Study: Small molecule proves successful in blocking tumor growth

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In an effort to treat glioblastoma multiforme (GBM), researchers have used a combination of radiotherapy and the clinically approved drug AMD3100--a small molecule inhibitor-- to successfully block a secondary tumor-growth process in laboratory mice, according to an article published online Feb. 22 in the Journal of Clinical Investigation.

Lead author Mitomu Kioi and colleagues from the division of radiation and cancer biology, department of radiation oncology at Stanford University School of Medicine, discovered that vasculogenesis--a process that irradiated tumors turn to recruit cells from the bone marrow to form new blood vessels where none existed before--must be blocked in order to stop the oxygen and nutrient supply to the cancer cells to prevent any growth after radiation.

The authors said that  “despite the high doses of radiation delivered in the treatment of patients with GBM, the tumors invariably recur within the irradiation field, resulting in a low cure rate.” The researchers noted that while radiotherapy can shrink tumors, regrowth typically occurs quickly, often within weeks or months post-radiation treatment.

Utilizing immunocompromised lab mice implanted with GBM cells to study the tumors, the authors focused their 100-day study primarily on GBM and how these tumors, similar to other tumors, use vasculogenesis as a backup blood supply.

"What we hadn't realized until recently is that radiation meant to kill the cancer cells also destroys the existing blood vessels that nourish the tumor,” said Martin Brown, PhD, co-author and professor of radiation oncology. “As a result, [the tumors must] rely on a backup blood delivery pathway."

Similar to the process that occurs in humans, radiation brought about tumor regression in the mice. After tumor starvation had begun, the researchers noted that the cancer cells began to express a molecule called hypoxic-inducible factor 1 (HIF-1), which initiates vasculogenesis. Blocking HIF-1 activity by employing AMD3100 to prevent this secondary tumor-growth process stopped irradiated tumors from recurring, wrote the authors.

In addition, the authors found that when HIF-1 activity was uncompromised, irradiated tumor growth recurred quickly and approached lethal size by around day 70.

The researchers administered a continuous infusion of AMD3100 to the mice, as well as an antibody against HIF-1, and found that this process prevented tumor recurrence in the mice.

AMD3100 has already been cleared for clinical use in humans and the study authors hope that future research together with this drug will include clinical tests in humans, while noting that this is most likely years away.