Patient-derived tumor xenograft study with CDK4/6 inhibitor plus AKT inhibitor for management of metastatic castrate resistant prostate cancer

We applied DNA content flow cytometry to a series of prostate cancer (PC) patient derived tumor xenografts (PDTXs). We interrogated purified sorted tumor fractions from each sample with whole genome copy number variant (CNV) analyses. These identified a variety of somatic genomic lesions targeting genes and cellular pathways in PC. Of significant interest are lesions that may affect responses to therapies. Guided by the genomic alterations in these models and interrelated mechanisms between androgen signaling axis, the cell cycle, and AKT pathway, we identified and investigated the combination of CDK4/6 inhibitors with AKT inhibitors as a potential therapy for patients with mCRPC. Using 3-D spheroid drug assays followed by in vivo experiments in three unique PDTX models, these preclinical results highlight the potential use of CDK4/6 inhibitor with AKT inhibitors for the treatment of mCRPC who have intact retinoblastoma pathway, thereby, providing the experimental data support and rationale for future clinical investigation We applied DNA content based flow sorting to isolate the nuclei of clonal populations from prostate tumor patient derived tumor xenografts (PDTXs). We coupled this strategy with oligonucleotide array CGH (aCGH) thereby obtaining high definition genomic profiles of clonal populations from each tumor. Response to CDK4/6 and AKT inhibition was assesed with organoid models derived from the PDTXs.