PENTAAZA MACROCYCLES REDUCING TOXICITY AND INCREASING EFFICACY OF RADIATION THERAPY

Robert A. Beardsley

Research & Development Department, Galera Therapeutics, Inc, USA

Abstract

Radiation therapy’s (RT) well-established effectiveness is limited by tumor radio-resistance or dose restrictions to avoid normal tissue toxicity. Manganese pentaaza macrocycles selectively target the superoxide to hydrogen peroxide pathway – reducing RT normal tissue toxicity while increasing tumor response. These dismutase mimetics significantly reduce radiation toxicity to oral mucosa, lung, liver and other organs in preclinical studies. Normal toxicity reduction appears to result from both previously described anti-inflammatory activities, and additional mechanisms. In a Phase 1b/2a study, GC4419 appeared, compared to contemporary expectations, to reduce incidence (by up to 50%) and duration (by 90%) of severe oral mucositis (OM) in head and neck cancer patients undergoing chemoRT. One-year tumor control and patient survival, and major RT treatment breaks associated with inferior tumor control, compared favorably with contemporary expectations. A placebo-controlled Phase 2b study in this indication is ongoing. In several human xenograft and murine syngeneic tumors, GC4419 also potentiates RT efficacy, including increasing activity of chemoRT and immunoRT combinations, especially with high-dose fraction (up to 18 Gy) RT. Combined results suggest that as dual-action radiation response modifiers - increasing anti-tumor activity and reducing normal tissue toxicity - pentaaza macrocycle dismutase mimetics may transform the use of RT in cancer treatment

Keywords: Radiation, patient, tumor, murine, treatment.