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（由申请人提供）：耐药性是癌症治疗中的一个重大问题，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，针对抗药性恶性肿瘤的新疗法有未满足的临床需求，这是由于对耐药性机制的知识有限以及缺乏适当的癌症模型和研究工具而具有挑战性的。我们的长期目标是阐明癌细胞获得对治疗能力的机制，并基于这样的知识来合理地发展抗肿瘤药，这些知识将有效治疗耐药性恶性肿瘤。耐药性白血病过表达的抗凋亡Bcl-2家族蛋白和P-糖蛋白。有些还具有升高的肌肉/内质网Ca2+-ATPase（SERCA），据报道与Bcl-2蛋白相互作用。我们最近确定了一组源自HA 14-1（推定的Bcl-2抑制剂）并称为CXL的小分子，这些分子表现出对抗药性白血病的优先抗癌活性，尽管此类癌症揭示了对标准疗法的交叉抗性。白血病细胞也无法发展对CXL的抗性。实际上，CXL将白血病重新敏感到标准疗法（30-130倍）。从机械上讲，CXL诱导ER Ca2+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，尤其是它们治疗耐药性白血病的潜力。 然而，说明包括CXL在内的独特抗癌概况（包括CXL的细胞靶标）的确切机制尚未牢固确定。在初步研究的过程中，我们开发了两个结构上相似的CXL，与化学探针和几对白血病细胞系一起作为癌症模型进行机械研究。该提案的主要目标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的作用机理，并在临床相关的植入模型中验证其抗癌潜力。预计所得的知识将合理化CXL对耐药性白血病的选择性抗癌活性，并为将来的转化发展奠定基础。目的1。定义抗凋亡Bcl-2家族蛋白和SERCA蛋白对耐药性及其在CXL选择性抗癌活性中的作用的贡献。目的2。要介绍CXL阳性铅优先与药物抗药性癌细胞相互作用的蛋白质，我们假设这是CXLS的细胞靶标，并负责耐药性。目的3。验证抗植入模型中针对抗药性AML的CXL阳性铅的抗癌选择性和作用机理。 公共卫生相关性：耐药性是癌症治疗中的一个重大问题，由于对耐药性耐药机制的知识有限，缺乏适当的癌症模型和研究工具的知识有限，因此需要开发出针对抗药性恶性肿瘤的新疗法的临床需求。这项研究的目的是阐明分子机制通过使用我们实验室中开发的一组新工具和模型系统来获得抗药性，并在临床上相关的植入模型中验证我们对耐药性抗药性的抗癌潜力。