Progress of molecular targeted therapies for prostate cancers

Abstract

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.

Figure 1. Prostate cancer's progression and treatment

Prostate cancer patients with high risk are recommended to have surgery, radiation, and/or hormone therapies. Although these treatments are efficient in general, some patients have recurrent diseases, at which stage current treatment options, mostly chemotherapy, are limited in terms of clinical outcome. It is hoped that development in targeted therapies can provide more options for the recurrent and metastatic prostate cancers.

Figure 2. Molecular targets and designed intervention in targeted therapies for prostate cancer

In addition to androgen/ androgen receptor (AR) pathways, many growth receptors (EGFR/HER2, IGFR, PDGFR, and VEGFR), and their downstream molecules, have been explored as the targets to block growth signaling of tumor cells or the angiogenesis process that provides nutrients to cancer cells. Antibodies to some prostate cancer specific antigens (e.g. PSMA and the F77 antigen) have also been developed.

Figure 3

Structure of small molecule agents in targeted therapies for prostate cancer.