For metastatic castration resistant prostate cancer, recent advances have led to the deployment of "second- generation" ADT (ADT2) therapies, including abiraterone acetate (AA), which targets a component of androgen biosynthesis, and enzalutamide, which targets the androgen receptor directly. Both AA and enzalutamide have demonstrated an overall survival benefit in patients with metastatic CRPC;however, most patients still develop resistance to these agents, which drives prostate cancer-associated morbidity and mortality. Several mechanisms of resistance to ADT2 have recently been identified, although the overall spectrum of resistance mechanisms to ADT2 remains incompletely characterized, as does the biological impact of these events. Moreover, the extent to which such mechanisms might generalize across ADT2 regimens or operate in specific therapeutic contexts remains unknown. Finally, subsequent treatment options for this patient population beyond the use of cytotoxic chemotherapies (e.g. taxanes) are not well defined. The goal of this proposal is to create and apply computational biology algorithms that 1) systematically interrogate genomic resistance effectors to ADT2 in clinically relevant time points, 2) integrate in vitro models of ADT2 resistance with genomic features to define biological modules germane to ADT2 resistance, and 3) model clinical resistance with genomic data to inform subsequent treatment strategies. In doing so, we aim to discover new modules for clinical ADT2 resistance, provide insight into the expansion of rational treatment approaches for ADT2-resistant patients, and create an inferential framework through which clinicians may ultimately predict those treatment strategies most likely to benefit individual patients based on tumor genomic profiles. These efforts will facilitate a focused and comprehensive assessment of ADT2 resistance in the neoadjuvant and metastatic CRPC settings, explain genetic resistance to ADT2 in prostate cancer, and define subsequent therapeutic strategies.
Emerging therapies have improved clinical outcomes for patients with metastatic prostate cancer, although most patients develop resistance to these agents and cannot be cured. Resistance mechanisms may be driven by genetic changes in the tumors of these patients, which may be targetable with other therapies. This project aims to dissect clinical resistance to these agents and determine subsequent treatment approaches for this large patient population.
|Gibson, William J; Ruan, Daniel T; Paulson, Vera A et al. (2016) Genomic heterogeneity and exceptional response to dual pathway inhibition in anaplastic thyroid cancer. Clin Cancer Res :|
|Kryukov, Gregory V; Bielski, Craig M; Samocha, Kaitlin et al. (2016) Genetic Effect of Chemotherapy Exposure in Children of Testicular Cancer Survivors. Clin Cancer Res 22:2183-9|
|Ritter, Deborah I; Roychowdhury, Sameek; Roy, Angshumoy et al. (2016) Somatic cancer variant curation and harmonization through consensus minimum variant level data. Genome Med 8:117|
|Braun, David A; Burke, Kelly P; Van Allen, Eliezer M (2016) Genomic Approaches to Understanding Response and Resistance to Immunotherapy. Clin Cancer Res 22:5642-5650|
|Garofalo, Andrea; Sholl, Lynette; Reardon, Brendan et al. (2016) The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome Med 8:79|
|Mullane, Stephanie A; Van Allen, Eliezer M (2016) Precision medicine for advanced prostate cancer. Curr Opin Urol 26:231-9|
|Beltran, Himisha; Prandi, Davide; Mosquera, Juan Miguel et al. (2016) Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 22:298-305|
|Allen, Eliezer M Van; Robinson, Dan; Morrissey, Colm et al. (2016) A comparative assessment of clinical whole exome and transcriptome profiling across sequencing centers: Implications for precision cancer medicine. Oncotarget :|
|Pritchard, Colin C; Mateo, Joaquin; Walsh, Michael F et al. (2016) Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53|
|Hsieh, Chen-Lin; Botta, Ginevra; Gao, Shuai et al. (2015) PLZF, a tumor suppressor genetically lost in metastatic castration-resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy. Cancer Res 75:1944-8|
Showing the most recent 10 out of 12 publications