| Popis: |
In this proposal, we aim to test the hypothesis that complete AR pathway inhibition selects for subpopulations of tumor cells that are completely independent of AR signaling and further, that these resistant cells will have activated---and be dependent upon---a limited set of specific survival and growth regulatory pathways (stemming from genomic alterations in specific oncogene networks) that can be identified and targeted. We propose three aims to test our hypotheses. Aim 1 will define the genomic alterations and transcript variants that comprise states of ARIPC. Aim 2 will determine if targeting/inhibiting the survival pathway(s) that emerge following AR pathway ablation will restrain tumor growth. Aim 3 will determine if simultaneously co-targeting the AR pathway and ARIPC survival pathway(s) in AR-sensitive prostate cancers will augment tumor responses and delay/prevent recurrences. During this funding period we have: (i) completed laser capture microdissection of CRPC prostate cancers to acquire RNA and DNA; (ii) completed transcript profiling for 150 CRPC metastasis; (iii) completed genomic analyses for 150 prostate cancer metastasis; (iv) identified a program of AR-repressed genes that may influence the development of CRPC; (v) initiated preclinical studies of two putative AR-bypass pathways. Initiated an integrated molecular analyses of advanced metastatic CPRC to identify additional molecular pathways that operate to promote prostate cancer growth in the absence of AR siganling. |
