Inhibition of Autophagy: A Novel Therapeutic Strategy for Advanced Solid Tumors

描述（由申请人提供）：尽管开发了几种靶向药物，但常规治疗失败的晚期癌症患者预后极差。确定导致治疗耐药的机制对于改善临床结果至关重要。自噬是一种细胞生存途径，使细胞通过降解受损的蛋白质和细胞器来恢复ATP和其他形式的代谢燃料。面对治疗性应激，自噬可能通过提供替代能量来源来促进生存，从而在耐药过程中发挥重要作用。我们最近发现抗疟疾药物氯喹（CQ）及其衍生物羟氯喹（HCQ）抑制自噬，并显著提高组蛋白去乙酰化酶抑制剂亚eroylanilide羟肟酸（SAHA）的疗效。TP53肿瘤抑制基因在人类肿瘤中经常发生突变/缺失，其功能丧失与耐药和临床预后不良有关。值得注意的是，在临床前研究中，无论是否存在功能性TP53， HCQ和SAHA的联合作用都是相同的。为了将这些发现转化为临床效益，我们将对HCQ和SAHA联合治疗晚期实体瘤患者进行I期临床药代动力学（PK）和药效学（PD）研究。我们推测，添加HCQ可以增强SAHA的抗肿瘤活性，但不会增加主要毒性。我们提出3个具体目标来检验我们的假设。在Specific Aim 1中，我们将研究HCQ联合SAHA治疗晚期实体瘤患者的安全性、耐受性和活性。在Specific Aim 2中，我们将通过对患者外周血单个核细胞和肿瘤组织的一系列相关研究来评估HCQ与SAHA联合使用的PD。我们将量化自噬抑制和治疗对与SAHA活性相关的关键生物标志物的影响。将测定TP53的突变状态和拷贝数，以研究TP53状态与应答率之间的潜在相关性。在具体目标3中，我们将研究HCQ对SAHA的PK的潜在影响。从这些研究中获得的知识将为未来研究HCQ和其他新型自噬抑制剂提供一个平台。抑制自噬是一种创新的抗癌策略，针对癌细胞的内在脆弱性，有可能显著影响晚期实体瘤和其他治疗难治性恶性肿瘤患者的护理。我们的研究将立即为NCI的使命做出贡献，将新的临床前研究结果转化为癌症患者的临床益处。公共卫生相关性：在临床前模型中，羟基氯喹（HCQ）抑制自噬可显著增强组蛋白去乙酰化酶抑制剂亚羟苯胺羟肟酸（SAHA）的抗癌活性。拟议的I期临床试验将研究这种新型治疗策略在晚期实体瘤患者中的安全性、耐受性和活性。提出的相关研究将使我们更好地了解自噬抑制作为一种抗癌策略的作用。从这项研究中获得的知识有可能显著影响晚期实体瘤和其他难治性恶性肿瘤患者的护理，并将为HCQ和其他新型自噬抑制剂的未来研究提供平台。

DESCRIPTION (provided by applicant): Despite the development of several targeted agents, patients with advanced cancer that fail conventional therapies have an extremely poor prognosis. Identification of the mechanisms that contribute to therapeutic resistance is essential to improve clinical outcomes. Autophagy is a cell survival pathway that enables cells to recoup ATP and other forms of metabolic fuel by degrading damaged proteins and organelles. Autophagy may play a significant role in drug resistance by providing alternative energy sources to promote survival in the face of therapeutic stress. We recently established that the antimalarial drugs chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) inhibit autophagy and significantly increase the efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). The TP53 tumor suppressor gene is frequently mutated/deleted in human tumors and its loss of function is associated with drug resistance and a poor clinical prognosis. Notably, the combination of HCQ and SAHA was equipotent in the presence and absence of functional TP53 in preclinical studies. In order to translate these findings into clinical benefit, we will conduct a Phase I, clinical pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of HCQ and SAHA in patients with advanced solid tumors. We hypothesize that the addition of HCQ will enhance the antitumor activity of SAHA without adding major toxicity. We propose 3 Specific Aims to test our hypothesis. In Specific Aim 1, we will investigate the safety, tolerability, and activity of HCQ in combination with SAHA in patients with advanced solid tumors. In Specific Aim 2, we will evaluate the PD of HCQ administrated in combination with SAHA with a series of correlative studies in peripheral blood mononuclear cells and tumor tissue from patients. We will quantify autophagy inhibition and the effects of treatment on key biomarkers associated with SAHA activity. The mutation status and copy number of TP53 will be determined to investigate a potential correlation between TP53 status and response rate. In Specific Aim 3, we will investigate the potential impact of HCQ on the PK of SAHA. The knowledge gained from these studies will provide a platform for future investigations with HCQ and other novel autophagy inhibitors. Inhibition of autophagy is an innovative anticancer strategy that targets an intrinsic vulnerability in cancer cells and has the potential to significantly impact the care of patients with advanced solid tumors and other treatment-refractory malignancies. Our study will immediately contribute to the NCI's mission to translate the findings of novel preclinical investigations into clinical benefit for cancer patients. PUBLIC HEALTH RELEVANCE: The inhibition of autophagy with hydroxychloroquine (HCQ) significantly enhances the anticancer activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in preclinical models. The proposed Phase I clinical trial will investigate the safety, tolerability, and activity of this novel therapeutic strategy in patients with advanced solid tumors. The proposed correlative studies will enable us to better understand the role of autophagy inhibition as an anticancer strategy. The knowledge gained from this investigation has the potential to significantly impact the care of patients with advanced solid tumors and other treatment- refractory malignancies and will provide a platform for future studies with HCQ and other novel autophagy inhibitors. )