Our proposal is focused on improving treatment options for men with advanced prostate cancer through investigative research. We have been developed a novel experimental paradigm, which combines preclinical analyses in genetically-engineered mouse (GEM) models of castration-resistant prostate cancer with sophisticated cross-species computational analyses to identify master regulators of drug response. We will apply this strategy to study Abiraterone, which is an inhibitor of androgen biosynthesis that has been shown to improve survival of men with advanced prostate cancer. However, although Abiraterone has shown promising results in clinical trials, not all patients respond to Abiraterone and most of those who do respond initially eventually fail treatment. Therefore, there is a critica need to pursue preclinical investigations to understand the mechanisms of action of Abiraterone in specific tumor contexts, and to define biomarkers predictive of response and resistance. Toward this end, our studies will focus on the following critical questions:
(Aim 1) : In which tumor contexts is Abiraterone responsive? We will perform preclinical studies using our GEM models, with the goal of identifying responsive and non-responsive tumors. Using gene expression signatures from these responsive and non-responsive tumors, we will perform cross-species computational analyses to identify master regulators that predict response to Abiraterone. Candidate master regulators will be validated to human prostate cancer, as well as to assess their functional relevance for response to Abiraterone in vivo. The goal of these studies is to elucidate mechanisms of Abiraterone response and biomarkers that predict its efficacy.
(Aim 2) : Can the efficacy of Abiraterone be improved by co-targeting with anti-androgens? We will perform preclinical studies in GEM models to evaluate the efficacy of Abireratone in combination with the anti-androgen, MDV3100. Using molecular signatures from mice treated with the individual versus combinatorial agents, we will identify master regulators that inform on the mechanisms of the drug interaction and as biomarkers of multi-drug response. Candidate master regulators will be validated to human prostate cancer, as well as in functional studies to asses their efficacy for drug action in vivo. The goal of these studies is to inform on mechanisms underlying the interaction of Abiraterone and anti-androgens, and to identify biomarkers of multi-drug response.
(Aim 3) : Why does treatment with Abiraterone fail? Considering mechanisms of intrinsic versus acquired resistance, we will establish GEM models that are resistant to Abiraterone treatment. Using molecular signatures from mice prior to or immediately following Abiraterone treatment or following tumor recurrence, we will identify master regulators of drug resistance. These will be validated to human prostate cancer, and to assess their ability to affect resistance to drug treatment. The goal of these studies is to eludicate mechanisms of Abiraterone resistance, and to identify biomarkers of resistance.
Among the new treatments now available for advanced prostate cancer, Abiraterone is an inhibitor of androgen biosynthesis that has been shown to improve survival. However, not all men with advanced prostate cancer respond to Abiraterone and even those who initially respond eventually fail treatment. Our studies will identify tumor contexts that are responsive to Abiraterone, as well as mechanisms of drug resistance and, therefore, will have direct translational relevance for men with advanced prostate cancer.
|Arriaga, Juan M; Abate-Shen, Cory (2018) Genetically Engineered Mouse Models of Prostate Cancer in the Postgenomic Era. Cold Spring Harb Perspect Med :|
|Abate-Shen, Cory (2018) Prostate Cancer Metastasis - Fueled by Fat? N Engl J Med 378:1643-1645|
|Le Magnen, Clémentine; Shen, Michael M; Abate-Shen, Cory (2018) Lineage Plasticity in Cancer Progression and Treatment. Annu Rev Cancer Biol 2:271-289|
|Dutta, Aditya; Panja, Sukanya; Virk, Renu K et al. (2017) Co-clinical Analysis of a Genetically Engineered Mouse Model and Human Prostate Cancer Reveals Significance of NKX3.1 Expression for Response to 5?-reductase Inhibition. Eur Urol 72:499-506|
|Zou, Min; Toivanen, Roxanne; Mitrofanova, Antonina et al. (2017) Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer. Cancer Discov 7:736-749|
|Dutta, Aditya; Le Magnen, Clémentine; Mitrofanova, Antonina et al. (2016) Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352:1576-80|
|Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory (2016) Optimizing mouse models for precision cancer prevention. Nat Rev Cancer 16:187-96|
|Santanam, Urmila; Banach-Petrosky, Whitney; Abate-Shen, Cory et al. (2016) Atg7 cooperates with Pten loss to drive prostate cancer tumor growth. Genes Dev 30:399-407|
|Goodwin, Jonathan F; Kothari, Vishal; Drake, Justin M et al. (2015) DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. Cancer Cell 28:97-113|
|Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min et al. (2015) Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models. Cell Rep 12:2060-71|
Showing the most recent 10 out of 17 publications