The standard approach for treating metastatic prostate cancer (PC) is androgen deprivation (ADT). ADT is also used to treat men relapsing after primary local therapies and, in combination with radiation, men with locally advanced disease. Although highly effective, ADT invariably fails over time. After patients fail ADT, i.e. once they develop castration resistant prostate cancer (CRPC), therapeutic options are limited. Chemotherapy has provided limited benefit in metastatic CRPC patients, and no effective second-line therapies exist after first line docetaxel chemotherapy. Thus, there is an urgent need to develop more effective treatments for PC. The past two decades have seen a major change in cancer treatment paradigms. Anti-cancer agents are no longer being developed based on empiricism, but are now being aimed to inhibit validated targets that are relatively specific for tumor cells. In PC, however, there is a paucity of novel, targeted drugs;in fact, other than anti- androgens, targeted therapies are essentially non-existent in this disease. Pre-clinical models suggest that androgen-sensitive (AS) and androgen-independent (AI) PC cells may be present from the very outset and/or AI cancer cells are selected from AS cells during the course of ADT. Since ADT targets AS cancer cells, it is destined to fail. Thus, for optimal disease control, both AS and AI cells need to be targeted effectively. Under the auspices of the ongoing Merit Review Award, consistent with our original hypothesis, we have determined that sequential treatment of docetaxel followed by ADT provides the best outcomes in xenograft models bearing androgen-sensitive PC cells. However, even the most optimal chemohormone treatments fail over time in this model, suggesting that other targets need to be integrated with chemohormone therapy to enhance outcomes. Other studies in our laboratory with the transgenic TRAMP model have evaluated the effects of ADT and docetaxel with respect to anti-tumor activity and neuroendocrine differentiation. In addition, our initial in vitro studies demonstrate recruitment of ERK- and/or Akt-dependent pathways in PC cells under certain conditions of androgen deprivation and taxane exposure. Finally, angiogenesis appears to be activated soon after ADT in LNCaP xenografts. Taken together, these studies provide additional potential targets for therapeutic intervention.
Our aim i n the renewal application is to build on this work and study systematically the mechanisms underlying the recruitment of ERK- and Akt-dependent pathways under conditions of ADT, androgen resistance, docetaxel treatment and docetaxel resistance in human PC cells in vitro, and to evaluate the effects of specific inhibitors of these pathways as single agents and in certain combinations with ADT and docetaxel. We will extend this work to in vivo xenograft models, with the goal to optimize anti-tumor activity, particularly of the sequential chemohormone therapy backbone. We believe a strength of this proposal is that it has direct clinical relevance, which is underscored by the fact that our previous pre-clinical studies have been successfully translated to two clinical trials in men with hormone sensitive recurrent PC.
Proec arrtv: Theleding cncerinmenintheU.S.isprosaecncer. I isalsoaledingcncerin ouragingVeern popultion.Todte,therearenocurtietretmensforadancedsages ofprosae cncer,including recurrentandmeasatic disease.Alhoughhormonetherapyandchemotherpy cnpalliteprosttecancer, heyaregenerallyno curtie.Thisproposalwillanalyesysemticallyhowtoimproethetretmen of prosae cancerbytrgetingadditional pthwaysactiaed inthisdiseaseinspecficcombnations wth chmothrpyand hormon thrpy.Both cll cultur ndmous modelswillb usd.Ths studieswill providenoelinformtiononhowtodeelopmoreeffecietretmen regimens forprosaecancer.Thus,t proposlishighlyrelean tothehealhcremission oftheDeprmen ofVeernsAffairsas wellasthe helhcr of the generlpopultion.
|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|
|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|
|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 :|
Showing the most recent 10 out of 11 publications