Despite improvements in survival achieved by the addition of temozolomide (TMZ) to adjuvant radiation therapy (RT) for newly diagnosed glioblastoma multiforme (GBM), patients with this deadly disease experience a 100% recurrence rate. Molecular mechanisms that allow tumor cells to survive adjuvant therapy must be identified and therapeutically targeted to improve outcomes. Autophagy, an intracellular process characterized by the formation of autophagic vesicles that sequester cytoplasmic contents and target them for degradation in lysosomes has been observed in GBM cells treated with TMZ or RT. Preclinical studies have determined that therapy-induced autophagy is a survival response that can contribute to chemotherapy resistance and tumor recurrence. These studies found that the lysosomotropic antimalarial hydroxychloroquine(HCQ) can inhibit therapy-induced autophagy and enhance tumor cell death. Autophagy inhibition with HCQ is associated with an accumulation of large ineffective autophagic vesicles which can be quantified in both tumor tissue and peripheral blood mononuclear cells (PMBC). In order to translate these preclinical findings into clinical benefit, a phase I/II protocol testing HCQ with TMZ and RT for newly diagnosed GBM will be conducted through the New Approaches to Brain Tumor Therapy consortium. This 9-center CTEP- approved clinical trial will enroll 88-94 patients in one year. The correlative studies outlined in this proposal will test two hypotheses: 1) autophagy inhibition can be measured using a novel assay at clinically achievable doses of HCQ in combination with TMZ and RT;and 2) the genetic characteristics of tumors most susceptible to autophagy inhibitors can be identified. These hypotheses will be tested through the completion of three specific aims using blood, and tissue samples from patients enrolled on this clinical trial:
Specific aim 1 is to measure autophagy inhibition in PBMCs.
Specific aim 2 is to characterize the pharmacokinetic profile of HCQ and correlate this to measurements of autophagy inhibition.
Specific aim 3 is to characterize the mutational status and copy number of genes that control autophagy and are frequently dysregulated in GBM, and correlate genotype to survival. The knowledge gained from these studies will provide the basis for proposals of future clinical trials and preclinical investigations of HCQ, or other novel autophagy inhibitors. This long-term objective has the potential to significantly impact the care of patients with GBM and other treatment-refractory malignancies and is immediately relevant to the NCI mission of incorporating of state-of-the-art cancer treatments into clinical practice.
The inhibition of therapy-induced autophagy with hydroxychloroquine enhances tumor regression in mouse models. This proposal describes correlative studies designed to understand the role of autophagy inhibition as a therapeutic strategy using biological tissue from patients with newly diagnosed glioblastoma multiforme enrolled on a multi- institution phase I/II trial of hydroxychloroquine in combination with standard therapy. The knowledge gained from these correlative studies has the potential to impact the treatment of patients with brain tumors and other treatment-refractory cancers.
|Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G et al. (2014) A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 10:1359-68|