Phase 1 Bioassay-guided Trial of Lycopene and Docetaxel for Prostate Cancer

描述（由申请人提供）：虽然许多局限性前列腺癌（PCa）病例可以治愈，但伴有转移的晚期PCa难以治疗，目前无法治愈。化疗是晚期PCa患者的重要治疗方法，但效果不佳。我们的总体目标是确定植物源性营养素是否会通过增加细胞杀伤或降低化疗毒性来改善化疗效果。具体的假设是，番茄红素（番茄中的一种红色素）将通过抑制一种称为胰岛素样生长因子受体（IGF-1 R）的酶来增加多西他赛化疗对PCa的作用。 番茄红素是前列腺疾病患者经常服用的营养素。番茄红素可能有能力减少前列腺癌的发展，或减少良性前列腺肥大的症状。然而，关于其用于实际治疗已确诊PCa患者的数据很少。没有发表的报告描述其用于增强晚期疾病患者多西他赛化疗的效果。我们小组和其他人发表的研究表明，番茄红素抑制表达IGF 1 R的PCa细胞的生长，但对几乎没有这种酶的细胞活性较低。番茄红素似乎与酶结合并直接抑制酶的活性，阻断其促进细胞生长和存活的作用。用番茄红素和多西他赛的组合治疗的小鼠比单独用任一药剂治疗的小鼠具有更好的PCa控制。因此，番茄红素可能是一种廉价、无毒、方便的方法来改善PCa患者的多西他赛治疗。 我们的建议包括三个具体目标：具体目标1是在PCa患者中进行番茄红素联合多西他赛的I期研究。主要目标是确定这些药物的剂量，毒性小，并且能够抑制患者的IGF 1 R活性。具体目标2是确定当这些药物联合使用时，番茄红素是否会干扰多西他赛的药代动力学。多西他赛和番茄红素血液水平的系列测量将用于模拟药物从血液中的摄取和消失。具体目标3旨在确定新的生物标志物，以监测番茄红素和多西他赛在PCa受试者中的作用。我们将连续测量患者血液中IGF 1、IGF 2、IGFBP 3和IL 6的水平，并测量血细胞上IGF 1 R的水平。如果这些测量值的任何变化预测谁的副作用最少（3-4级剂量限制性毒性），或者与不同的治疗量相关，我们将进行评估。 支持或反对使用植物化学物质作为安全，廉价的癌症治疗方法的论点将仍然是理论上没有基于机制的临床研究。该提案试图通过将番茄红素与多西他赛联合使用，使番茄红素癌症治疗进一步沿着从实验室到床边的连续性。我们的研究将确定所提出的分子靶点是否正确，并可能指出其他酶和细胞因子作为番茄红素的潜在靶点。

DESCRIPTION (provided by applicant): 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.