Inhibition of Senescence to Increase Cancer Cell Death: A New Paradigm

抑制衰老以增加癌细胞死亡：一种新范式

• 批准号: 9122743
• 负责人: SUSAN BAND HORWITZ
• 金额: $ 42.98万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122743
• 关键词: Accounting; Adverse effects; Antibodies; Attention; Binding; Binding Proteins; Biological; Biological Factors; Cancer cell line; Cell Death; Cells; Chemical Structure; Chemicals; Clinical; Clinical Drug Development; Collaborations; Data; Development; Drug Efflux; Drug Kinetics; Drug resistance; Epothilones; Future; Goals; Health; Human; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Laboratories; Mainstreaming; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Microtubules; Modality; Molecular; Mutation; Natural Product Drug; P-Glycoprotein; Paclitaxel; Parents; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Plasminogen Activator Inhibitor 1; Property; Proteins; Pulmonary Fibrosis; Radiolabeled; Relative (related person); Research; Research Proposals; Resistance; Role; Signal Pathway; Structure-Activity Relationship; Testing; Toxic effect; Translation Process; Treatment Efficacy; Tubulin; Work; analog; antitumor drug; base; beta Tubulin; cancer cell; cellular targeting; cytotoxic; differential expression; discodermolide; drug development; efflux pump; experience; extracellular; functional group; human FRAP1 protein; improved; in vivo; interest; novel; overexpression; preclinical study; programs; radiotracer; screening; senescence; small molecule; targeted treatment; therapeutic development; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): This proposal represents a multifaceted program for studying drug development. The natural product, discodermolide has the potential to be an important antitumor drug, particularly in Taxol resistant tumors. The preclinical studies that were done in our laboratory were crucial for the clinical development of Taxol and we believe that meaningful research with discodermolide could pave the way for its clinical development. Today, there is an immense interest in "targeted therapies", utilizing small molecules and antibodies that target aberrant signaling pathways in cancer cells. However for many malignancies, standard cytotoxic-based therapies, some in combination with targeted therapies, will remain the mainstream. Discodermolide is a natural product with a chemical structure very different from Taxol, but whose mechanism of action has major similarities, but also has distinct and intriguing differences. Relative to Taxol, discodermolide-treated cells have a low propensity for developing acquired resistance. This is attributable to discodermolide's ability to induce accelerated senescence and undergo a prolonged state of proliferative arrest. It has taken us several years to develop a discodermolide-resistant cancer cell line and unlike Taxol-resistant cells, these do not have classic mechanisms of Taxol resistance, namely beta-tubulin mutations or overexpression of the ATP- dependent drug efflux pump, P-glycoprotein. It is likely that the unique properties of discodermolide are related to its ability to induce senescence and also to its initial characterization as an immunosuppressive agent. This proposal will focus on delineating the effect of disocodermolide on the molecular pathways involved in drug- induced senescence and how that relates to modulation of 4EBP and mRNA processing and translation. Although senescence in cancer cells is a recognized mechanism of suppressing tumor-growth, the possibility exists that senescent cells may contribute to tumorigenesis through the induction of several pathways involved in inflammation and extracellular remodeling (reviewed in [64]), and in the case of discodermolide, this may render some patients susceptible to the development of pulmonary fibrosis. Thus, a fundamental component of this proposal is specific aim 3 that details a comprehensive chemical-biological approach to selecting promising structural analogs of discodermolide that have modified senescent-inducing properties. These compounds ideally would retain the very potent and unique microtubule-binding properties of the parent compound that initially attracted our attention for the therapeutic development of this drug, while minimizing the potential for senescence. The co-P.I.'s have had many productive years working with natural products and drug development and have assembled a superb group of colleagues at Albert Einstein and a unique group of synthetic chemists as collaborators.

描述（由申请人提供）：该提案代表了一个用于研究药物开发的多方面计划。天然产物，dincodermolide有可能成为重要的抗肿瘤药物，尤其是在抗紫杉醇的肿瘤中。在我们的实验室进行的临床前研究对于紫杉醇的临床发展至关重要，我们认为使用discodermolide的有意义的研究可以为其临床发育铺平道路。如今，对“靶向疗法”的兴趣极大，利用针对癌细胞中异常信号通路的小分子和抗体。但是，对于许多恶性肿瘤，标准基于细胞毒性的疗法与靶向疗法结合使用，将仍然是主流。 desodermolide是一种天然产物，具有与紫杉醇完全不同的化学结构，但其作用机理具有主要相似之处，但也具有独特的差异。相对于紫杉醇，经二甲甲酚处理的细胞具有较低的发展耐药性的倾向。这归因于desodermolide诱导加速衰老并长时间进行增生的捕捉状态的能力。我们花了几年的时间开发了耐抑制剂的癌细胞系，并且与抗紫杉醇耐药细胞不同，这些细胞没有经典的紫杉醇耐药机制，即β-微管蛋白突变或ATP依赖性药物外排泵的过表达。二甲甲甲苯甲酯的独特特性可能与其诱导衰老的能力以及其作为免疫抑制剂的最初表征有关。该建议将着重于描述非胚层甲醇对药物诱导衰老涉及的分子途径的影响，以及与4EBP和mRNA处理和翻译的调节有关的影响。尽管癌细胞中的衰老是抑制肿瘤增长的一种公认的机制，但存在衰老细胞可能通过诱导涉及炎症和细胞外重塑的几种途径而导致肿瘤发生的可能性（在[64]中进行了综述），以及在discodermolide的情况下，这可能会导致一些患者，使某些患者呈现一些易于发育的患者。因此，该提案的基本组成部分是特定的目的3，详细介绍了一种综合化学生物学方法，用于选择已修改衰老特性的dinesodermolide的有希望的结构类似物。理想情况下，这些化合物将保留母体化合物的非常有效且独特的微管结合特性，该特性最初吸引了我们对这种药物的治疗发育的关注，同时最大程度地降低了衰老的潜力。 Co-p.i。已经有很多富有成效的年份与天然产品和药物开发合作，并在艾伯特·爱因斯坦（Albert Einstein）组建了一群出色的同事，并作为合成化学家作为合作者的独特群体。