New Glioblastoma Trial Adds Whole-Brain Irradiation to Plerixafor

Lawrence Recht, MD
Martin Brown D.Phil, FASTRO

A Q&A with Martin Brown D.Phil, FASTRO, Emeritus Professor, and Lawrence Recht, MD, Professor, at Stanford University’s Department of Neurology

Q: The treatment of glioblastoma multiforme (GBM) is a serious challenge. Recurrence after initial surgery is common and subsequent treatment almost always unsuccessful. Just as “an army marches on its stomach,” GBM growth depends on blood supply. Successful use of the FDA-approved drug plerixafor (Mozobil) combined with irradiation for mouse model gliomas some years ago has lead to clinical trials in human GBM.

What is the current status of these investigations, and how could our readers help the effort?

A: A little over ten years ago, Dr. Brown began a series of preclinical studies to test the possibility that an important contributor to the recurrence of malignant brain tumors after radiation therapy was reconstitution of the tumor vasculature. Specifically, he hypothesized that this reconstitution stemmed at least in part from circulating pro-angiogenic cells not in the tumor at the time of radiation—a phenomenon known as “vasculogenesis.” In agreement with this concept, a finding common to all of the tumor models he tested was a major influx into the irradiated tumors of bone marrow-derived cells, most of which were macrophages, that correlated with when tumors began to grow two to three weeks after completion of radiation. Further, he demonstrated that the mechanism for this influx was a radiation-induced hypoxia that triggered a cascade that led to the secretion of stromal cell-derived factor-1 (SDF-1), which was instrumental in attracting these cells. The apparent importance of excluding these cells’ entry into tumors post-irradiation suggests a new treatment strategy, which we call macrophage exclusion radiation therapy (MERT). Continue reading…