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

番茄红素和多西他赛治疗前列腺癌的 1 期生物测定指导试验

基本信息

批准号：
8512436
负责人：
MICHAEL B LILLY
金额：
$ 20.99万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512436
关键词：
Adverse effects American Antioxidants Benign Prostatic Hypertrophy Binding Biochemical Biological Assay Biological Markers Blood Blood Cells CYP3A4 gene Cancer Control Cancer Patient Caring Cell Survival Cells Cessation of life Clinical Clinical Research Clinical Trials Combined Modality Therapy Data Development Dose Dose-Limiting Drug Kinetics Enzymes Exercise Fright Generations Goals Growth Growth Factor Hematologic Agents Human IGF1 gene IGF1R gene IGF2 gene IGFBP3 gene IL6 gene In Vitro Insulin-Like Growth Factor Receptor Laboratory Study Malignant Neoplasms Malignant neoplasm of prostate Maximum Tolerated Dose Measurement Measures Methods Modeling Molecular Target Monitor Mus Neoplasm Metastasis Normal Cell Nutrient Patients Pharmaceutical Preparations Pharmacodynamics Phase Phosphorylation Phytochemical Pigments Plants Plasma Prostate Cancer therapy Prostatic Diseases Publishing Reactive Oxygen Species Reporting Research Resistance Sampling Signal Transduction Stress Symptoms Testing Therapeutic Therapeutic Agents Tomatoes Toxic effect Toxicity due to chemotherapy Uncertainty advanced disease base bench to bedside cancer cell cancer therapy castration resistant prostate cancer cell growth cell killing chemotherapy clinical effect cohort cytokine cytotoxic docetaxel enzyme activity improved in vivo killings lifetime risk lycopene male novel phase 1 study preclinical study prostate cancer cell public health relevance tumor tumor growth uptake

项目摘要

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.

描述（由申请人提供）：虽然可以治愈许多局部前列腺癌（PCA）病例，但带有转移的晚期PCA很难治疗，目前是无法治愈的。化学疗法是晚期PCA患者的重要治疗方法，但结果是次优的。我们的总体目标是确定植物来源的营养是否会通过增加细胞杀伤或减少化学疗法的毒性来改善化学疗法的作用。具体假设是，番茄红素（西红柿中的红色色素）通过抑制一种称为胰岛素样生长因子受体（IGF-1R）的酶来增加多西他赛化学疗法对PCA的作用。番茄红素是前列腺疾病患者常见的一种营养素。番茄红素可能具有降低PCA发育的能力，或减少良性前列腺肥大的症状。但是，很少有数据用于实际治疗已建立PCA的患者。没有发表的报告描述了其用于增强多西他赛化学疗法对晚期疾病患者的影响的使用。我们小组和其他人发表的研究表明，番茄红素抑制了表达IGF1R的PCA细胞的生长，但对细胞的活性较小，几乎没有酶。番茄红素似乎与酶的TE活性直接结合，阻止其在促进细胞生长和存活中的作用。与单独使用任何一种药物治疗的小鼠相比，用番茄红素和多西他赛的组合处理的小鼠具有更好的PCA控制。因此，番茄红素可能是改善PCA患者多西他赛治疗的廉价，无毒，方便的方法。我们的建议包括三个具体目标：具体目标1是在PCA患者中对番茄红素加多西他赛进行I期研究。主要目标是鉴定这些毒性很少的药物的剂量，并且能够抑制患者的IGF1R活性。具体目的2是确定当这些药物合并时，番茄红素是否会渗透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对血液中药物的摄取和消失进行建模。特定目标3旨在鉴定新型生物学标记，以监测番茄红素和多西他赛对PCA受试者的影响。我们将在患者血液中序列测量IGF1，IGF2，IGFBP3和IL6的水平，并测量血细胞上IGF1R的水平。如果这些测量值中的任何一个变化预测谁将具有最少的副作用（3-4级限制剂量毒性），或者与不同量的治疗相关。在没有基于机制的临床研究的情况下，要使用植物化学物质作为安全，廉价的癌症治疗的争论或反对使用。该提案试图通过将番茄红素与多西他赛结合在一起，以进一步移动沿底层连续体的番茄红素癌疗法。我们的研究将确定所提出的分子靶标是否正确，并可能指出其他酶和细胞因子是番茄红素的潜在靶标。