Emerging molecularly targeted therapies in castration refractory prostate cancer.

Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.

Outcomes in 144 patients with colorectal cancer treated in a phase I clinic: the MD Anderson Cancer Center experience.

BACKGROUND: Patients with advanced colorectal cancer have a poor prognosis once standard therapies fail. This retrospective study presents the characteristics and outcomes in 144 patients treated in phase I clinical trials. METHODS: We retrospectively reviewed the clinical outcomes in 144 consecutive patients with colorectal cancer referred to the phase I clinic at MD Anderson. RESULTS: Median age was 60 years (range, 35-86 years). The median number of previous systemic therapies was 4 (range, 1-7). The median PFS with the last line of conventional systemic treatment was 12.3 weeks (95% confidence interval [CI], 11.0-14.4); the median PFS of the best phase I treatment was shorter at 8.1 weeks (95% CI, 7.9-8.7 weeks; log-rank test, P < .0001). In the multivariate analysis that included the RMH score, sex (male vs. female, P = .02; hazard ratio [HR], 1.57), hemoglobin (< 10.5 vs. ≥ 10.5 g/dL; P = .03; HR 1.79), and the RMH score (2-3 vs. 0-1; P < .003; HR, 1.85) were significant predictors of poor survival. CONCLUSION: The PFS of patients with colorectal cancer in phase I treatment was shorter than it was on their last line of conventional systemic treatment. Multivariate analysis confirmed the value of the RMH score for predicting overall survival in patients with colorectal cancer enrolled in phase I studies.