tbuckley/cabot-search huggingface dataset:
Abstract 2068: Development of a rational triple combination therapy for castration-resistant prostate cancer
Authors: Yuanyuan Qiao, Todd M. Morgan, Arul M. Chinnaiyan
Journal: Cancer Research (2017)

Abstract Background The androgen receptor (AR) signaling pathway drives prostate cancer development and progression, making it a major target for drug development. However, resistance to AR targeted therapies invariably develops and eventually leads to an aggressive, castrate-resistant prostate cancer (CRPC). Although CRPC often remains dependent on AR signaling, anti-androgen therapies can lead to the development of AR independent disease and metastatic CRPC. Understanding the molecular basis of this transition and resistance to current anti-androgen therapy will provide important insight and reveal novel therapeutic strategies for both AR-positive and -negative disease pathways. Methods and Results We analyzed in silico data of AR (signaling)-positive or -negative human CRPC tissue samples and discovered that MET expression is specifically increased only in AR-negative CRPC samples. When AR-positive CRPC models are subjected to AR signaling inhibition (by the AR antagonist enzalutamide or androgen deprivation), MET is increased and susceptible to activation by its ligand HGF. Therefore, we postulate that dual targeting of AR and MET signaling pathways may be a better approach to prevent and overcome resistance-related disease progression. Our preliminary AR ChIP-seq data suggested that MET transcription is not affected by AR directly rather, MET protein is modulated by AR signaling at the post-translational level. Therefore, we hypothesize that a combination therapy of a proteasome inhibitor and MET inhibitor may have potential therapeutic benefit for some CRPC patients. By using in vitro and in vivo models of AR-dependent CRPC, we have showed that combination of the dual MET/VEGFR2 inhibitor cabozantinib and enzalutamide treatment is more efficacious than either inhibitor alone. In addition, Bortezomib, an FDA-approved proteasome inhibitor, showed significant synergistic effect when paired with cabozantinib in our preliminary data using in vitro and in vivo CRPC models. In vitro results suggest that triple combination of anti-androgen, MET inhibitor and proteasome inhibitor therapies will maximize inhibition in CRPC. Conclusion MET is a compensatory survival pathway in AR+ CRPC upon anti-androgen therapy. The rational for triple combination of anti-androgen, MET inhibitor and proteasome inhibitor therapies is a feasible approach to maximize inhibition in CRPC while minimizing development of drug resistance to any single agent. Citation Format: Yuanyuan Qiao, Todd M. Morgan, Arul M. Chinnaiyan. Development of a rational triple combination therapy for castration-resistant prostate 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 2068. doi:10.1158/1538-7445.AM2017-2068
Adipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression
Authors: Francesca Reggiani, Valentina Labanca, Patrizia Mancuso, Cristina Rabascio, Giovanna Talarico, Stefania Orecchioni, Andrea Manconi, Francesco Bertolini
Journal: Cancer Research (2017)

A cell population with progenitor-like phenotype (CD45-CD34+) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer-derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in in vitro and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer. Cancer Res; 77(18); 5169-82. ©2017 AACR.
Hyperkalemia With Cardiac Arrhythmia
Authors: Vicente Yap
Journal: JAMA (1976)

In two patients, severe hyperkalemia and serious cardiac arrhythmia developed after excessive use of potassium-containing salt substitutes. Both had impaired ability to handle and excrete additional potassium load due to chronic congestive heart failure, azotemia, and administration of spironolactone. Prompt recognition of the arrhythmia and immediate restoration of the cardiac rate and rhythm by pacemaker support followed by intensive regimen to lower the serum potassium prevented a potentially fatal outcome. These cases emphasize the potential danger of salt substitutes when used by patients who are predisposed to retain potassium. (<i>JAMA</i>236:2775-2776, 1976)
Abstract 1793: Telomere length and mitochondrial DNA copy number variations as predictors for survival in hepatocellular carcinoma patients treated with sorafenib
Authors: Dong Yan
Journal: Cancer Research (2017)

Abstract Background: The study aims to evaluate the potential predictive value of relative telomere length (RTL) and mitochondrial DNA (mtDNA) copy number variations for survival in hepatocellular carcinoma (HCC) patients treated with sorafenib. Methods: The study was conducted in 120 patients with pathologically or radiologically confirmed HCC who were treated with sorafenib as their first-line or second-line monotherapy. RTL and mtDNA copy number in peripheral lymphocytes were measured using quantitative real-time polymerase chain reaction (PCR)-based method. ANOVA and non-parametric tests were applied to compare the RTL and mtDNA copy number between groups. Progression-free survival (PFS) and overall survival (OS) time was analyzed using Kaplan Meier plot, log-rank test, and Cox proportional hazards regression model. Results: A longer telomere was observed in patients with early stage disease or normal body weight and in Hispanics compared to their counterparts. Patients with longer RTL compared to those with shorter RTL had significantly better PFS (6.90 vs 4.40 months, P=0.048) and OS (16.53 vs 7.72 months, P=0.006). Cox regression analysis demonstrated that longer RTL was an independent predictor for OS (hazard ratio [HR]=0.47, 95% confidence interval [CI]=0.29-0.76, P&amp;lt;0.01) in all patients and for PFS in patients received sorafenib (HR=0.37, 95% CI=0.15-0.94, P=0.01) after adjusting for other clinical predictors. RTL was positively correlated to mtDNA copy numbers (r=0.312, P=0.001), but no significant association of mtDNA copy numbers and PFS or OS was observed. Conclusion: RTL, but not mtDNA copy number, might be a potential predictor for OS and for response to sorafenib treatment in HCC. Note: This abstract was not presented at the meeting. Citation Format: Dong Yan. Telomere length and mitochondrial DNA copy number variations as predictors for survival in hepatocellular carcinoma patients treated with sorafenib [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 1793. doi:10.1158/1538-7445.AM2017-1793
Abstract 700: Characterization of the mode of action of Fenretinide treatment in alveolar rhabdomyosarcoma cells
Authors: Eva Brack, Marco Wachtel, Beat W. Schaefer
Journal: Cancer Research (2017)

Abstract Alveolar rhabdomyosarcoma (aRMS) is a highly malicious childhood malignancy characterized by a specific chromosomal translocation encoding the oncogenic transcription factor PAX3-FOXO1. As aRMS cells are addicted to the tumor-specific fusion protein, it may serve as an ideal therapeutic target. Previously, we have identified from a large drug library screen the compound Fenretinide (retinoic acid p-hydroxyanilide), which is already in clinical use, to affect both PAX3-FOXO1 expression as well as aRMS cell viability. The aim of this study was therefore to characterize the mode of action of Fenretinide in more detail. First, we were able to show that Fenretinide induced the generation of reactive oxygen species (ROS) in mitochondria. A more detailed characterization revealed that the Fenretinide-induced ROS derived from an interaction of Fenretinide around complex II of the mitochondrial respiratory chain, leading to the production of superoxides. ROS scavenging as well as complexing of iron ions completely abolished cell death. To identify the mode of cell death involved, we then used a range of pharmacological inhibitors of specific cell death pathways including Z-vad (pan -caspase inhibitor), Necrostatin-1 (necroptosis pathway inhibitor (RIP-1 kinase inhibitor)), 3-Methyadenine (3-MA) (autophagy pathway inhibitor (phosphatidylinositol 3-kinase inhibitor)) and Ferrostatin (ferroptosis pathway inhibitor) during Fenretinide treatment. Surprisingly, none of these inhibitors alone was able to prevent cell death and even different combinations were not sufficient to completely inhibit cell death. CRISPR/Cas9 mediated depletion of key players in the apoptotic and necroptotic pathway (Bak, Bax and RIPK1) confirmed the pharmacological data. We therefore conclude that other, less characterized cell death pathways or a combination of several pathways including apoptosis and necroptosis might be crucial. Interestingly, electron microscopic examination of cells pointed towards an excessive accumulation of vacuoles to be characteristic. Taken together, our data show that Fenretinide shows high potential for the treatment of aRMS, inducing several forms of cell death mediated through the production of ROS. These properties open the search for additional compounds acting in a combinatorial manner. Citation Format: Eva Brack, Marco Wachtel, Beat W. Schaefer. Characterization of the mode of action of Fenretinide treatment in alveolar rhabdomyosarcoma 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 700. doi:10.1158/1538-7445.AM2017-700
Abstract 3670: Treatment of epithelial ovarian cancer with folate receptor (α/β) targeted chemotherapy is enhanced by CTLA-4 blockade: Learning from animal models
Authors: Yingjuan Lu, Theresa P. Johnson, Leroy W. Wheeler, Alex M. Lloyd, Vicky A. Cross, Elaine M. Westrick, Nikki L. Parker, Christopher P. Leamon
Journal: Cancer Research (2017)

Abstract Epithelial ovarian cancer (EOC) remains to be the most lethal form of gynecologic malignancies despite aggressive cytoreductive surgery (i.e. debulking) followed by standard chemotherapy. The alpha folate receptor (FRα) has long been recognized as a tumor target for EOC due to its frequently intense overexpression (&amp;gt;80%) in the most common serous histotype. Recently, the beta folate receptor (FRβ) has been discovered on tumor-associated macrophages (TAMs) which are present at various densities in solid tumors but are also found abundant in malignant ascites of EOC patients. The ascites TAMs are strongly immunosuppressive, and high TAM frequency is correlated with poor patient prognosis and treatment resistance. Respectively, tumor- and TAM-associated FRα and FRβ are both functionally active which allows for folate-targeted delivery of small-molecule drug payloads via receptor-mediated endocytosis. Using flow cytometry, we characterized total ascites cells harvested from human IGROV1 xenograft (hFRα) and murine ID8-CL15 syngeneic (mFRα) models at the time of euthanasia. Approximately 70% of IGROV1 and 25% of ID8-Cl15 ascites TAMs (F4/80+ CD11b+) were found to express a functional mFRβ. While ascites fluids from both models caused a dramatic reduction of FRα functionality on tumor cells in-vivo and ex-vivo, FRβ expression and functionality on ascites TAMs were largely unaffected. Interestingly, in the ID8-CL15 model, the ratio of ascites CD8+ T cells to CD4+ T cells decreased as total FR functionality on TAMs increased. Two small-molecule folate-drug conjugates with different mechanisms of action showed activity in extending the survival of tumor-bearing animals. While CTLA-4 blockage alone was completely inactive in the ID8-CL15 model, a combination regimen significantly enhanced the activity of a folate conjugate carrying a potent DNA cross-linking agent. Our data suggest that EOC treatment may require a multi-pronged approach by targeting both FRα-expressing tumor cells and FRβ-expressing TAMs. In addition, immune checkpoint inhibitors may further enhance the FR-targeted therapeutics by modulating the ascites tumor microenvironment. Citation Format: Yingjuan Lu, Theresa P. Johnson, Leroy W. Wheeler, Alex M. Lloyd, Vicky A. Cross, Elaine M. Westrick, Nikki L. Parker, Christopher P. Leamon. Treatment of epithelial ovarian cancer with folate receptor (α/β) targeted chemotherapy is enhanced by CTLA-4 blockade: Learning from animal models [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 3670. doi:10.1158/1538-7445.AM2017-3670
Abstract 3811: Defining the relevant genome in solid tumors
Authors: Habib R. Hamidi, Santoshi Bandla, Nick Khazanov, Paul William, Nikki Bonevich, Chris Zurenko, Sarah Anstead, Chris Taylor, Reuban Richmonds, David Galimberti, Ken Kopp, Dinesh Cyanam, Michael Hogan, Vinay Mittal, Seth Sadis
Journal: Cancer Research (2017)

Abstract Decades of cancer research including comprehensive molecular profiling combined with the development of a broad array of targeted therapies have created the opportunity to transform cancer care by implementing precision oncology based approaches. An important element of this system is the widespread availability of robust and cost-effective multi-variate profiling methods to characterize relevant cancer associated molecular alterations in the future. Current commercially available multi-variate profiling methods vary dramatically with regard to the number of cancer genes that are interrogated. Given that many large scale and detailed molecular profiling studies have been completed, the landscape of somatic alterations in solid tumors is reasonably well-known. Furthermore, the specific gene variants that are relevant to application of targeted therapies are also a matter of record. Therefore, we set out to define the number of relevant cancer genes for precision oncology research based on the currently available empirical evidence. To define recurrent somatic alterations in solid tumors, we created a compendium of variant calls from &amp;gt; 15,000 exomes, defined focal amplifications and deletions from &amp;gt; 30,000 arrays, and defined recurrent fusions from several thousand RNAseq profiles. Statistical approaches were implemented to define genes containing recurrent missense mutations (i.e., hotspots), enriched in truncating mutations or subject to recurrent copy number gain/loss or translocation. This gene set was then used to comprehensively search approved cancer drug labels, clinical practice guidelines, and clinical trials to identify records containing published evidence that specific recurrent somatic gene variants were used as part of the indication statement of an approved targeted therapy, were recommended for testing as part of clinical practice for therapeutic decisions, or were used as enrollment criteria in clinical trials. The relevant cancer genome thus defined consists of &amp;lt; 100 genes. These results suggest that targeted multi-variate profiling approaches may be sufficient to support precision oncology goals in the future. Citation Format: Habib R. Hamidi, Santoshi Bandla, Nick Khazanov, Paul William, Nikki Bonevich, Chris Zurenko, Sarah Anstead, Chris Taylor, Reuban Richmonds, David Galimberti, Ken Kopp, Dinesh Cyanam, Michael Hogan, Vinay Mittal, Seth Sadis. Defining the relevant genome in solid tumors [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 3811. doi:10.1158/1538-7445.AM2017-3811
Abstract 2411: The role of A-to-I RNA editing in human cancer
Authors: Han Liang
Journal: Cancer Research (2017)

Abstract Recent studies show that A-to-I RNA editing introduces a large number of specific nucleotide changes in cancer transcriptomes. Using the genomic/transcriptomic data from The Cancer Genome Atlas, we systematically characterized the landscape of RNA editing in a variety of cancer types and revealed many sites with clinically relevant patterns. We further integrated proteomic data from the Clinical Proteomic Tumor Analysis Consortium and found that mutations and RNA editing introduced similar numbers of amino acids changes per tumor sample in breast and ovarian cancers. The amino acid changes engendered by these RNA editing events may significantly alter protein stability. Some of the identified RNA editing events show critical consequent changes driving tumor growth and altering therapeutic activity. We also identified the RNA editing hotspots in miRNAs across cancer types, and some of RNA editing events modify the miRNA target genes. They could function as potential therapeutic targets and therapeutics. Our study suggests a large contribution of A-to-I RNA editing to protein diversity and gene regulation, and highlights its translational potential as both biomarkers and therapeutic targets. Citation Format: Han Liang. The role of A-to-I RNA editing in human 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 2411. doi:10.1158/1538-7445.AM2017-2411
Abstract 4155: Crosstalk of SOX2 and epithelial-to-mesenchymal transition on EGFR-TKI resistance
Authors: An-Chun Lee, Yu-Fan Chiu, Ming-Han Kuo, Yuan-Hung Wang, Yu-Ting Chou
Journal: Cancer Research (2017)

Abstract EGFR-tyrosine kinase inhibitors (TKIs) have been shown to produce profound therapeutic responses in lung adenocarcinoma harboring EGFR mutations. Despite this initial response, patients with EGFR-mutated lung adenocarcinoma ultimately developed resistance to EGFR-TKIs. Although both SOX2 and epithelial-to-mesenchymal (EMT) have been linked to the EGFR-TKI resistance in lung adenocarcinoma, the interplay between SOX2 and EMT in EGFR-TKI resistance is not known. Here, we report that cancer plasticity switched by SOX2 and EMT regulates EGFR-TKI resistance. We found that the selection of EGFR-TKI resistant cells induced EMT while attenuating SOX2 expression. We observed that EGFR-TKI treatment induced SOX2 expression in EGFR-mutated lung cancer cells, and SOX2 silencing encouraged EGFR-TKI resistance. Preselection of EGFR-mutated lung cancer cells with the EMT feature endowed cells with EGFR-TKI resistance but suppressed SOX2 expression. We found that TGF-β induced EMT but attenuated SOX2 expression, resulting in increased EGFR-TKI resistance. Pharmacological inhibition of HDACs in EGFR-mutated cells attenuated SOX2 expression but induced EMT, causing increased EGFR-TKI resistance. Enriching SOX2 expression in EGFR-mutated cells attenuated EMT and rendered cells more sensitive to EGFR-TKIs. Correlation analysis exhibited negative correlations between SOX2 and EMT markers in primary non-small cell lung cancer. Kaplan-Meier analysis revealed that a SOX2 low/Vimentin high signature predicted a poor survival in EGFR-mutated lung adenocarcinoma. Our findings support the notion that the cancer plasticity regulated by SOX2 and EMT plays a critical role in EGFR-TKI resistance, and SOX2 and Vimentin can function as prognostic biomarkers in lung cancer progression. Citation Format: An-Chun Lee, Yu-Fan Chiu, Ming-Han Kuo, Yuan-Hung Wang, Yu-Ting Chou. Crosstalk of SOX2 and epithelial-to-mesenchymal transition on EGFR-TKI 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 4155. doi:10.1158/1538-7445.AM2017-4155