An example of this approach is my laboratory's work with AZD6244, a MEK inhibitor. My laboratory demonstrated the therapeutic potential of MEK inhibition as a radiation sensitizer in several cancers both in vitro and in vivo,(12) evaluated the impact of concurrent chemotherapy on the radiosensitizing effect of MEK inhibition,(13) identified biomarkers that may predict efficacy of this approach, and highlighted the mechanisms of radiation sensitization when this pathway is targeted.(12-14) This work culminated in the initiation of a CTEP sponsored Phase I trial at the NCI investigating MEK inhibition combined with the current standard chemoradiotherapy in the neoadjuvant setting in patients with locally advanced rectal cancer. There are currently three open and two completed Phase I clinical trials evaluating MEK inhibition combined with radiation and chemotherapy for the treatment of localized cancers. We have recently identified additional compounds that show preliminary efficacy in vitro as radiation sensitizers. The approach we have used in the past to select agents for study has been effective in identifying radiation sensitizers. However, this approach is evolving as we collect tumor tissue and clinical outcomes data from prostate cancer patients on my protocol, 13-C-0119. This clinical trial will allow us to evaluate multiple biologic, clinical, and radiographic predictors of local failure in patients treated with radiotherapy for localized prostate cancer. Patients enrolled in this study undergo a pretreatment multiparametric MRI and MRI-guided research biopsy of all tumors within their prostate. Following radiation therapy, patients with a rising PSA who meet biochemical failure criteria undergo repeat multiparametric MRI of the prostate and repeat MRI-guided research biopsy of persistent tumor. Tumor is processed simultaneously for DNA and RNA, with matched specimens collected for diagnostic purposes. Planned analyses include whole exome sequencing in tumor to compare to somatic DNA, copy number analysis, and microarray in tumor to evaluate for predictors of failure and to study tumor evolution after radiation. Data from the tissue studies described above will be mined to generate a list of candidate pathway responsible for radiation resistance in prostate cancer. These data will inform laboratory studies aimed at determining the importance of these pathways in radiation response and the effects of inhibiting these pathways. It is anticipated that a number of candidate mutations and pathways will be identified. Priority will be given to those that are novel in the context of prostate cancer and radiation response, and those with available agents for targeting.
