Because prostate cancer develops under the influence of androgenic steroids, androgen deprivation therapy (ADT) has been used for the last 60 years as a standard of care for patients diagnosed with metastatic disease or disease that recurs after local treatment. Unfortunately, ADT is only effective for a brief period before patiens relapse with castration-resistant prostate cancer (CRPC) and die from their disease. Taxanes are the only chemotherapies shown to prolong survival for patients with metastatic CRPC, and both docetaxel and cabazitaxel are FDA approved for this indication. Despite the initial efficacy of taxanes in treating CRPC, patients ultimately fail due to the development of drug resistance. Resistance to taxane therapy has been attributed to several cellular mechanisms such as decreased cellular taxane accumulation, defects in apoptotic pathways by taxane induced activation of anti-stress and anti-apoptotic mechanisms that promote survival or alterations in microtubule dynamics. Based on preliminary results we have shown that ERG over-expression, which occurs in roughly 50% of prostate cancer patients, is associated with taxane resistance in pre-clinical models. However, the precise mechanism of ERG-induced taxane resistance to taxanes remains to be characterized. Understanding ERG-induced taxane resistance is essential for developing strategies to circumvent this resistance. We hypothesize that ERG plays a critical role in taxane resistance through at least two mechanisms: 1) alteration of microtubule dynamics and 2) direct regulation of anti-stress/apoptosis pathways. To test these and determine the clinical relevance of ERG as a biomarker for taxane resistance we propose the following: to demonstrate the effects of ERG expression on distinct parameters of microtubule dynamics, microtubule post-translational modifications, and effective drug-target engagement by taxanes (Aim 1);to investigate the mechanism by which ERG mediates resistance to taxanes through directly regulating gene expression related to cell survival, apoptosis and/or microtubule dynamics in the context of taxane treatment (Aim 2);and to screen pre-treated tissue samples and CTCs from a prospective cohort of men diagnosed with castration-resistant prostate cancer and that have been treated with taxanes (Aim 3). At the conclusion of this study, our findings will provide biological insight into the role ERG in taxane resistance. Data from our study will provide insight and clinical rationale for treatment decisions and for patient selection for appropriate therapies, a step towards personalized cancer care.
Taxanes such as docetaxel and cabazitaxel are the only chemotherapies shown to prolong survival for patients with metastatic castration resistant prostate cancer but despite the initial efficacy patients ultimately fail due to the development of drug resistance. Our multidisciplinary project builds on extensive and validated preliminary data showing ERG over-expression leads to resistance to taxane-based therapies however the mechanism remains unclear and this result has yet to be tested in a clinical cohort of prostate cancer patients. Data from our study will provide insight and clinical rationale for treatment decisions and for patient selection for appropriate therapies, a step towards personalized cancer care.
|Beltran, Himisha; Eng, Kenneth; Mosquera, Juan Miguel et al. (2015) Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response. JAMA Oncol 1:466-74|
|Beltran, Himisha; Tomlins, Scott; Aparicio, Ana et al. (2014) Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res 20:2846-50|
|Galletti, Giuseppe; Matov, Alexandre; Beltran, Himisha et al. (2014) ERG induces taxane resistance in castration-resistant prostate cancer. Nat Commun 5:5548|
|Salami, Simpa S; Schmidt, Folke; Laxman, Bharathi et al. (2013) Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol Oncol 31:566-71|
|Elemento, Olivier; Rubin, Mark A; Rickman, David S (2012) Oncogenic transcription factors as master regulators of chromatin topology: a new role for ERG in prostate cancer. Cell Cycle 11:3380-3|
|Rickman, David S; Soong, T David; Moss, Benjamin et al. (2012) Oncogene-mediated alterations in chromatin conformation. Proc Natl Acad Sci U S A 109:9083-8|
|Rickman, David S; Chen, Ying-Bei; Banerjee, Samprit et al. (2010) ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression. Neoplasia 12:1031-40|