Novel targeted therapeutics for metastatic castration-resistant prostate cancer

Abstract

Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

“…In fact, receptor activator of NF-κB ligand-activated IκB kinase-α has been shown to translocate to the nucleus of prostate epithelial cells, resulting in inhibition of Maspin, thereby inducing prostate cancer metastasis to bone (33). Receptor activator of NF-κB ligand is known to regulate bone metastasis in prostate and breast cancers but does not seem to play a major role in melanoma metastasis (34)(35)(36). Although PAR-1 is known to activate the NF-κB pathway (37,38), IκB kinase-α does not seem to function as a Maspin inhibitor in melanoma cells, again pointing to the tissue-specific regulation and function of Maspin.…”

Linc00963: A novel, long non-coding RNA involved in the transition of prostate cancer from androgen-dependence to androgen-independence

“…More importantly, EGFR itself may be under the regulation of androgen signaling pathway, being negative in normal prostate cells but positive in prostate cancer cells, especially in androgen-independent cancer cells (7). In an effort to overcome castration-resistance, trials combining EGFR or dual kinase inhibitors with other novel agents are in development (8).…”

[99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours

“…Particularly in prostate cancer, inhibition of IGF-1R-signalling is regarded as a promising methodology for treatment of androgen independent prostate cancer [9,10], because excessive signalling of IGF-1R leads to activation of androgen receptors in the absence of androgens, i.e. it causes androgen independence.…”