Inhibition of IGF-1R: A Therapeutic Strategy for Colon Cancer Stem-like Cells

抑制 IGF-1R：结肠癌干细胞样细胞的治疗策略

• 批准号: 9206070
• 负责人: Bhaumik B Patel
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206070
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; AKT1 gene; Acetyl Coenzyme A; Affect; Aging; Anabolism; Animal Model; Anticholesteremic Agents; Antineoplastic Agents; Biochemical; Biological Process; Biophysics; Breast; Cells; Chemotherapy-Oncologic Procedure; Cholesterol; Clinic; Clinical; Clinical Trials; Coenzyme A; Colon; Colon Carcinoma; Colorectal; Colorectal Cancer; Combined Modality Therapy; Critical Pathways; Development; Diet; Distal; Dolichol; Down-Regulation; Drug Combinations; Exhibits; FDA approved; FRAP1 gene; Genes; Genetic; Genetic Transcription; Geranyltranstransferase; Growth; Hormones; Human; In Vitro; Individual; Insulin; Insulin-Like Growth Factor I; Laboratories; Malignant Neoplasms; Mediating; Molecular; Mutation; Neoplastic Cell Transformation; Obesity; Oncologist; Oxidoreductase; PIK3CG gene; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physicians; Play; Population; Production; Protein Inhibition; Protein Isoprenylation; Proto-Oncogene Proteins c-akt; Recurrence; Regulation; Research Personnel; Resistance; Role; Sampling; Scientist; Signal Transduction; Stem cells; Steroids; Supplementation; TCF7L2 gene; TP53 gene; Terpenes; Testing; Therapeutic; Transactivation; Transcriptional Regulation; Translating; Up-Regulation; Veterans; attenuation; base; beta catenin; biophysical techniques; bisphosphonate; cancer cell; cancer recurrence; cancer stem cell; cancer survival; cancer therapy; cell growth; clinical development; clinically relevant; colon cancer cell line; enzyme pathway; expectation; experience; experimental study; farnesyl pyrophosphate; glycosylation; in vivo; in vivo Model; indexing; inhibitor/antagonist; interest; isopentenyl pyrophosphate; isoprenoid; mevalonate; neoplastic cell; novel; novel therapeutics; prenylation; prevent; public health relevance; screening; self-renewal; stem; stem cell population; stem-like cell; success; targeted agent; tumor

 DESCRIPTION (provided by applicant): Inhibition of IGF-1R: A therapeutic strategy to inhibit colon cancer stem-like cells PD/PI: Patel, Bhaumik B. PROJECT DESCRIPTION Abstract: Despite recent advances in therapeutics, colorectal cancer remains the third deadliest cancer in the USA. This is mainly attributable to survival of a small population of cancer cells called stem cells (CSCs), which display dysregulated self-renewal, aberrant differentiation at the cellular level, and resistance to most cancer chemotherapies preventing complete cure of cancer. Others and we have shown that inhibition of IGF-1R- AKT-mTOR (InAT) axis is a promising approach to target this resistant population within the tumors. However, this promise has not lived up to the high expectations. We have uncovered a novel, critical and clinically relevant mechanism of IGF-1R inhibition's effect on CSCs that involves downregulation of mevalonate- isoprenoid biosynthesis (MIB) pathway, a precursor pathway of steroid synthesis, at levels distal to that targeted by statins, th widely used anti-cholesterol drugs. Inhibition of MIB pathway results in depletion of several bioactive terpenes that are involved in critical biological processes such as protein prenylation and N- Glycosylation, which in turn regulates ß-catenin signaling, a critical pathway governing colonic CSCs growth. We hypothesize that that a combination strategy employing simultaneous inhibition of InAT axis and MIB pathway, with FDA-approved agents or those that are in advanced clinical development, will results in synergistic downregulation of MIB pathway, ß-catenin signaling, and CSCs growth. This hypothesis will be tested in three specific aims. In vitro and in vivo models of CSCs as well as utilizing primary human colon cancer samples, we will establish significance of InAT axis and MIB pathway upregulation on CSCs growth (Aim 1). Subsequently, we will determine optimal therapeutic combination(s) of select agents from targeting InAT axis combined with those that suppress MIB pathway by employing sequential strategy of in vitro screening of the proposed drug combination in 10 selected colon cancer cell lines, with diverse genetic changes representing sporadic CRC, to identify highly synergistic combinations that will be advanced in animal models of CSCs growth (Aim 2). Moreover, we will examine detailed molecular mechanisms of inhibition of InAT axis (alone or in combination with a MIB pathway inhibitor, also 'optimum anti-CSCs combination(s)') on MIB pathway downregulation as well as CSCs growth by employing advanced biophysical and biochemical studies to a) determine levels of mevalonate pathway metabolites, b) determine the role of InAT-SREBP axis in regulating gene specific transcription of MIB pathway enzymes, and c) examining the role of downstream terpene molecules (which regulate prenylation and N-glycosylation) in regulating ß-catenin/TCF-4 signaling (Aim 3). The results from the proposed experiments would greatly expand our understanding of mechanisms of colon CSCs growth and identify 'optimum anti-CSCs combination(s)' therapy that will be immediately testable in the clinical trial(s), and will have paradigm-shifting implications in the treatment of colorectal cancr. 1

 描述（由申请人提供）： IGF-1 R的抑制：抑制结肠癌干细胞样细胞PD/PI的治疗策略：Patel，Bhaumik B。项目描述摘要：尽管最近在治疗方面取得了进展，但结直肠癌仍然是美国第三大致命癌症。这主要归因于称为干细胞（CSC）的一小群癌细胞的存活，其显示出失调的自我更新、细胞水平的异常分化以及对大多数癌症化疗的抗性，从而阻止癌症的完全治愈。其他人和我们已经表明，抑制IGF-1 R-AKT-mTOR（InAT）轴是针对肿瘤内耐药群体的一种有希望的方法。然而，这一承诺并没有达到人们的高度期望。我们已经发现了IGF-1 R抑制对CSC的作用的新的、关键的和临床相关的机制，其涉及在远离他汀类药物（广泛使用的抗胆固醇药物）靶向的水平下调甲羟戊酸-类异戊二烯生物合成（MIB）途径（类固醇合成的前体途径）。MIB途径的抑制导致参与关键生物学过程（如蛋白质异戊二烯化和N-糖基化）的几种生物活性萜烯的消耗，这反过来调节β-连环蛋白信号传导，这是控制结肠CSC生长的关键途径。我们假设，采用同时抑制InAT轴和MIB途径的联合策略，与FDA批准的药物或处于高级临床开发中的药物，将导致MIB途径、β-连环蛋白信号传导和CSC生长的协同下调。这一假设将在三个具体目标中得到检验。在CSC的体外和体内模型中以及利用原发性人结肠癌样品，我们将确定InAT轴和MIB途径上调对CSC生长的意义（目的1）。随后，我们将通过在10种选择的结肠癌细胞系中采用体外筛选所提出的药物组合的顺序策略，确定靶向InAT轴的选择药物与抑制MIB途径的药物组合的最佳治疗组合，其中不同的遗传变化代表散发性CRC，以鉴定将在CSC生长的动物模型中推进的高度协同组合（目的2）。此外，我们将研究抑制InAT轴的详细分子机制，（单独或与MIB途径抑制剂组合，也称为“最佳抗CSC组合”）对MIB途径下调以及CSC生长的影响，通过采用先进的生物物理学和生物化学研究来确定甲羟戊酸途径代谢物的水平，B）确定InAT-SREBP轴在调节MIB途径酶的基因特异性转录中的作用，和c）检测下游萜烯分子（其调节异戊二烯化和N-糖基化）在调节β-连环蛋白/TCF-4信号传导中的作用（目的3）。拟议实验的结果将极大地扩展我们对结肠CSC生长机制的理解，并确定“最佳抗CSC组合”疗法，该疗法将立即在临床试验中进行测试，并将在治疗中产生范式转变影响结直肠癌。1