BOSTON -- James W. Mier, MD, an investigator in the Division of Hematology/Oncology and Director of Basic Research for the Biologic Therapy Program at Beth Israel Deaconess Medical Center (BIDMC), has been awarded an AACR-Kure It Grant for Kidney Cancer Research from the American Association for Cancer Research (AACR) and the nonprofit organization Kure It. The $250,000 award will be presented to Mier on April 9, during the 2013 AACR Annual Meeting in Washington, DC.
The AACR Kure-It grants provide support for innovative translational kidney cancer research designed to improve the survival and quality of life of patients with kidney cancer. Mier is one of only two recipients of the two-year grants.
Mier's research focuses on tumor angiogenesis in renal cell carcinomas and an understanding of how and why renal cell carcinomas develop resistance to VEGF (vascular endothelial growth factor) inhibitors. "An immediate challenge in kidney cancer concerns determining what drives resistance to VEGF inhibition and how to overcome it," explains Mier, an Associate Professor of Medicine at Harvard Medical School and investigator in the Dana-Farber/Harvard Cancer Center.
Common mutations in kidney cancer turn on genes that signal oxygen deprivation. This promotes the growth of new blood vessels and alters cancer cell metabolism towards pathways that support more rapid growth, proliferation and metastasis. A tumor's dependence on new blood vessel growth, known as angiogenesis, makes it sensitive to anti-angiogenesis drugs, which have been used to treat kidney cancer. However, over time, kidney cancer can become resistant to these agents.
But as Mier explains, unlike in lung cancer and other cancers, kidney cancer's resistance to VEGF inhibitor drugs does not result from the cancer cells acquiring new mutations. "Instead, the kidney tumor makes reversible, metabolic adaptations to survive hypoxia, the depletion of oxygen induced by the loss of vascular supply," he explains. In addition, kidney tumors also adapt to VEGF inhibitor agents by disabling the important tumor suppressor p53.
The new AACR-Kure It grant will support Mier's preclinical work developing a way to foil kidney cancer's dual-survival strategy and prevent or delay resistance to VEGF inhibitor drugs. "We are finding that by inhibiting an enzyme called HDM2—which tags p53 for deactivation – we can raise p53 activity levels and block the influx of myeloid cells into the tumor," explains Mier. "HDM2 inhibitors thus both promote cell death and suppress a resistance strategy." His laboratory will explore the mechanism by which HDM2 antagonists and VEGF-targeted drugs act together to block tumor angiogenesis and induce disease regression in renal cell carcinomas.
"The Mier Lab has long been a leader in improving our understanding of melanoma and kidney cancer biology," adds David McDermott, MD, Co-director of the Kidney Tumor Program and Clinical Director of the Biologic Therapy Program at BIDMC. "This grant is well deserved recognition of their efforts. With HDM2 antagonists entering the clinic, we hope to bring this novel combination therapy to patients within the next year."
A graduate of the Indiana University School of Medicine, Mier completed his internship and residency at Emory University and received oncology training at the National Cancer Institute in the Laboratory of Tumor Cell Biology.
"I am honored to have been selected for this grant and am grateful to Kure It and the AACR for making the funds available," said Mier. "Everyone in my lab feels encouraged by this award. We are planning to use the funds to carry out preclinical studies of novel agents that may prove useful in patients with renal cell carcinoma."
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www.bidmc.org.
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