Abstract
Stereotactic Ablative Radiotherapy (SAbR) has revolutionized the treatment of non-small cell lung cancer (NSCLC). Despite these advances, treatment-limiting normal tissue toxicities preclude the use of fully potent radiation prescriptions in large or centrally located tumors. Radiation-induced lung fibrosis (RILF), thought to be generated by the production of superoxide in irradiated tissues, is a natural target for agents to limit RILF and allow for fully potent SAbR. GC4419 (Galera Therapeutics, St. Louis, MO), a selective, small molecule superoxide dismutase (SOD) mimetic, acts as both a protector and mitigator from RILF. However, GC4419 also enhances the response of NSCLC tumor xenografts to radiation, especially high dose per fraction schedules. The described studies serve to highlight this dual utility. All normal tissue studies were conducted using C57.Bl/6 mice and all human tumor xenograft studies were conducted using NSCLC cell lines grafted onto athymic nu/nu mice. A single pretreatment with GC4419 reduced the fibrotic density at 24 weeks of focally irradiated murine lung tissue (54 Gy, single dose). Furthermore, daily post-irradiation (54 Gy, single dose) use of GC4419 also increasingly reduced lung fibrosis based upon the length of time of daily delivery. Since tumor radioprotection is a concern, animals with H1299, A549, and HCC827 lung tumor xenografts were treated with GC4419 30 minutes prior to the tumors being irradiated with a single 18 Gy dose, followed by 4 additional daily doses of GC4419. Tumor growth was significantly delayed (p = 0.0022). Subsequent Tumor Cure Dose (TCD50) assays demonstrated that GC4419 enhanced the efficacy of radiation by a factor of 1.67. Dose enhancement by GC4419 is driven by the size of the dose per fraction. If the dose fractionation scheme is altered to include the biologically equivalent dose schedules of daily irradiations of 2 Gy for 16 days, 4.98 Gy for 5 days, 7.3 Gy for 3 days, or 9.9 Gy for 2 days, the radiation enhancing properties of GC4419 are more pronounced as the dose per fraction increases. This tumor response enhancement is hypothesized to be driven by the overwhelming and persistent production of H2O2 from radiation-induced superoxide by GC4419. This is supported by the fact that the GC4419-enhanced response to radiation treatment of tumors derived from H1299CAT cells, (doxycycline driven catalase overexpressing) is completely abrogated upon catalase overexpression. These findings suggest that GC4419 not only displays clinical potential as a normal tissue radiation protector and mitigator, but also has the additional advantage of enhancing tumor response to radiation treatment, especially SAbR.
Published Version
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