Update on cancer therapeutics最新文献

The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) have been implicated in transformation of a variety of malignancies. Chronic or dysregulated activation of the MET/HGF pathway may lead to increased cell growth, invasion, angiogenesis, and metastasis, reduced apoptosis, altered cytoskeletal functions and other biological changes. It has been suggested that ligand activated MET stimulation can be sufficient for a transforming phenotype. In addition, amplification and activation mutations (germline and/or somatic) within the tyrosine kinase domain, juxtamembrane domain, or semaphorin domain have been identified for MET. MET gain-of-function mutations lead to either deregulated or prolonged tyrosine kinase activity, which are instrumental to its transforming activity. A number of therapeutic strategies targeting ligand-dependent activation or the kinase domain have been employed to inhibit MET. The different structural requirements for activation of signaling events and biological functions regulated by MET will be summarized. Therapeutic targets and current pre-clinical and clinical approaches will be described. Targeting the HGF/MET pathway, alone or in combination with standard therapies, is likely to improve present therapies in MET-dependent malignancies.

Treatment for metastatic castration resistant prostate cancer (CRPC) represents a critical need. While docetaxel-based chemotherapy has been shown to extend life, relieve pain, and improve the quality of life expanded treatment options are necessary. No standard second line therapy exists and secondary hormonal manipulations before and after docetaxel offer marginal benefits. The increased understanding of the mechanisms of progressive castration resistant prostate cancer has translated into an increasing pipeline of novel therapies such as vaccines, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, anti-angiogenic drugs, small molecule receptor tyrosine kinase inhibitors and more specific targets of the androgen receptor. The future treatment for the most advanced prostate cancer patients is encouraging with broadened clinical benefit.

Epithelial ovarian cancer, the fourth leading cause of cancer deaths in American women, is a devastating disease. Although the combined intraperitoneal and intravenous administration of first-line chemotherapy does produce some improvement in patient outcomes in comparison with intravenous administration alone, the results of completed clinical trials suggest that a plateau has been reached in the benefits that can be achieved with cytotoxic chemotherapy alone in ovarian cancer. Epithelial ovarian cancer is currently classified by surgical and histologic criteria. However, the predictive value of this classification is limited. Moreover, the complexity of the different subtypes of ovarian cancer presents challenges to our understanding of the origin and pathogenesis of this disease. The sequential acquisition of molecular anomalies as occurs in colorectal carcinogenesis has not been described for ovarian cancer. However, increasing evidence indicates that multiple genetic and epigenetic events contribute to epithelial ovarian carcinogenesis. These events include aberrations in the expression of patterning genes, genomic instability, and resultant chromosomal changes, and may be triggered by excessive exposure of surface epithelial cells to autocrine/paracrine stimulation by sex steroids and other growth factors. As the disease progresses, activation of kinase pathways and continued abnormal autocrine/paracrine stimulation contribute to genomic instability and chemoresistance but also identify novel potential targets for therapeutic intervention. Although the list of genomic and other aberrations in ovarian cancer is daunting, a systems approach and the integration of therapies targeting multiple component ‘driver’ genes of important genetic aberrations has potential in treatment and for potentiation of cytotoxic chemotherapy efficacy.