The most common form of prostate cancer, adenocarcinoma, is a major healthcare problem facing Veterans. Prostate cancer is a hormonally driven disease in that it is primarily dependent on androgens for survival and propagation. Androgens provide such survival signals by interacting with androgen receptors (AR) within the prostate cancer cells. Since the testes are the primary source of androgenic steroids, the standard approach to treating advanced prostate cancer is to minimize gonadal production of androgens so as to disrupt androgen/AR signaling. Thus, androgen deprivation therapy (ADT) is the mainstay of treating metastatic disease, and in conjunction with radiation, is also an integral part of treating locally advanced/high risk prostate cancer. Although initially effective, ADT is not curative, and the majority of patients with advanced prostate cancer progress on ADT within a couple of years. Patients who fail ADT are deemed to have castration resistant prostate cancer (CRPC). Such patients may, at least initially, respond to further manipulation of the androgen/AR axis since this signaling pathway is often restored in ADT-failing patients. Hence, considerable efforts have been made to further target this pathway by developing newer generation of androgen biosynthesis and AR inhibitors. This strategy has proven to be beneficial, but again for a limited period of time. The other major treatment for advanced PC is docetaxel- based chemotherapy, which is generally used in men with progressive CRPC. Remarkably, to date, no other agent added to docetaxel has shown to provide better outcomes than single agent docetaxel, which again provides disease control for a limited period of time. Given these challenges, our goal is to use well-defined cell culture models of prostate cancer that encompass a range of disease states to study and interrogate certain ?nodes? that integrate specific components of the prostate cancer metabolome. We will target key mediators that regulate and interact with proliferative/anabolic and anti-proliferative/catabolic signals in prostate cancer cells. More specifically, we will study and define interactions between the proliferative erbB-PI3K-Akt-mediated anabolic and the anti-proliferative AMPK- mediated catabolic pathways in AR-expressing and non-AR-expressing prostate cancer cells. For these studies, we will utilize agents that are already in clinical use or in active clinical development, which will facilitate the translation of this work to the clinic if the pre-clinical studies are successful. In other studies, knock down via siRNA or shRNA of some of these key regulatory mediators will provide additional mechanistic insights into the interacting and feedback signals of the prostate cancer metabolome in treatment-sensitive and treatment-resistant prostate cancer cells. We will determine the effects of specific treatments or treatment combinations on the sensitive and resistant prostate cancer cells via metrics that assess drug-drug interactions (synergistic, additive, antagonistic), cell proliferation/growth inhibition, cell cycling and/or cell apoptosis. We will extend some of the studies to SCID-mouse based xenografts to help further define anti-tumor activity and potential treatment-related toxicities in the vivo setting. We believe these combinations of studies, taken together, will have direct clinical relevance, and may help in the development of multi-modal treatments for prostate cancer.
The leading cancer in men in the U.S. is prostate cancer. It is also a leading cancer in our aging Veteran population. To date, there are no curative treatments for advanced stages of prostate cancer, including recurrent and metastatic disease. Although hormone therapy and chemotherapy can palliate prostate cancer, they are generally not curative. This proposal will analyze systematically how to improve the treatment of prostate cancer by targeting additional pathways activated in this disease in specific combinations with or without hormone therapy. Both cell culture and mouse models will be used. These studies will provide novel information on how to develop more effective treatment regimens for prostate cancer. Thus, the proposal is highly relevant to the healthcare mission of the Department of Veterans Affairs as well as the healthcare of the general population.
|Imperial, Robin; Ahmed, Zaheer; Toor, Omer M et al. (2018) Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles. Mol Cancer 17:177|
|Toor, Omer M; Ahmed, Zaheer; Bahaj, Waled et al. (2018) Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next-Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers. Mol Cancer Ther 17:1123-1132|
|Hussain, Arif; Yong, Candice; Tkaczuk, Katherine H R et al. (2018) Prevalence and risk of skeletal complications and use of radiation therapy in elderly women diagnosed with metastatic breast cancer. PLoS One 13:e0193661|
|Kujtan, Lara; Hussain, Arif; Subramanian, Janakiraman et al. (2018) The evolving genomic landscape in urothelial cancer. Curr Opin Oncol 30:197-202|
|Onukwugha, Eberechukwu; Albarmawi, Husam; Sun, Kai et al. (2018) Physician visits and the timing of skeletal-related events among men newly diagnosed with metastatic prostate cancer: A cohort analysis. Urol Oncol 36:340.e23-340.e31|
|Fan, Lingling; Zhang, Fengbo; Xu, Songhui et al. (2018) Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells. Proc Natl Acad Sci U S A 115:E4584-E4593|
|Onukwugha, Eberechukwu; Kwok, Young; Ciezki, Jay P et al. (2017) Skeletal-related events and mortality among men diagnosed with advanced prostate cancer: The impact of alternative measures of radiation to the bone. PLoS One 12:e0175956|
|Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Kwegyir-Afful, Andrew K et al. (2017) Targeting of protein translation as a new treatment paradigm for prostate cancer. Curr Opin Oncol :|
|Imperial, Robin; Toor, Omer M; Hussain, Arif et al. (2017) Comprehensive pancancer genomic analysis reveals (RTK)-RAS-RAF-MEK as a key dysregulated pathway in cancer: Its clinical implications. Semin Cancer Biol :|
|Schardt, John S; Oubaid, Jinan M; Williams, Sonya C et al. (2017) Engineered Multivalency Enhances Affibody-Based HER3 Inhibition and Downregulation in Cancer Cells. Mol Pharm 14:1047-1056|
Showing the most recent 10 out of 11 publications