Abstract 1817: Overcoming tumor hypoxia in MPNSTs using an implantable micro-catheter

Samual Hatfield; Ryan Courtney; Emily Witt; Jianling Bi; James Byrne

doi:10.1158/1538-7445.AM2025-1817

Malignant peripheral nerve sheath tumors (MPNSTs) are a devastating and rare type of tumor, accounting for 5-10% of all soft-tissue sarcomas, with a 5-year overall survival rate of only 50%. A key contributing factor to the poor outcomes is treatment resistance due to tumor hypoxia. Despite efforts to mitigate tumor hypoxia as a therapeutic strategy, significant challenges remain, including the kinetics of oxygenation, peak partial pressures achieved, and the safety of existing methods. Here, we report on an implantable system for direct intratumoral oxygen injection that synergizes with radiotherapy. We demonstrate that tumor oxygenation using this system slows tumor growth and extends survival in a mouse model of MPNST. Six-to-eight-week-old female C57BL/6J mice bearing subcutaneous right-flank MPNST allograft tumors were separated into four treatment cohorts: oxygen infusion + radiation, radiation, oxygen infusion, and no treatment. For mice receiving oxygen infusion, the center of the tumor was catheterized once tumors reached a volume of 200 mm3. Intratumoral oxygen infusion was achieved using a syringe pump to deliver oxygen at a partial pressure of 50 mmHg. The microcatheters were then removed, and a single 15 Gy radiation dose was administered using a small animal radiation research platform. Following treatment, tumor growth was monitored and measured three times weekly using calipers. Tumor volume was approximated using the formula V = 0.5 × length (L) × width (W)2, where length and width correspond to the x and y measurements of the tumor in mm. Animals were euthanized, and tumors were harvested once their volume reached 2000 mm3. In a separate cohort of mice, tumors were resected one hour after irradiation, formalin-fixed, paraffin-embedded, and stained for γ-H2AX foci. Intratumoral oxygen infusion combined with radiation inhibited tumor growth and extended the median survival of mice with MPNSTs from 13 days (no treatment) to 25 days (oxygen infusion + radiation). Additionally, there was a significant increase in γ-H2AX foci per nucleus in tumors treated with oxygen infusion + radiation compared to radiation alone. We demonstrate that direct intratumoral oxygenation can radiosensitize MPNSTs in a mouse model. The significant reduction in tumor growth observed in mice receiving oxygen infusion + radiation, compared to radiation alone, suggests that tumor oxygenation may improve outcomes when combined with current standard-of-care therapies.

Abstract 1817: Overcoming tumor hypoxia in MPNSTs using an implantable micro-catheter

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