While many cases of localized prostate cancer (PCa) can be cured, advanced PCa with metastases is difficult to treat, and is currently incurable. Chemotherapy is an important treatment for patients with advanced PCa, but results are suboptimal. Our overall goal is to determine if plant-derived nutrients will improve the effect of chemotherapy by increasing cell kill or decreasing toxicity from chemotherapy. The specific hypothesis is that lycopene (a red pigment in tomatoes) will increase the effect of docetaxel chemotherapy against PCa, by inhibiting an enzyme called the insulin-like growth factor receptor (IGF-1R). Lycopene is a nutrient commonly taken by patients with prostatic diseases. Lycopene may have the ability to decrease PCa development, or to decrease the symptoms of benign prostatic hypertrophy. However, there are few data on its use to actually treat patients with established PCa. No published reports describe its use to potentiate the effects of docetaxel chemotherapy in patients with advanced disease. Published studies by our group and others demonstrate that lycopene inhibits the growth of PCa cells that express IGF1R but is less active against cells with little of the enzyme. Lycopene appears to bind to, and directly inhibit te activity of the enzyme, blocking its effects in promoting cell growth and survival. Mice treated with a combination of lycopene and docetaxel have better PCa control than mice treated with either agent alone. Thus, lycopene may be an inexpensive, non-toxic, convenient way to improve docetaxel treatment in PCa patients. Our proposal includes three specific aims:
Specific Aim 1 is to conduct a Phase I study of lycopene plus docetaxel in PCa patients. The primary goal is to identify doses of these agents that have little toxicity, and that are able to inhibit IGF1R activity in patients.
Specific Aim 2 is to determine whether lycopene perturbs the pharmacokinetics of docetaxel when these agents are combined. Serial measurements of docetaxel and lycopene blood levels will be used to model the uptake and disappearance of the drugs from the blood.
Specific Aim 3 seeks to identify novel biological markers to monitor effects of lycopene and docetaxel in PCa subjects. We will serially measure levels of IGF1, IGF2, IGFBP3, and IL6 in the blood of the patients, and measure levels of IGF1R on blood cells. We will if changes in any of these measurements predicts who will have the fewest side effects (grade 3-4 dose-limiting toxicity), or are associated with different amounts of treatment. Arguments for or against the use of phytochemicals as safe, inexpensive cancer therapeutics will remain theoretical without mechanism-based clinical studies. This proposal attempts to move lycopene cancer therapy further along the bench-to-bedside continuum by combining lycopene with docetaxel. Our studies will determine if the proposed molecular target is correct, and may point to other enzymes and cytokines as potential targets of lycopene.
The lifetime risk of dying of prostate cancer is 3% for American males;most of these advanced PCa patients will probably receive treatment with docetaxel or other chemotherapy agents before their death. This clinical trial will test the effect of combination of docetaxel with lycopene (the red pigment of tomatoes) on clinical measurements (treatment toxicity, tumor growth) and on the activities of enzymes and growth factors. If we demonstrated that lycopene, an inexpensive nutrient, can improve clinical effects of docetaxel treatment, we can positively impact the lives of millions of PCa patients.
| Yokoyama, Noriko N; Shao, Shujuan; Hoang, Bang H et al. (2014) Wnt signaling in castration-resistant prostate cancer: implications for therapy. Am J Clin Exp Urol 2:27-44 |
