Mechanisms of Anticancer Agents Selective against Drug Resistant Leukemia

抗癌药物选择性对抗耐药性白血病的机制

• 批准号: 8369783
• 负责人: CHENGGUO XING
• 金额: $ 30.63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369783
• 关键词: Accounting; Acute Myelocytic Leukemia; Antineoplastic Agents; Apoptotic; Biological; Biological Models; Ca(2+)-Transporting ATPase; Cancer Model; Cell Line; Cells; Chemicals; Clinical; Data; Development; Drug resistance; Endoplasmic Reticulum; Engraftment; Foundations; Future; Goals; HL60; Investigation; Knowledge; Laboratories; Lead; Malignant Neoplasms; Modeling; Molecular; Multi-Drug Resistance; P-Glycoprotein; Pathway interactions; Patients; Photoaffinity Labels; Protein Family; Proteins; Reporting; Research; Resistance; Resistance development; Role; Sampling; Solutions; Stress; Structure-Activity Relationship; Testing; anticancer activity; anticancer research; antitumor agent; base; cancer cell; cancer therapy; cellular targeting; clinically relevant; defined contribution; drug sensitivity; effective therapy; inhibitor/antagonist; insight; knowledge of results; leukemia; mouse model; multidrug resistance inhibition therapy; novel; prevent; protein profiling; resistance mechanism; small molecule; success; therapy design; tool

DESCRIPTION (provided by applicant): Drug resistance is a significant problem in cancer therapy, because it is a general phenomenon among all malignancies and there is no effective solution. Therefore there is an unmet clinical need for new therapies to be developed targeting drug-resistant malignancies, which is challenging due to the limited knowledge about drug resistance mechanisms and the lack of appropriate cancer models and research tools. Our long-term goal is to elucidate the mechanisms whereby cancer cells acquire resistance to treatment, and to rationally develop antitumor agents based on such knowledge that will effectively treat drug-resistant malignancies. Drug-resistant leukemias over-express anti-apoptotic Bcl-2 family proteins and p-glycoprotein. Some also have elevated levels of Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA), which has been reported to interact with the Bcl-2 protein. We have recently identified a set of small molecules, derived from HA 14-1 (a putative Bcl-2 inhibitor) and termed CXLs, that demonstrate preferential anticancer activity toward drug- resistant leukemias, despite the fact that such cancers reveal cross resistance to standard therapies. Leukemia cells also fail to develop resistance to CXLs. In fact, CXLs re-sensitize leukemias to standard therapies (30-130 fold). Mechanistically, CXLs induce ER Ca2+ release and ER stress, inhibit SERCA and p- glycoprotein. These data overall demonstrate the unique biological features of CXLs, particularly their potential to treat drug-resistant leukemias. Nevertheless, the precise mechanism that accounts for the distinctive anticancer profile of CXLs, including CXL's cellular targets, has yet to be firmly established. During the course of our preliminary studies, we have developed two structurally similar CXLs as chemical probes and several pairs of leukemia cell lines as cancer models for mechanistic investigation. The main objectives of this proposal are to elucidate the mechanisms of action for CXLs by employing the unique chemical probes and cancer models we developed and to validate its anticancer potential in a clinically relevant engraftment model. The resulting knowledge is expected to rationalize the selective anticancer activity of CXLs towards drug- resistant leukemias and to establish the foundation for future translational development. Aim 1. To define the contribution of the anti-apoptotic Bcl-2 family proteins & SERCA proteins to drug resistance and their roles in CXL's selective anticancer activity. Aim 2. To profile the proteins that CXL positive lead preferentially interacts with in drug-resistant cancer cells, which we hypothesize to be the cellular targets for CXLs and be responsible for drug resistance. Aim 3. To validate the anticancer selectivity and mechanism of action for CXL positive lead against drug resistant AML in engraftment models. PUBLIC HEALTH RELEVANCE: Drug resistance is a significant problem in cancer therapy and there is an unmet clinical need for new therapies to be developed targeting drug-resistant malignancies, which is challenging, due to the limited knowledge about drug resistance mechanisms and the lack of appropriate cancer models and research tools. The objective of this research is to elucidate the molecular mechanisms whereby cancer cells acquire resistance by using a set of novel tools and model systems developed in our laboratory and to validate the anticancer potential of our positive lead against drug resistance in a clinically relevant engraftment model.

描述(申请人提供)：耐药是癌症治疗中的一个重要问题，因为它是所有恶性肿瘤中的普遍现象，目前还没有有效的解决方案。因此，针对耐药恶性肿瘤开发新的治疗方法的临床需求尚未得到满足，这是具有挑战性的，因为对耐药机制的了解有限，缺乏合适的癌症模型和研究工具。我们的长期目标是阐明癌细胞产生抗药性的机制，并在此基础上合理开发有效治疗耐药恶性肿瘤的抗肿瘤药物。耐药白血病过表达抗细胞凋亡的Bcl2家族蛋白和P糖蛋白。其中一些也有高水平的Sarco/内质网钙-ATPase(SERCA)，据报道，该酶与Bcl-2蛋白相互作用。我们最近发现了一组源自HA14-1(一种假定的Bcl2抑制剂)的小分子，被称为CXLS，它们对耐药白血病表现出优先的抗癌活性，尽管这类癌症对标准治疗显示出交叉耐药。白血病细胞也不能对CXLS产生抗药性。事实上，CXL使白血病对标准疗法重新敏感(30-130倍)。机制上，CXLS诱导内质网钙离子释放和内质网应激，抑制SERCA和P-糖蛋白。这些数据总体上证明了CXL独特的生物学特性，特别是它们治疗耐药白血病的潜力。 然而，包括CXL的细胞靶点在内的CXL独特的抗癌特征的确切机制尚未得到确定。在我们的初步研究过程中，我们开发了两个结构相似的CXL作为化学探针，并开发了几对白血病细胞系作为机制研究的癌症模型。这项建议的主要目的是通过使用我们开发的独特的化学探针和癌症模型来阐明CXLS的作用机制，并在临床相关的植入模型中验证其抗癌潜力。由此获得的知识有望使CXLS对耐药白血病的选择性抗癌活性合理化，并为未来的翻译开发奠定基础。目的1.明确抗凋亡蛋白Bcl2家族蛋白SERCA在肿瘤耐药中的作用及其在CXL选择性抗癌活性中的作用。目的2.分析CXL阳性铅在耐药癌细胞中优先与之相互作用的蛋白质，我们假设这些蛋白质是CXL的细胞靶点，并与耐药有关。目的3.在移植模型中验证CXL阳性铅对耐药AML的抗癌选择性及其作用机制。 公共卫生相关性：耐药性是癌症治疗中的一个重大问题，针对耐药恶性肿瘤开发新疗法的临床需求尚未得到满足，这是具有挑战性的，因为对耐药性机制的了解有限，缺乏适当的癌症模型和研究工具。本研究的目的是利用我们实验室开发的一系列新的工具和模型系统来阐明癌细胞获得耐药性的分子机制，并在临床相关的植入模型中验证我们的正性铅对抗耐药性的抗癌潜力。