OHSU partners with UO, Harvard to expedite research into compounds that may prevent Fanconi anemia

National Institutes of Health grant expands OHSU's 15-year research effort into the cause, prevention, treatment of the disease

Oregon Health & Science University is partnering with the University of Oregon and Harvard Medical School to expedite basic science research into new and existing drugs and compounds that may prevent the complications associated with Fanconi anemia, an inherited condition that can lead to bone marrow failure and cancer.

With a new $10.7 million grant from the National Heart Lung and Blood Institute, a branch of the NIH, the research teams will screen and sort thousands of drug candidates in mice at OHSU, zebra fish at UO and human cell lines at Harvard.

Approximately 1,000 of the drug candidates to be screened already have been approved by the FDA to treat other medical conditions, which could expedite their application in Fanconi anemia. Another 10,000 molecules with similar properties, but randomly modified for various biological reactions, also will be screened for therapeutic benefits.

"This generous NIH grant coupled with our long-running association with the Fanconi Anemia Research Fund will allow us to quite literally pursue the bench-to-bedside vision of turning fundamental basic research into therapies we can use with patients. This project highlights the value of integrative collaboration," said Markus Grompe, M.D., principal investigator and director of the OHSU Pap- Family Pediatric Research Institute, and professor of pediatrics, OHSU Doernbecher Children's Hospital.

Some of the potential drugs candidates were first identified at a Fanconi Anemia Research Fund workshop in Portland. The fund - founded by former UO President Dave Frohnmayer and his wife, Lynn, who have lost two daughters to the disease - provided nearly $650,000 to pursue ideas developed at the workshop.

"This NIH grant will expand and hasten the efforts of this large collaborative effort to identify new therapies for Fanconi anemia patients," said Lynn Frohnmayer. "The projects involved in this grant have direct implications for our family. Our 23-year-old daughter is at high risk for bone-marrow failure and cancer. The identification of therapeutic compounds that could delay or prevent these life-threatening complications cannot happen too soon."

"Markus Grompe's choice to focus on experimental therapeutics was a risky step that all of us supported but tends to push the comfort zone of scientific reviewers," said Grover Bagby, M.D., co-investigator and member of the OHSU Knight Cancer Institute. "Our goal of finding drugs that will reduce the complications of this disease is a huge one, but we know enough about the development and characteristics of this disease to embark on this exciting new research path with a good deal of optimism."

Grompe will test the efficacy of small molecules in preventing tumors in mice with Fanconi anemia, identify small molecules that enhance the production of blood cells by the bone marrow cells of humans and mice with Fanconi anemia, and clarify the role of male hormones in enhancing the function of Fanconi stem cells. Grompe, also an investigator in the OHSU Knight Cancer Institute, has identified a promising agent for cancer prevention and blood cell production in his mouse model.

Grompe also will test each promising molecules identified by co-investigators John Postlethwait, Ph.D., professor of biology and member of the UO Institute of Neuroscience, and Alan D'Andrea, M.D., professor of radiation oncology at Harvard Medical School.

Postlethwait will use an assay-based drug-screening technology developed in zebra fish. He previously created mutant strains of zebra fish that contain the disease version of the genes.

Fanconi anemia results from a breakdown of DNA repair in cells with mutations in the involved genes. The breakdown occurs just after DNA synthesis and before cell division. When DNA repair fails to take place, mutations can lead to a rapid proliferation of damaged cells.

Bagby will test the idea that some complications of Fanconi anemia, including cancer and leukemia, might depend on Fanconi protein functions other than DNA repair. He and Postlethwait will be able to test this hypothesis using the zebra fish model. This research is based on his prior discovery that some of the Fanconi anemia proteins have more than one function and that some of these functions include controlling biochemical pathways for cell survival and the function of the innate immune system.

"There are human cell lines for all of these mutations," Postlethwait said. "In principle, you could test these molecules more cheaply and rapidly in human cell lines. The problem is that human cell lines don't have livers, which detoxify or metabolize chemicals, or kidneys that often excrete drugs. Zebra fish are whole animals. We can test for excretion of the molecules by filtering organs and for toxicity issues in living organisms."

Research on Fanconi anemia feeds into the pathways of general breast, ovarian and prostate cancers because one of the Fanconi anemia genes, FANCD1, is involved in all of them. "So all of this work is relevant to all of those cancers and probably others, especially several types of leukemia," Postlethwait said.