LAT1/Asct2 Targeted Inhibition of Efflux Pumps for the Treatment of MDR Cancers

描述（由申请人提供）：癌症中能量依赖性药物外排泵的过表达已被证明与多药耐药性相关。这是一个严重的问题，因为患有难治性癌症的患者的平均五年生存率低至10- 30%。已经探索了药物外排泵抑制剂的施用以使多药耐药（MDR）癌症对化疗药物重新敏感。然而，许多抑制剂在有效泵抑制所需的水平下是有毒的，并显示出许多脱靶副作用。通过受体介导的内吞作用选择性递送这些抑制剂提供了一种有吸引力的策略，以选择性地使MDR癌症再敏感，同时使毒性和副作用最小化。两种氨基酸受体LAT 1和Asct 2在许多癌症中过表达，这些癌症通常也会产生多药耐药性。最新一代泵抑制剂的选择性递送可以通过与LAT 1或Asct 2识别元件缀合来实现。MDR癌细胞系将用于指导和优化LAT 1/Asct 2识别元件和缀合位点。将缀合的敏化剂的抑制与母体化合物进行比较，并且将通过阻断LAT 1/Asct 2受体来确定载体在缀合物递送中的作用。将通过DMPK分析和原位异种移植模型探索效力、疗效、选择性、毒性和脱靶效应。 公共卫生相关性：癌症对多种抗癌药物产生耐药性的最常见原因是外排泵的过度表达。靶向抑制这些泵可以使癌症对化疗药物重新敏感，同时最大限度地减少副作用。

DESCRIPTION (provided by applicant): Overexpression of energy dependant drug efflux pumps in cancers has been shown to be correlated with multi-drug resistance. This is a serious issue as patients who develop refractory cancers have average five year survival rates as low as 10-30%. Administration of drug efflux pump inhibitors has been explored to resensitize multi-drug resistant (MDR) cancers to chemotherapy drugs. Many inhibitions however were toxic at levels required for effective pump inhibition and showed many off-target side effects. Selective delivery of these inhibitors via receptor mediated endocytosis provides an attractive strategy to selectively resensitize MDR cancers while minimizing toxicity and side effects. Two amino acid receptors, LAT1 and Asct2, are overexpressed in many cancers which also commonly develop multi-drug resistance. Selective delivery of the latest generation pump inhibitors may be achieved via conjugation to LAT1 or Asct2 recognition elements. MDR cancer cell lines will be used to guide and optimize the LAT1/Asct2 recognition element and conjugation site. Inhibition of the conjugated sensitizer will be compared to the parent compound and the role of the vector in delivery of the conjugate will be determined by blocking LAT1/Asct2 receptors. Potency, efficacy, selectivity, toxicity, and off-target effects will be explored though DMPK analysis and orthotopic xenograft models. PUBLIC HEALTH RELEVANCE: The most common reason for the development of resistance of cancers to multiple classes of anticancer drugs is through the over-expression of efflux pumps. Targeted inhibition of these pumps could resensitize the cancer to chemotherapy drugs while minimizing side effects.