The lethality of prostate cancer (PCa) is attributable to the metastatic castration resistant state (CRPC). Accordingly, an understanding of the biochemical and genetic alterations that drive metastasis and castration resistance offers the potential and promise of identifying molecular targets for therapeutic intervention. During the current SPORE funding period, we have made significant advances in the elucidation of key signaling pathways that mediate castration resistance and metastasis. To investigate the molecular underpinnings of metastasis in Aim 1 of our proposal, we will use our recently developed mouse model in which the PI3K/AKT and Ras/MAPK pathways are simultaneously altered, as seen in humans, in a prostate-specific fashion. The double mutants spontaneously develop metastases, which are absent in mice with single pathway alterations. Thus, these mouse models will allow us to establish the role of interactions between the PISK/AKT and Ras/MAPK pathways in the development of metastasis as well as castration resistance and screen for therapeutic agents that can prevent or delay metastatic progression. Our recent studies also identified a novel mechanism of PI3K/AKT activation in response to androgen deprivation therapy, which leads to castration resistant growth. Conversely, PISK inhibition results in enhanced AR transcriptional output. Thus, the compensatory activation of one of these pathways in response to inhibition of the other represents a "built-in" mechanism of resistance to therapies aimed at targeting either one of these pathways in isolation and suggests that simultaneous inhibition of both the PISK/AKT and AR pathways is necessary to achieve maximal anti-tumor effects and avert castration resistance. Based on this finding, a three-arn phase 2 randomized neoadjuvant pre-prostactomy trial is designed (Aim 2) to target the PISK/AKT and AR pathways alone or in combination and study the downstream signaling and transcriptional output. Associated with this trial, we will also test non-invasive imaging technologies for monitoring pathway alterations and target responses. The success of our proposed research will provide vital insight into and identify therapies for metastasis and castration resistance, two processes that render PCa lethal.
PCa mortality is invariably associated with the development of metastases and resistance to castration. We have designed experiments in mice and a clinical trial in patients to elucidate the crucial biochemical signals that promote the metastatic and castration resistant states. We will not only gain a better understanding of these lethal processes, but more importantly, identify relevant drug targets and specific drugs that can be applied to patients who suffer from deadly forms of PCa.
|Chen, Changhao; Cai, Qingqing; He, Wang et al. (2016) An NKX3.1 binding site polymorphism in the l-plastin promoter leads to differential gene expression in human prostate cancer. Int J Cancer 138:74-86|
|Yan, Yunwen; Li, Zhen; Xu, Xiang et al. (2016) All-trans retinoic acids induce differentiation and sensitize a radioresistant breast cancer cells to chemotherapy. BMC Complement Altern Med 16:113|
|Hurley, Paula J; Sundi, Debasish; Shinder, Brian et al. (2016) Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer. Clin Cancer Res 22:448-58|
|Faltermeier, Claire M; Drake, Justin M; Clark, Peter M et al. (2016) Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A 113:E172-81|
|Liang, Pei; Henning, Susanne M; Schokrpur, Shiruyeh et al. (2016) Effect of Dietary Omega-3 Fatty Acids on Tumor-Associated Macrophages and Prostate Cancer Progression. Prostate 76:1293-302|
|Lee, John K; Phillips, John W; Smith, Bryan A et al. (2016) N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. Cancer Cell 29:536-47|
|Wang, Piwen; Henning, Susanne M; Magyar, Clara E et al. (2016) Green tea and quercetin sensitize PC-3 xenograft prostate tumors to docetaxel chemotherapy. J Exp Clin Cancer Res 35:73|
|Hu, Yangyang; Dong, Xuecheng; Wang, Guangchun et al. (2016) Five-Year Follow-Up Study of Transurethral Plasmakinetic Resection of the Prostate for Benign Prostatic Hyperplasia. J Endourol 30:97-101|
|Park, Jung Wook; Lee, John K; Phillips, John W et al. (2016) Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay. Proc Natl Acad Sci U S A 113:4482-7|
|Stoyanova, Tanya; Riedinger, Mireille; Lin, Shu et al. (2016) Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci U S A 113:E6457-E6466|
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