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

描述(申请人提供)：虽然许多局限性前列腺癌(PCA)可以治愈，但晚期前列腺癌转移很难治疗，目前是无法治愈的。化疗是晚期前列腺癌患者的重要治疗方法，但效果并不理想。我们的总体目标是确定植物来源的营养物质是否会通过增加细胞杀伤力或减少化疗的毒性来改善化疗的效果。具体的假设是，番茄红素(番茄中的一种红色色素)将通过抑制一种名为胰岛素样生长因子受体(IGF-1R)的酶来增强多西紫杉醇化疗治疗前列腺癌的效果。番茄红素是前列腺癌患者常用的一种营养素。番茄红素可能有能力减缓前列腺癌的发展，或减轻良性前列腺肥大的症状。然而，关于它实际用于治疗已确诊的前列腺癌患者的数据很少。没有发表的报告描述了它在晚期疾病患者中用于增强多西紫杉醇化疗的效果。我们团队和其他人发表的研究表明，番茄红素可以抑制表达IGF1R的前列腺癌细胞的生长，但对缺乏这种酶的细胞的活性较低。番茄红素似乎结合并直接抑制该酶的TE活性，阻断其促进细胞生长和存活的作用。番茄红素和多西紫杉醇联合治疗的小鼠比单独使用任何一种药物的小鼠都有更好的PCA控制。因此，番茄红素可能是一种廉价、无毒、方便的方法来改善多西紫杉醇对前列腺癌患者的治疗。我们的建议包括三个具体目标：具体目标1是对PCa患者进行番茄红素加多西紫杉醇的I期研究。主要目标是确定这些药物的剂量，这些药物毒性小，并且能够抑制患者的IGF1R活性。具体目的2是确定当番茄红素与多西紫杉醇联合使用时，番茄红素是否干扰多西他赛的药代动力学。多西紫杉醇和番茄红素血液水平的连续测量将被用来模拟药物从血液中的吸收和消失。具体目标3寻求寻找新的生物标志物来监测番茄红素和多西紫杉醇对前列腺癌受试者的影响。我们将连续检测患者血液中IGF1、IGF2、IGFBP3和IL6的水平，并检测血细胞上的IGF1R水平。如果这些测量中的任何一项的变化预测了谁的副作用最少(3-4级剂量限制毒性)，或者与不同剂量的治疗相关，我们会这样做的。如果没有基于机制的临床研究，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的。这项提案试图通过将番茄红素和多西紫杉醇结合起来，进一步推动番茄红素癌症治疗沿着从病床到床边的连续体发展。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是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.