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Improving the Efficacy of Docetaxel-Based Chemotherapy for Hormone-Refractory Prostate Cancer Using the Novel Mechanism of XIAP Depletion

Principal Investigator: KUTIKOV, ALEXANDER
Institution Receiving Award: FOX CHASE CANCER CENTER
Program: PCRP
Proposal Number: PC094474
Award Number: W81XWH-10-1-0187
Funding Mechanism: Physician Research Training Award
Partnering Awards:
Award Amount: $418,585.00


PUBLIC ABSTRACT

Docetaxel is the only chemotherapeutic agent approved by the FDA for treatment of hormone-refractory prostate cancer. Unfortunately, docetaxel's effectiveness in clinical practice is compromised by its substantial toxicity. Serious adverse effects associated with docetaxel treatment lead to substantial morbidity and early mortality and may disrupt treatment with potentially curative regimens. Preliminary findings from our laboratory suggest that 5-aminolevulinic acid (5-ALA), a compound that has been extensively studied for use in other human cancers, may hold promise for prostate cancer treatment when administered in combination with docetaxel.

Administration of 5-ALA results in the synthesis of protoporphyrin IX, specifically in tumor cells. In fact, two techniques that capitalize on the tendency of protoporphyrin IX to concentrate in malignant cells -- photodetection and photodynamic therapy -- have proven clinically useful in the identification and treatment of various hollow-organ tumors, such as laryngeal, stomach, and bladder cancer. Nevertheless, the need for light delivery to the tumor has limited their clinical utility in the treatment of solid-organ malignancies such as prostate cancer. Encouragingly, data from our laboratory identify an association between intracellular accumulation of protoporphyrin IX in prostate cancer cells and downregulation of X-linked inhibitor of apoptosis protein (XIAP), a potent inhibitor of cell death, in the absence of light exposure.

Our experiments have demonstrated increased sensitivity of prostate cancer cells to therapeutic agents when administered in combination with 5-aminolevulinic acid. We hypothesize that other compounds related to 5-ALA may demonstrate a greater effect upon XIAP expression and, therefore, on the sensitivity of tumor cells to docetaxel. The overall objective of the current proposal is to evaluate the efficacy of 5-ALA analogues as adjuvant therapy for treatment of drug-resistant prostate tumors.

In the first specific aim, we will evaluate various analogues of 5-ALA for improved efficacy in decreasing XIAP levels in malignant prostate cells. In the second specific aim, we will examine the therapeutic efficacy of 5-ALA analogues in combination with docetaxel using an animal model of human prostate cancer. Our previous identification of 5-ALA-induced downregulation of XIAP presents a novel opportunity to evaluate these two clinically tested drugs as a combination therapy for advanced prostate cancer.

The proposed project will also consolidate the PI's clinical training with a robust basic science experience in the field of prostate cancer research. Fox Chase Cancer Center fosters an environment conducive to strong collaboration across all disciplines, both scientific and medical. Training programs at Fox Chase Cancer Center include educational seminars and conferences, career seminars and grant writing courses. In addition, journal clubs, joint laboratory meetings, and intramural and extramural seminar series at Fox Chase provide a concerted training program specifically designed to maximize productivity and equip trainees to pursue fruitful careers as physician-scientists. The Physician Research Training Award will undoubtedly act as a solid foundation for the PI's future career as a prostate cancer researcher.