Sweet gum extract and late stage prostate cancer

枫香提取物与晚期前列腺癌

基本信息

批准号：
7530841
负责人：
PEIYING YANG
金额：
$ 20.24万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7530841
关键词：
70-kDa Ribosomal Protein S6 Kinases AIPC Affect Androgens Biological Markers Cancer cell line Cause of Death Cells Chemopreventive Agent Class Clinical Clinical Research Cultured Cells DU145 Data Depth Development Disease Feedback Foundations Fruit Future Grant Hormones Human Immunocompromised Host Inhibitory Concentration 50 Knowledge LNCaP Liquidambar Lupinus Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Monitor Mus PTEN gene Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phosphorylation Population Prostate Prostatic Neoplasms Protocols documentation Public Health Research Ribosomal Protein S6 Safety Series Signal Pathway Signal Transduction Staging Standardization Testing Therapeutic Effect Toxic effect Treatment Efficacy Trees UVB induced Work Xenograft Model anticancer activity base cancer cell cancer diagnosis cell type chemotherapeutic agent design disorder control hormone refractory prostate cancer human FRAP1 protein in vivo inhibitor/antagonist mTOR Inhibitor mTOR inhibition men novel preclinical study prostate cancer prevention research clinical testing tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer in U.S. men and the second leading cause of death in this population. We have recently discovered that a discrete sweet gum extract (LIS-100), prepared from Liquidambar styraciflua L. fruits may provide a novel effective treatment for this disease. Our preliminary data has shown that this product produces simultaneous inhibition of mTOR and PI3K/Akt pathways in hormonally refractive disease. mTOR inhibitors are showing promise as useful targeted chemotherapeutic agents in many malignancies, including late stage prostate cancer. However, unexpected feedback activation of Akt by mTOR inhibitors has become a barrier for the effective use of this class of drugs. Our preliminary data indicates that LIS- 100 was found to effectively inhibit proliferation of prostate cancer (IC50 -1.85 ug/ml), especially androgen independent PC3 cells. At concentrations as low as 2.5 ug/ml, LIS- 100 almost totally shut down the expression of effectors of the mTOR pathways, yet did not cause activation of Akt. In fact, it simultaneously inhibited phosphorylation of Akt in PC3 cells, suggesting that LIS-100 is dual inhibitor of PI3K/Akt and mTOR pathways. This exciting discovery prompted this proposal to evaluate the efficacy, mechanisms and safety of LIS-100 in androgen-dependent more metastatic prostate cancer (LNCaP-LN4) and androgen independent PC3 cells as well as antitumor activity in associated orthotopic xenograft models. LNCaP-LN4 cells express a functional AR, which is similar to majority of human AIPC, and hence will serve a better model representing the aggressive late stage of prostate cancer. It is our hypothesis that effective use of mTOR inhibitors must include a means of inhibiting activation of Akt. We believe that LIS-100 may represent one of the most effective dual inhibitors of mTOR and PI3K/Akt pathways yet described and, as such, may be very effective in treatment of late stage prostate cancer. This grant is designed to thoroughly explore the mechanisms of action of LIS100 in inhibition of proliferation of hormone sensitive as well as hormone refractory prostate cancer. Furthermore, studies aimed at determining it's efficacy in vivo against xenograft tumors will be used to assess its potential as a future clinical candidate. PUBLIC HEALTH RELEVANCE: The proposed research involves studies of an extract of fruit of a "sweet gum" tree that we have found to be very effective for treatment of hormone refractory prostate cancer. Initial promising work in human cell cultures will be expanded to look at specific mechanisms of action of the extract as well as to test the product against human prostate tumors in immunocompromised mice. This will determine if sufficient promising data can be obtained to warrant clinical evaluation of the extract in men with advanced hormone refractory prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性中最常诊断出的癌症，也是该人群的第二大死因。我们最近发现，从枫香果实中提取的一种独立的枫香提取物（LIS-100）可能为这种疾病提供一种新的有效治疗方法。我们的初步数据表明，该产品可同时抑制激素性屈光疾病中的 mTOR 和 PI3K/Akt 通路。 mTOR 抑制剂在许多恶性肿瘤（包括晚期前列腺癌）中显示出作为有用的靶向化疗药物的前景。然而，mTOR抑制剂对Akt的意外反馈激活已成为此类药物有效使用的障碍。我们的初步数据表明，LIS-100 可有效抑制前列腺癌的增殖（IC50 -1.85 ug/ml），尤其是雄激素非依赖性 PC3 细胞。在浓度低至 2.5 ug/ml 时，LIS-100 几乎完全关闭 mTOR 途径效应子的表达，但不会引起 Akt 激活。事实上，它同时抑制 PC3 细胞中 Akt 的磷酸化，表明 LIS-100 是 PI3K/Akt 和 mTOR 途径的双重抑制剂。这一令人兴奋的发现促使我们提议评估 LIS-100 在雄激素依赖性转移性前列腺癌 (LNCaP-LN4) 和雄激素非依赖性 PC3 细胞中的功效、机制和安全性，以及相关原位异种移植模型中的抗肿瘤活性。 LNCaP-LN4 细胞表达功能性 AR，与大多数人类 AIPC 相似，因此将成为代表前列腺癌侵袭性晚期的更好模型。我们的假设是，mTOR 抑制剂的有效使用必须包括抑制 Akt 激活的方法。我们相信，LIS-100 可能是迄今为止描述的最有效的 mTOR 和 PI3K/Akt 通路双重抑制剂之一，因此可能对治疗晚期前列腺癌非常有效。该资助旨在彻底探索 LIS100 抑制激素敏感和激素难治性前列腺癌增殖的作用机制。此外，旨在确定其体内抗异种移植肿瘤功效的研究将用于评估其作为未来临床候选者的潜力。公共健康相关性：拟议的研究涉及对“枫香”树果实提取物的研究，我们发现这种提取物对于治疗激素难治性前列腺癌非常有效。人类细胞培养中最初有希望的工作将扩大到研究提取物的具体作用机制，并在免疫功能低下的小鼠中测试该产品对人类前列腺肿瘤的作用。这将决定是否可以获得足够有希望的数据来保证对患有晚期激素难治性前列腺癌的男性提取物进行临床评估。