Posted March 25, 2014
Alexander Kutikov, M.D., Attending Surgeon in Urologic Oncology and Associate Professor of Cancer Biology, Fox Chase Cancer Center of Temple University, Philadelphia with collaborator Vladimir Kolenko, M.D., Ph.D.
In the United States, prostate cancer is the most common malignancy and the second most common cause of cancer death in men. Of the available treatments, androgen deprivation therapy (ADT) is commonly used. However, following this treatment a majority of patients eventually develop castration-resistant prostate cancer (CRPC), which no longer responds to ADT and metastasizes to numerous locations throughout the body. Systemic therapies currently being used to treat metastatic CRPC (mCRPC) are helpful for some patients, but have limited efficacy, often extending overall survival by only 2-3 months.
To address the difficulties in treating mCRPC, Dr. Alexander Kutikov of the Fox Chase Cancer Center, with funding from a 2009 PCRP Physician Research Training Award, sought to develop new therapeutic strategies based on the discovery that zinc concentrations may play an important role in prostate carcinogenesis. The prostate gland accumulates the highest levels of zinc of any soft tissue in the human body. Interestingly, zinc concentrations fall early during prostate cancer development and continue to decline during progression toward castration-resistant disease. While studying the reduction of zinc levels, Dr. Kutikov and colleagues demonstrated that decreases in zinc appear to relate to the degradation of a protein, called XIAP (X-linked inhibitor of apoptosis), that inhibits cell death. Building upon these observations, Dr. Kutikov treated mice with prostate cancer with a combination of zinc-binding drugs and docetaxel, and then observed that tumor growth was significantly reduced.
To fully realize the potential of zinc-binding compounds in the treatment of prostate cancer, Dr. Kutikov is investigating novel zinc chelator platforms. He hopes to harness these versatile molecular systems in order to move these compounds into the clinic as stand-alone drugs or in combination with other therapies to provide optimal management of castration-resistant disease and improved outcomes for men with prostate cancer.
A proposed model for the enhanced susceptibility of prostate cancer cells to programmed cell death (apoptosis) due to zinc chelation. Zinc-specific chelators induce rapid depletion of XIAP at the post-translational level, abrogating its apoptosis-inhibitory function, and thereby promoting amplification of an apoptotic signaling via activation of caspases-3 and -9.
Makhov P, Kutikov A, Golovine K, Uzzo RG, Canter DJ, Kolenko VM. Docetaxel-mediated apoptosis in myeloid progenitor TF-1 cells is mitigated by zinc: potential implication for prostate cancer therapy. Prostate, 2011, 71(13), 1413-19.
Makhov PB, Golovine KV, Kutikov A, Canter DJ, Rybko VA, Roshchin DA, Matveev VB, Uzzo RG, Kolenko VM. Reversal of epigenetic silencing of AP-2alpha results in increased zinc uptake in DU-145 and LNCaP prostate cancer cells. Carcinogenesis, 2011, 32(12):1773-81.
Kolenko VM, Teper E, Kutikov A, Uzzo R. Zinc and zinc transporters in prostate carcinogenesis. Nature Reviews Urology, 2013, 10(4):219-26.
Public and Technical Abstracts: Improving the Efficacy of Docetaxel-Based Chemotherapy for Hormone-Refractory Prostate Cancer Using the Novel Mechanism of XIAP Depletion.