Re-purposing androgen receptor antagonists for the treatment of glioblastoma
Glioblastoma, a primary brain tumor, is one of the most aggressive solid tumors in current oncological patients. The documented median survival time is 15 months with the current standard of care, including safe surgical resection followed by radiotherapy and temozolomide (TMZ) and adjuvant chemotherapy with TMZ. However, current glioblastoma chemotherapy regimens are primarily inefficient.
Dr. Iris Lavon, an expert in glioblastoma research from the Hadassah Medical Center, discovered that 56% of glioblastoma tumors express high levels of the androgen receptor (AR). This receptor is usually expressed in the prostate but not in the adult brain. Based on this discovery, Dr. Lavon tested the ability of two AR antagonists, enzalutamide (XTANDI®) and bicalutamide, which are approved drugs for prostate cancer, to treat glioblastoma tumors. Although the treatment of nude mice bearing human intracranial glioblastoma with the AR antagonist enzalutamide demonstrated a significant result (p=0.495), it achieved only a moderate prolongation in the mice’s lifespan, possibly due to limited penetration through the blood-brain barrier.
Through a collaboration with Prof. Shlomo Magdassi from the Hebrew University, a novel formulation for enzalutamide and bicalutamide was developed, using generally regarded as safe-(GRAS)-grade excipients. The newly formulated bicalutamide increased its solubility in water by ~1000-folds and enhanced its efficacy.
In two intracranial models of human glioblastoma in mice, treatment with the newly-formulated drug significantly increased the mice’s lifespan compared to the unmodified drug and the TMZ standard-of-care drug.
In a clinical trial, using a unique computerized imaging PET-CT test developed by Prof. Eyal Mishani from Hadassah Medical Center, androgen receptors could be detected for the first time in real-time within brain tumors. In future clinical trials, these patients can be potential responders to androgen antagonist treatment.
Glioblastoma treatment: the potential responders for this treatment from the newly diagnosed patients, selected by the newly developed PET/CT scan, will be treated with this drug, following the six weeks of concomitant therapy of TMZ and radiotherapy on top of the standard-of-care adjuvant TMZ.
The glioblastoma incidence in USA and Europe is 3 per 100,000. Glioblastoma is considered an orphan disease; each year, about 30,000 new cases will be diagnosed in the 7-major markets and 15,000 in the United States. The global glioblastoma treatment market size was valued at USD 2.14Bn in 2020 and is expected to reach USD 4.2Bn by 2028.
A second clinical trial is underway to test whether the PET scan can not only detect the expression of androgen receptors within the tumor but also monitor therapy response. This trial has promising interim results, as seen in the figure below.
- For the treatment of glioblastoma – Patents granted in the US (US 11,478,453 B2) and Europe (3487497)
- For the new formulation –PCT/IL2022/050570 filed on 29/05/2022
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- Zalcman N,. … Lavon, I. Androgen Receptor Activation in Glioblastoma Can Be Achieved by Ligand-Independent Signaling through EGFR-A Potential Therapeutic Target. Int J Mol Sci. 2021 Oct 11;22(20):10954
- Orevi M, Shamni O, Zalcman N, Mordechai A,….. , Mishani E, Lossos A, Lavon I. [18F]-FDHT PET/CT as a tool for imaging androgen receptor expression in high-grade glioma. Neurooncol Adv. 2021 Jan 29;3(1):vdab019.