Digital Commons Network^™

Erbb3-Erbb2 Complexes As A Therapeutic Target In A Subset Of Wild-Type Braf/Nras Cutaneous Melanomas., Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Amel Salhi, Nadège Gaborit, Tingting Zhan, Inna Chervoneva, Jason Roszik, Scott E. Woodman, Michael A. Davies, Yulius Y. Setiady, Iman Osman, Yosef Yarden, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 …

Rac1 P29s Regulates Pd-L1 Expression In Melanoma., Ha Linh Vu, Sheera Rosenbaum, Timothy J. Purwin, Michael A. Davies, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 …

Expression Of The Il-11 Gene In Metastatic Cells Is Supported By Runx2-Smad And Runx2-Cjun Complexes Induced By Tgfβ1., Xuhui Zhang, Hai Wu, Jason R. Dobson, Gillian Browne, Deli Hong, Jacqueline Akech, Lucia R. Languino, Gary S. Stein, Jane B. Lian

Department of Cancer Biology Faculty Papers

In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes …

Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen

Department of Cancer Biology Faculty Papers

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …

Dna-Pkcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression And Metastasis., Jonathan F Goodwin, Vishal Kothari, Justin M Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher Mcnair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver …

Paracrine Effect Of Nrg1 And Hgf Drives Resistance To Mek Inhibitors In Metastatic Uveal Melanoma., Hanyin Cheng, Mizue Terai, Ken Kageyama, Shinji Ozaki, Peter Mccue, Takami Sato, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and …

Chromatin To Clinic: The Molecular Rationale For Parp1 Inhibitor Function., Felix Y. Feng, Johann S. De Bono, Mark A. Rubin, Karen E Knudsen

Department of Cancer Biology Faculty Papers

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.

The Endogenous Cell-Fate Factor Dachshund Restrains Prostate Epithelial Cell Migration Via Repression Of Cytokine Secretion Via A Cxcl Signaling Module., Ke Chen, Kongming Wu, Xuanmao Jiao, Liping Wang, Xiaoming Ju, Min Wang, Gabriele Disante, Shaohua Xu, Qiong Wang, Kevin Li, Xin Sun, Chongwen Xu, Zhiping Li, Mathew C. Casimiro, Adam Ertel, Sankar Addya, Peter Mccue, Michael P. Lisanti, Chenguang Wang, Richard J. Davis, Graeme Mardon, Richard Pestell

Department of Cancer Biology Faculty Papers

Prostate cancer is the second leading form of cancer-related death in men. In a subset of prostate cancer patients, increased chemokine signaling IL8 and IL6 correlates with castrate-resistant prostate cancer (CRPC). IL8 and IL6 are produced by prostate epithelial cells and promote prostate cancer cell invasion; however, the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein, the cell-fate determinant factor DACH1 inhibited CRPC tumor growth in mice. Using Dach1(fl/fl)/Probasin-Cre bitransgenic mice, we show IL8 and IL6 secretion was altered by approximately 1,000-fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to …

Novel Actions Of Next-Generation Taxanes Benefit Advanced Stages Of Prostate Cancer., Renée De Leeuw, Lisa D. Berman-Booty, Matthew J. Schiewer, Stephen J Ciment, Robert Den, Adam P. Dicker, William Kelly, Edouard J. Trabulsi, Costas D. Lallas, Leonard G. Gomella, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

PURPOSE: To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.

EXPERIMENTAL DESIGN: Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro …