Prostate cancer (PCa) develops under the influence of androgenic steroids, which is why androgen deprivation therapy (ADT) has been used for the last 60 years as a standard of care for patients diagnosed with metastatic disease or that recur after local treatments. Unfortunately, ADT is only effective for a brief period before patients relapse and die from their disease. For these ADT-resistant patients, overall survival is only slightly improved by subsequent treatment with Docetaxel-based chemotherapy. Nevertheless, the idea has emerged from preclinical data that combined chemo-hormonal therapies could be particularly effective if administrated as early as possible in the PCa development. The rationale for it is to prevent the emergence of androgen-insensitive clones and to eradicate occult metastases in order to minimize the total metastatic tumor burden and hence maximize the possibility of cure. Clinical observations that a subset of patients respond to ADT with adjuvant taxane suggest that identifying responders could lead to important clinical and biological insight into PCa therapy. We strongly suspect that the recently described ETS rearranged PCa will respond differently to hormone-based treatment. This is based on the overwhelming data that ETS rearranged PCa, most commonly TMPRSS2-ERG, are driven by one of three 5'promoters (i.e., TMPRSS2, SLC45A3 and NDRG1). All three promoters are under tight regulation by both androgen and estrogen providing a strong rationale how these oncogenic fusion transcripts are active in states of normal testosterone (DHT) levels but can also remain active following hormone castration. Indeed, recent findings from a recent phase I/II clinical trial of the CYP17 inhibitor, abiraterone, in 89 men with castrate resistant prostate cancer confirm this by showing a clear treatment benefit in patients harboring ERG rearrangement. It is unknown if ETS fusion PCa respond differently to current taxane-based therapies than non-fusion PCa. Therefore, the overarching goal of this proposal is to determine the influence ETS fusion gene products to the response of hormonal therapy alone versus hormonal therapy and taxane-based chemotherapy and to identify other molecules that will target fusion gene products. The two specific aims are the following:
In Aim 1, we will determine the effect of tERG (or NDRG1-ERG) expression on taxane sensitivity in 6 PCa cell lines that differ in terms of androgen sensitivity or androgen receptor expression using in vitro (2-dimensional (2D) and 3D cell culture) and in vivo (xenograft) PCa models.
In Aim 2 we will use a novel small-molecule microarray platform to identify compounds that interact specifically with fusion gene protein products and that are effective in reverting the undesired oncogenic state to more nonmalignant or drug-sensitive states. At the conclusion of this study our findings will provide biological insight into the role of ETS gene rearrangement in PCa treatment response and will lead to better targeted therapeutics and management of high risk PCa patients.
Prostate cancer is a major public health problem in the United States with over 219,000 cases diagnosed and over 27,000 deaths in 2007. Androgen deprivation therapy (ADT) has been used for the last 60 years as a standard of care for men diagnosed with metastatic prostate cancer or disease that recurs after local treatment such as radical prostatectomy. Unfortunately, ADT is only effective for a brief period before patients relapse and die from their disease. Overall survival is only slightly improved by adjuvant treatment with taxane-based chemotherapy. Nevertheless, preclinical data suggests that combined chemo-hormonal therapies could be particularly effective if administrated as early as possible after the detection of high-risk prostate cancer. The rationale is to prevent the emergence of androgen-insensitive tumor cells and to eradicate occult metastases in order to minimize the total metastatic tumor burden and hence maximize the possibility of cure. We strongly suspect that the approximately 50% of prostate cancer patients who harbor a specific molecular alteration leading to the fusion of highly sensitive androgen regulated gene and a tumor producing gene will respond differently to taxane-based treatment than men without this gene fusion. These so-called ETS gene rearrangements act as an """"""""on switch"""""""" in the presence of the male hormone androgen. The successful completion of this proposal should lead to a better understanding of why men with advanced PCa fail to respond to taxane-based chemotherapies and to new therapeutic agents that are tailored to better treat these men.
|Dhingra, Priyanka; Martinez-Fundichely, Alexander; Berger, Adeline et al. (2017) Identification of novel prostate cancer drivers using RegNetDriver: a framework for integration of genetic and epigenetic alterations with tissue-specific regulatory network. Genome Biol 18:141|
|Galletti, Giuseppe; Matov, Alexandre; Beltran, Himisha et al. (2014) ERG induces taxane resistance in castration-resistant prostate cancer. Nat Commun 5:5548|