Abstract PO-096: Blocking the CXCL12/CXCR4 pathway both radiosensitizes brain metastases in mice and protects against radiation-induced cognitive dysfunction following whole brain irradiation in rats

We have previously shown using an antagonist of CXCR4 (plerixafor) with brain implanted tumors in mice(1)or by blocking CXCL12 by olaptesed pegol (ola-peg) with chemically-induced brain tumors in rats(2) that the radiation response of the tumors is markedly enhanced by blocking the CXCL12/CXCR4 pathway. In the present study we aimed to test whether a similar radiation enhancement is produced in mice with multiple brain metastases, and in addition, in preparation for a clinical trial of whole brain irradiation (WBI) with plerixafor, we sought to determine whether blocking the CXCL12/CXCR4 pathway would affect the cognitive dysfunction of rats given WBI. In the brain metastasis study we produced multiple brain metastases by injection of the luciferase transduced brain-tropic human breast triple negative cancer cell line MDA-MB-231 B3 into the internal carotid artery of nude mice. Adding the CXCL12 antagonist ola-peg after irradiation produced both a doubling of the regrowth delay (as monitored by bioluminescence imaging) and median survival time compared to irradiation alone. We also showed that similar to the brain implanted human glioblastoma studies that blocking the pathway prevented the radiation-induced influx of tumor associated macrophages (TAMs) into the brain metastases. In preliminary studies with cognitive dysfuction we gave adult Sprague-Dawley rats whole brain irradiation of 5, 10, 15 or 20 Gy and 2 months later measured their short term memory using the novel object recognition (NOR) test. We found that 20 Gy but not lower doses abrogated the rats’ ability to recognize novel objects, a key test of memory. Importantly we showed in a follow-up study that a 4-week infusion of plerixafor started immediately after irradiation (with the same dosing and schedule as our earlier tumor studies) not only did not affect memory in the controls and 15 Gy WBI groups but completely protected against memory loss in the 20 Gy group. In conclusion we showed that blocking the CXCL12/CXCR4 pathway not only potentiates the radiation response of a breast cancer brain metastasis model in mice but also protects against radiation-induced cognitive dysfunction in rats. This has led us to propose that blocking of this pathway which prevents the radiation-induced influx of TAMs into tumors and normal tissues is a novel strategy to enhance the therapeutic ratio of radiotherapy (3). 1. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 2010; 120:694-705. 2. Liu SC, Alomran R, Chernikova SB, Lartey F, Stafford J, Jang T, et al. Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats. Neuro Oncol 2014; 16:21-8. 3. Brown JM, Thomas R, Nagpal S, Recht L. Macrophage exclusion after radiation therapy (MERT): A new and effective way to increase the therapeutic ratio of radiotherapy. Radiother Oncol 2019; 144:159-64. Citation Format: Martin Brown, Mehrdad Shamloo, Sophia Chernikova, Lawrence Recht. Blocking the CXCL12/CXCR4 pathway both radiosensitizes brain metastases in mice and protects against radiation-induced cognitive dysfunction following whole brain irradiation in rats [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-096.