citation Format: Anne Marie Barrette, Benedicte Lenoir, Mihaela Skobe, Marc R. Birtwistle. Estimating tumor cell dissemination rates through lymph and blood via computational modeling [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 4527. doi:10.1158/1538-7445.AM2017-4527
How We Should Conceive of Creation: Natural Birth as an Ethical Guidepost for Neonatal Rescue
Authors: Douglas C. McAdams, W. Kevin Conley, Kevin T. FitzGerald, G. Kevin Donovan
Journal: The American Journal of Bioethics (2017)

Philosophically, biologically, and colloquially, “creation” belongs properly to the act of conception. After the new human organism comes into existence, all subsequent changes in its life cycle ar...
Abstract 4077: Application of drug sensitivity and resistance testing to identify novel therapeutic agents for Down syndrome patients with AML
Authors: Apurvi R. Patel, Justin J. Montoya, Daniel H. Wai, David W. Lee, Robert J. Arceci, David O. Azorsa
Journal: Cancer Research (2017)

Abstract Patients with Down’s syndrome who develop acute myeloid leukemia (AML) are at increased risk of toxicity secondary to chemotherapy regimens. These patients are harder to treat with conventional therapies at relapse. Overall, the use of targeted drug therapy is rising in the pediatric oncology field. Development of drug sensitivity and resistance test allows identification of specific targeted therapies for patient’s with difficult to treat leukemia. Our laboratory is working on the development of a drug sensitivity and resistance screening assay that would provide functionally relevant drug response data of the patient’s leukemia cells. Development of this assay included the preparation of pre-dosed drug library plates allowing for rapid initiation of the assay. AML cells are then added to the plate and treated for 72 hours after which cell viability was determined. Previous work in our laboratory tested a library of 56 anti-cancer and targeted agents on a panel of 16 AML cell lines that included two Down’s syndrome AML cell lines CMK and CMY. Drug dose response data including IC50 values and Area Under the Curve (AUC) were calculated for each cell line. Hierarchical clustering was performed to determine similar responses between cell lines. Down’s syndrome cell lines, CMK and CMY were found to be resistant to most conventional chemotherapeutic agents, but susceptible to targeted therapies such as Navitoclax and 17-AAG. We further tested several cell lines with the drug sensitivity and resistance assay under hypoxic conditions. Our screening results showed improved sensitivity of the CMK and CMY cells to Navitoclax and 17-AAG under normoxic and hypoxic conditions. Validation of the screening results was done using a 10-concentration drug dose response assay. Future studies will explore the mechanism by which the Down’s syndrome AML cells have increased sensitivity to these targeted agents under both normoxic and hypoxic conditions. Furthermore, we will investigate the activity of combinations of these targeted therapies with conventional therapies. The results from these studies could lead to the establishment of improved therapeutic regimens for Down’s syndrome patients with AML. Citation Format: Apurvi R. Patel, Justin J. Montoya, Daniel H. Wai, David W. Lee, Robert J. Arceci, David O. Azorsa. Application of drug sensitivity and resistance testing to identify novel therapeutic agents for Down syndrome patients with AML [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 4077. doi:10.1158/1538-7445.AM2017-4077
Abstract 236: Stearoyl-CoA desaturase-1, a novel target of omega-3 fatty acids for reducing breast cancer risk in obese postmenopausal women
Authors: Andrea Manni, John P. Richie, Susann E. Schetter, Ana Calcagnotto, Neil Trushin, Cesar Aliaga, Karam El-Bayoumy
Journal: Cancer Research (2017)

Abstract Preclinical and epidemiologic data suggest that a unique feature of lipogenesis in cancer cells which has received limited attention is the accumulation of monounsaturated fatty acids (MUFA) which are largely derived from saturated fatty acids (SFA) by the action of stearoyl-Co-A desaturase (SCD-1). Activation of SCD-1, a delta-9 fatty acid desaturase, is considered to be an important factor in the development of obesity and several types of cancer including breast cancer. However, no data are available on how changes in SCD-1 activity induced by potential chemopreventive agents relate to established biomarkers of breast cancer risk. To address this issue, we measured the activity of SCD-1, expressed as the ratios of palmitoleic acid (C16:ln7) to palmitic acid (C16:0) (SCD-16) and oleic acid (C18:ln9) to steric acid (C18:0) (SCD-18) in plasma samples of postmenopausal women enrolled in our recently published clinical trial (Sandhu N, et al Cancer Prev Res 9:275, 2016) designed to test the individual and combined effect of the antiestrogen Raloxifene and the omega-3 preparation Lovaza on breast density, a validated biomarker of breast cancer risk. We observed that daily administration of Lovaza (1,860 mg eicosapentaenoic [EPA] + 1,500 mg docosahexaenoic [DHA]) significantly reduced SCD-1 activity, an effect which was sustained for the two-year duration of the trial. Raloxifene, on the other hand, did not significantly alter SCD-1 activity in our subjects. SCD-1 activity was positively correlated with BMI (for SCD-16, r=0.45, p&amp;lt;01; for SCD-18, r=0.23, p&amp;lt;0.01) and paralleled changes in BMI in the same direction over the two years of the study. These findings support the role of this enzyme in the development of obesity. Importantly, decreasing levels of SCD-1 were found to be associated with a progressive reduction in breast density in obese women (BMI≥30) (for SCD-16; r=0.47, p&amp;lt;0.01; for SCD-18; r=0.36, p&amp;lt;0.05). No correlation between breast density and SCD-1 was observed in non-obese subjects (r=0.02 for SCD-16 and 0.04 for SCD-18). Our results suggest that BMI-related factors play an important role in the reduction of breast density by omega-3 fatty acids. They also indicate that SCD-1 may be a useful biomarker in future clinical trials testing the benefit of nutritional interventions in reducing obesity associated breast cancer risk. Citation Format: Andrea Manni, John P. Richie, Susann E. Schetter, Ana Calcagnotto, Neil Trushin, Cesar Aliaga, Karam El-Bayoumy. Stearoyl-CoA desaturase-1, a novel target of omega-3 fatty acids for reducing breast cancer risk in obese postmenopausal women [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 236. doi:10.1158/1538-7445.AM2017-236
Abstract 2140: Understanding molecular mechanisms underlying heme function in non-small cell lung cancer cells
Authors: Sagar Sohoni, Chantal Vidal, Li Zhang
Journal: Cancer Research (2017)

Abstract Heme is a central molecule for mitochondrial respiration and for all processes involved in oxygen utilization. Heme serves as a prosthetic group or as a cofactor for a number of oxidative phosphorylation enzymes and other oxygen-utilizing hemoproteins. Heme directly regulates the synthesis, translocation and assembly of these enzyme complexes. Most, if not all, human cells can synthesize and uptake heme from the circulation. A number of epidemiological studies have shown that high heme intake is associated with increased risk of cancer, including lung cancer. To assess the status of heme metabolism in lung cancer cells, we performed a series of experiments in non-small-cell lung cancer (NSCLC) cell lines such as HCC4017, H1299, A549, H2009, H1395, H460 and Calu-3. We then compared results with an immortalized normal lung cell line, HBEC30KT and observed significant increase in rates of heme synthesis and heme uptake in NSCLC cells compared to HBEC30KT. Previous studies carried out in our lab showed intensified mitochondrial respiration and increased levels of heme and hemoproteins in NSCLCs. We examined the effect of heme depletion on mitochondrial biogenesis and function. We observed that mitochondrial functions such as ATP production, NAD/NADH ratios and ROS production are also affected by heme depletion. Proteins involved in mitochondrial biogenesis are significantly affected when cells are grown in heme depleted medium. Studies are currently underway to check how heme depletion affects the interactions of various transcription factors involved in mitochondrial biogenesis and function. Citation Format: Sagar Sohoni, Chantal Vidal, Li Zhang. Understanding molecular mechanisms underlying heme function in non-small cell lung cancer cells [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 2140. doi:10.1158/1538-7445.AM2017-2140
Abstract 4025: Accelerating drug repurposing for cancer therapy using multiplexed viability assays
Authors: Steven M. Corsello, Christopher C. Mader, Jordan Bryan, Jennifer Roth, David Peck, John Davis, Samantha Bender, Li Wang, Alice Wang, Joshua Bittker, Francisca Vazquez, Aravind Subramanian, Aviad Tsherniak, Todd R. Golub
Journal: Cancer Research (2017)

Abstract New therapies are desperately needed for patients with advanced cancer, but making safe and efficacious drugs remains expensive and time consuming. Meanwhile, multiple non-oncology drugs have been successfully repurposed for cancer, including thalidomide for multiple myeloma and aspirin for prevention of colorectal cancer. While the benefits of repurposing are clear, successes to date have been largely serendipitous. We have created two foundational tools to identify drug repurposing opportunities at a much greater scale: a new world-class screening library of more than 4,000 drugs/clinical candidates and a multiplexed method to rapidly conduct cellular viability assays across hundreds of cell lines. PRISM, a recently developed high-throughput assay, employs DNA-barcoded cell lines to enable rapid testing of many drugs against pools of cancer cell lines. We have tested 4,100 compounds against 578 genomically characterized cancer cell lines using PRISM. Our experiment is among the largest cell line screens ever undertaken. Global analysis has revealed multiple strong clusters of active drugs, including vitamin D agonists, bromodomain inhibitors, and statins. In addition, many novel and established drug-biomarker relationships were identified, including alkylating agent response and low MGMT expression, BRAF inhibitor response and BRAF mutation, and MDM2 inhibitor response and TP53 wild-type status. Surprisingly, more than 100 non-oncology drugs unexpectedly killed multiple cancer cell lines, making them attractive repurposing candidates. For example, the FDA-approved phosphodiesterase inhibitor anagrelide selectively kills PDE3A-high lung cancer and melanoma cell lines. Confirmatory experiments are underway to validate screening results, evaluate putative biomarkers, and test drug activity in preclinical models. Importantly, this approach is expected to enable rapid initiation of clinical trials, dramatically accelerating patient access to potential new therapies. Citation Format: Steven M. Corsello, Christopher C. Mader, Jordan Bryan, Jennifer Roth, David Peck, John Davis, Samantha Bender, Li Wang, Alice Wang, Joshua Bittker, Francisca Vazquez, Aravind Subramanian, Aviad Tsherniak, Todd R. Golub. Accelerating drug repurposing for cancer therapy using multiplexed viability assays [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 4025. doi:10.1158/1538-7445.AM2017-4025
Abstract 4217: Consumer credit, cancer treatment, and health among women with a history of breast cancer
Authors: Lorraine T. Dean, Kathryn H. Schmitz, Kevin Frick, Lauren Nicholas, Yuehan Zhang, SV Subramanian, Kala Visvanathan
Journal: Cancer Research (2017)

Abstract Background: Breast cancer treatment may represent an economic shock that may be influenced by, or may influence a cancer survivor’s socio-economic position (SEP). Financial toxicity or economic burden due to cancer treatment and treatment’s adverse effects may be reflected in one’s consumer credit ratings; however, credit’s contribution to individual health for cancer survivors or those managing long-term adverse effects of cancer treatment has not been evaluated. This analysis examined associations between self-rated health outcomes of women with a history of breast cancer, type of cancer treatment, and presence of breast cancer-related lymphedema, a persistent adverse effect of treatment, and consumer credit rating. Methods: From May to September 2015, 129 women from Pennsylvania and New Jersey were enrolled in the PAL Social and Economic Quality of Life cross-sectional study. All participants had a history of breast cancer, and completed a survey of: demographics, SEP, co-morbidities, SF-12 self-rated health, psychosocial stress, adjuvant cancer treatments (chemotherapy, hormone therapy, radiation), breast cancer-related lymphedema symptoms, and credit quality (5-point scale self-reported as poor to excellent). Multivariable linear regression measured the association between credit and health. Results: Mean respondent age was 64, with 38.2% reporting excellent and 37.4% reporting very good/good credit. Participants completed cancer treatment on average 11.5 years ago. After adjusting for demographics and SEP, good credit was associated with a 4.5 (p=0.009) point increase in composite physical health t-score and -1.13 (p=0.02) decrease in psychosocial stress compared to women with poor credit, but was not associated with type of cancer treatment or lymphedema. Conclusion: While credit was associated with self-rated health for women with an average 11.5 year history of breast cancer, current credit quality did not appear to be associated with type of cancer treatment previously received or with the presence of lymphedema, a persistent adverse effect of cancer treatment. It is still possible that cancer treatment may have influenced credit close to time of treatment, and credit was able to rebound since that time. Future work should test causal pathways between credit and health outcomes after cancer diagnosis. Citation Format: Lorraine T. Dean, Kathryn H. Schmitz, Kevin Frick, Lauren Nicholas, Yuehan Zhang, SV Subramanian, Kala Visvanathan. Consumer credit, cancer treatment, and health among women with a history of 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 4217. doi:10.1158/1538-7445.AM2017-4217