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的预后极差。确定导致治疗耐药的机制对于改善临床结局至关重要。自噬是一种细胞存活途径，使细胞能够通过降解受损的蛋白质和细胞器来回收ATP和其他形式的代谢燃料。自噬可能在耐药性中发挥重要作用，提供替代能源，以促进在治疗压力下的生存。我们最近确定，抗疟疾药物氯喹（CQ）及其衍生物羟氯喹（HCQ）抑制自噬，并显着增加组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸（SAHA）的疗效。TP 53肿瘤抑制基因在人类肿瘤中经常突变/缺失，其功能丧失与耐药性和不良临床预后相关。值得注意的是，在临床前研究中，HCQ和SAHA的组合在存在和不存在功能性TP 53的情况下是等效的。为了将这些发现转化为临床获益，我们将在晚期实体瘤患者中开展HCQ和SAHA联合治疗的I期临床药代动力学（PK）和药效学（PD）研究。我们假设HCQ的加入将增强SAHA的抗肿瘤活性而不增加主要毒性。我们提出了三个具体目标来验证我们的假设。在特定目标1中，我们将研究HCQ与SAHA联合治疗晚期实体瘤患者的安全性、耐受性和活性。在具体目标2中，我们将通过对患者外周血单核细胞和肿瘤组织的一系列相关研究，评价HCQ与SAHA联合给药的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TP 53的突变状态和拷贝数，以研究TP 53状态与缓解率之间的潜在相关性。在具体目标3中，我们将研究HCQ对SAHA PK的潜在影响。从这些研究中获得的知识将为HCQ和其他新型自噬抑制剂的未来研究提供平台。抑制自噬是一种创新的抗癌策略，其靶向癌细胞的内在脆弱性，并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，用羟氯喹（HCQ）抑制自噬显著增强了组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸（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。这些相关研究将使我们更好地理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，并将为未来使用HCQ和其他新型自噬抑制剂的研究提供平台。)

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. )