Plerixafor Blocks Pathway That Limits Anti-Angiogenesis Therapy

New FDA approved drug, plerixafor, which is a CRCX4 inhibitor, reduces resistance to anti-angiogenesis treatment by blocking VEGF-signaling pathway.

A potential drug that improves efficacy of angiogenesis inhibitors was recently identified by a research team at the Massachusetts General Hospital. Angiogenesis inhibitors are drugs that fight cancer by blocking the formation of the blood vessels that feeds the tumor. However, earlier research has showed how anti-angiogenesis treatment can negatively interfere with immune response against colorectal cancer.//

The same team has now identified another pathway that induces an immuno-suppressive tumor microenvironment. The research team showed that using the FDA approved drug, plerixafor, this particular pathway can be blocked ensuring that the tumor is attacked by the immune cells.

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‘Anti-angiogenesis treatment using the drug, plerixafor, inhibited anti-VEGF induced immune cell accumulation, while maintaining basal levels of these important immune cells.’

Limitations of the Anti-Angiogensis Drugs

"Blocking VEGF signaling - the major target of approved anti-angiogenesis drugs - has shown significant but limited survival benefit for colorectal cancer patients, due to the development of resistance," explains Dai Fukumura, MD, PhD, deputy director of the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology and co-senior author of the current study, which has been published in the online PNAS Early Edition. "By unveiling a previously unknown mechanism of resistance to anti-angiogenic therapy, our findings provide a rapidly translatable strategy to enhancing treatment outcomes."

In their earlier study published in the Journal of Clinical Investigation, the researchers found that angiogenesis inhibitor treatment led to the accumulation of certain innate immune cells - monocytes and neutrophils - in the tumor microenvironment. The early infiltration of a specific subset of cells, called non-classical monocytes, induced the migration of neutrophils and the expression of factors that inhibit the proliferation and function of T cells, blocking the anti-tumor immune response.

Angiogenesis
Angiogenesis is the process of formation of new blood vessels from pre-existing blood vessels. It occurs both in health as well as disease.

While a gene therapy approach to blocking the immunosuppressive pathway identified in the JCI study improved treatment in a mouse model of colorectal cancer, no drug targeting that pathway is currently available, leading the MGH team to search for alternatives. A 2009 study from members of the same team had found that expression of a receptor molecule called CXCR4 and the molecule it binds to, CXCL12, were increased in tumor biopsies from rectal cancer patients treated with anti-VEGF therapy. Since the CXCR4/CXCL12 pathway is known to regulate immune cells, including the more common classical monocytes, the team explored its potential role in the regulation of non-classical monocytes.

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After confirming that anti-VEGF therapy increased expression of CXCR4 and CXCL12 in mouse models of colorectal cancer, the team tested the effects of using an FDA-approved CXCR4 inhibitor called AMD3100 or plerixafor to block the pathway. They found that the addition of AMD3100 significantly enhanced the effects of anti-VEGF therapy and alleviated the anti-VEGF-induced reduction in T cells. CXCR4 was found to be expressed primarily on monocytes and neutrophils in the tumor microenvironment, and blocking the pathway with AMD3100 reduced the infiltration of immunosuppressive non-classical monocytes and neutrophils, improving treatment efficacy.

"We anticipate that these novel findings on the immunosuppressive role of non-classical monocytes in colorectal cancer will trigger follow-up studies in other types of cancer, as well as in inflammatory diseases, leading to the development of multiple therapeutic regimens," says Fukumura, an associate professor of Radiation Oncology at Harvard Medical School (HMS).

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Rakesh K. Jain, PhD - director of the Steele Labs, Cook Professor of Radiation Oncology (Tumor Biology) at HMS, and co-senior author of the PNAS paper - adds, "While AMD3100 treatment abolished anti-VEGF-induced innate immune cell accumulation, it did not affect basal levels of these important cells, which supports the favorable safety profile of this agent and should facilitate clinical translation."

Source-Eurekalert