Induction of Sub-Clinical Hyperthyroidism as a Strategy to Boost Anti-Tumorigenic Hydrogen Sulfide Production as a Glioblastoma Therapy
Glioblastoma (GBM) is a debilitating and lethal form of brain cancer, with incidence increasing in the 6th and 7th decades of life. GBM growth and therapeutic resistance are driven by cancer stems cells (CSCs) and a tumor-supporting microenvironment. However, it is unclear how advanced age renders treatment refractory GBM progression. A recognized hallmark of advanced age is the suppression of enzyme-dependent hydrogen sulfide (H2S) generation and bioavailability. Recently, we found that H2S functions as a tumor suppressor in GBM with H2S attenuating CSC self-renewal and tumor growth in pre-clinical models. We also discovered the dampening of thyroid hormone (TH) signaling enhances H2S production. Surprisingly, clinical trials in the early 2000s utilizing hypothyroid-inducing drugs showed promise in enhancing survival in GBM patients. However, they were set aside for lack of mechanism. Given our recent success elucidating the importance of tumor suppressive H2S, we hypothesize that reduced TH production via oral methimazole intake will bolster the effectiveness of frontline therapy and extend survival by boosting H2S production and signaling within the tumor-bearing brain. This hypothesis will be tested in two aims which will use methimazole-induced hypothyroidism to probe: 1) extended overall survival and reduced CSC burden when combined with standard of care in preclinical GBM models, and 2) stimulating H2S generating enzymes to increase systemic and brain-specific H2S production and signaling within GBM tumor bearing mice. We anticipate these results will drive renewed interest in anti-thyroid drugs serving as anti-GBM interventions and rapidly stimulate new drug repurposing clinical trials.
Glioblastoma (GBM) is a lethal brain cancer found mainly in patients in their 60’s and 70’s. We want to see how age is connected to the increased growth of GBM in patients. The goal of our study is to increase the chance of survival in patients suffering from GBM by repurposing antithyroid hormone drugs.