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: 8690558
• 负责人: CHENGGUO XING
• 金额: $ 29.71万
• 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/8690558
• 关键词: Accounting; Acute Myelocytic Leukemia; Antineoplastic Agents; Apoptotic; BCL-2 Protein; BCL2 gene; 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.

描述（由申请人提供）：耐药性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，并且没有有效的解决方案。因此，针对耐药恶性肿瘤开发新疗法的临床需求尚未得到满足，由于对耐药机制的了解有限以及缺乏适当的癌症模型和研究工具，这具有挑战性。我们的长期目标是阐明癌细胞获得耐药性的机制，并基于这些知识合理开发有效治疗耐药恶性肿瘤的抗肿瘤药物。耐药白血病过度表达抗凋亡Bcl-2家族蛋白和p-糖蛋白。有些还具有升高的Sarco/内质网Ca 2 +-ATP酶（SERCA）水平，据报道，其与Bcl-2蛋白相互作用。我们最近鉴定了一组衍生自HA 14-1（一种推定的Bcl-2抑制剂）并被称为CXL的小分子，它们对耐药白血病表现出优先的抗癌活性，尽管这些癌症显示出对标准疗法的交叉抗性.白血病细胞也不能对CXL产生耐药性。事实上，CXL使白血病对标准疗法重新敏感（30-130倍）。CXLs诱导ER Ca ~（2+）释放和ER应激，抑制SERCA和P-糖蛋白。这些数据总体上证明了CXL的独特生物学特征，特别是其治疗耐药白血病的潜力。 然而，解释CXL独特的抗癌特征的精确机制，包括CXL的细胞靶点，还没有被牢固地建立。在我们的初步研究过程中，我们已经开发了两个结构相似的CXL作为化学探针和几对白血病细胞系作为癌症模型的机制研究。该提案的主要目的是通过采用我们开发的独特化学探针和癌症模型来阐明CXL的作用机制，并在临床相关的移植模型中验证其抗癌潜力。由此产生的知识有望使CXL对耐药白血病的选择性抗癌活性合理化，并为未来的转化开发奠定基础。目标1.明确抗凋亡Bcl-2家族蛋白和SERCA蛋白在CXL耐药中的作用及其在CXL选择性抗癌活性中的作用。目标2.分析耐药癌细胞中CXL阳性铅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，并负责耐药。目标3.验证CXL阳性先导化合物在移植模型中对耐药AML的抗癌选择性和作用机制。