Introduction: Hypoxia underlies aggressive behavior and therapy resistance in glioblastoma (GBM) through upregulation of hypoxia inducible transcription factors (HIFs). Renewed interest in transcription factor inhibition stems from underwhelming responses to downstream inhibitors. HIF-2a is expressed in glioma stem-like cells and correlates with REMBRANT patient survival. PT2385 is a novel, first-in-class, HIF-2a inhibitor in clinical trials. HIF-2a abundance was examined in GBM and PT2385 efficacy was tested in a preclinical model.

Methods: HIF-2a expression in fifty-seven gliomas (grade II-IV) was verified by a neuropathologist using immunohistochemistry. Epitopes were retrieved with Tris EDTA pH 9.0, probed with a HIF-2a antibody (sc-13596), and counterstained with horseradish peroxidase. Intracranial implantation of 6x105 luciferase-patient derived cells in nu/nu mice were followed with bioluminescent imaging. In the single agent cohort, PT2385 was administered 10mg/kg PO BID in half the animals. In the standard of care cohort, Radiation therapy (RT) (20Gy in 4 fractions) and 50mg/kg concurrent temozolomide (TMZ) was given in half with PT2385 added in the other half. OS was analyzed using a Mantel-Cox test.

Results: HIF-2a expression was absent in 4/4 Grade II and 8/11 Grade III (73%) gliomas. In 42 GBMs, HIF-2a was expressed in 27 (64%) with noted staining in recurrent samples. Staining was present in perivascular and perinecrotic regions. Single agent in vivo studies demonstrated increased tumor signal in placebo animals. Median OS improved from 127 to 138 days in placebo vs. PT2385 (p=0.04, n=21). TMZ/RT animals demonstrated increased imaging radiance compared to TMZ/RT/PT2385.

Conclusions: HIF-2a expression positively correlates with increasing glioma grade and clusters in perivascular and perinecrotic niches. In vivo testing demonstrated single agent efficacy of PT2385. Standard of care arm survival analysis is underway. These data support exploring HIF-2a as a therapeutic target in GBM.

Patient Care: Hypoxia has long been recognized central to malignant pathology and therapy resistance (i.e. radiation resistance) in gliomas, however, until now specific therapeutic targeting of this pathway did not exist. A new, first-in-class HIF2a inhibitor, PT2385, is under FDA consideration in renal cell carcinoma and the role of HIF2a in gliomas is of heightened interest. This work compliments an ongoing Phase II Clinical trial of PT2385 in recurrent gliomas and establishes preclinical evidence for the possible role for PT2385 as a adjunct in upfront treatment for patients with GBM.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of HIF2a as a target in gliomas 2) Discuss, in small groups the evidence support HIF2a as a value therapeutic target 3) Identify an effective treatment for patients with gliomas involving a HIF2a inhibitor, PT2385

References: Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93(4):266-276. http://www.ncbi.nlm.nih.gov/pubmed/11181773. Accessed October 30, 2017. Li Z, Bao S, Wu Q, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15(6):501-513 Courtney K, Infante J, Lam E, et al. A phase I dose escalation trial of PT2385, a first-in-class oral HIF-2a inhibitor, in patients with advanced clear cell renal cell carcinoma. In: ASCO Meeting Abstracts. Chicago; 2016