Prostate cancer (CaP) is the second leading cause of cancer-related death in American men. Recent advances in the management of advanced disease with chemotherapy androgen synthesis inhibitors have begun to improve outcomes;however, many challenges remain. The etiology of CaP remains unknown. It is not clear why the prostate is so susceptible to oncogenesis and why its formation is associated with chronic infection. The contribution of epigenetic alteration in CaP development also remains poorly defined. Why do malignant cancers develop without clear signs of chromosomal level changes? Finally, how do tumors become resistant to the newest forms of chemotherapy and androgen inhibition? This """"""""Collaborative Research in Tumor Microenvironment"""""""" UOl application is built upon the long term collaboration between Drs. Wu and Witte, and more recent studies involving the Nelson laboratory, and the synergies between the UCLA CaP Challenge Award, entitled """"""""Defining targets and biomarkers in CaP stem cells: New therapeutic opportunities"""""""" (2008-2011) and Fred Hutchinson Cancer Research Center/University of Washington TMEN U54 program, """"""""Significance of microenvironment for CaP initiation and progression (2007-2012). Building upon these efforts, we will now jointly address the critical questions involving """"""""Influences of microenvironment on cancer stem cells"""""""". Specifically, we focus on the role ofthe tumor microenvironment in controlling proliferation and transformation of normal prostate stem cells and on the role of the tumor microenvironment in causing CaP stem cells to develop resistance to current therapies. The first question, studied in Aim 1, has significant implications for cancer prevention, since strategies to reduce inflammation and infection could inhibit entry of normal stem cells into the cell cycle.
This Aim will also shed light on the mechanisms through which immune tolerance is established and how to sensitize CaPs to immune therapies. The second question, studied in Aim 2, has implications for expanding our understanding ofthe """"""""landscape"""""""" of cancer stem cells and shifts our therapeutic strategy from cancer cell and gene-based target to pathway oriented approaches.
Our Specific Aim 3 is designed to address the final question how cancer therapies can change the """"""""benign cellular constituents"""""""" associated with neoplastic cells and causes CSC expansion and tumor repopulation.
Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer remain unsolved. A central focus of this application is to investigate whether cells, molecule and regulatory pathways surrounding the prostate stem cells can alter stem cell properties and contribute to prostate cancer development and resistance to therapies. This will help in understanding the origin of the disease and provide rationales for novel, stem cell-targeted treatment.
|Zou, Yongkang; Qi, Zhi; Guo, Weilong et al. (2018) Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3K?/?/? Inhibitor BAY1082439. Mol Cancer Ther 17:2091-2099|
|Shenoy, T R; Boysen, G; Wang, M Y et al. (2017) CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair. Ann Oncol 28:1495-1507|
|Gomez-Sarosi, Luis; Sun, Yu; Coleman, Ilsa et al. (2017) DNA Damage Induces a Secretory Program in the Quiescent TME that Fosters Adverse Cancer Phenotypes. Mol Cancer Res 15:842-851|
|Park, Jung Wook; Lee, John K; Witte, Owen N et al. (2017) FOXA2 is a sensitive and specific marker for small cell neuroendocrine carcinoma of the prostate. Mod Pathol 30:1262-1272|
|Bianchi-Frias, Daniella; Basom, Ryan; Delrow, Jeffrey J et al. (2016) Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations. Mol Cancer Res 14:374-84|
|Lee, John K; Phillips, John W; Smith, Bryan A et al. (2016) N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. Cancer Cell 29:536-547|
|Ruscetti, M; Dadashian, E L; Guo, W et al. (2016) HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35:3781-95|
|Park, Jung Wook; Lee, John K; Phillips, John W et al. (2016) Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay. Proc Natl Acad Sci U S A 113:4482-7|
|Huber, Roland M; Lucas, Jared M; Gomez-Sarosi, Luis A et al. (2015) DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance. Oncotarget 6:2134-47|
|Ruscetti, Marcus; Quach, Bill; Dadashian, Eman L et al. (2015) Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells during Prostate Cancer Metastasis. Cancer Res 75:2749-59|
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