A physician-scientist, Shahin Rafii is motivated by his cancer patients to explore new therapeutic frontiers—and so far, he's charting promising new territory. The innovative work in his lab suggests entirely new approaches to treating leukemia and lymphoma, and may soon enable higher, more effective doses of chemotherapy that do not induce severe toxicity. He has also paved the way for cellular stem cell therapy for vascular insufficiencies, such as stroke and heart attack.
Rafii introduced the concept that both tumors and regenerating organs rely on stem cells from the bone marrow to help build new blood vessels. By deciphering the molecular pathways that orchestrate recruitment, differentiation, and patterning of these vessels, he hopes to exploit those pathways for multiple clinical applications.
Both tumor cells and injured tissue—such as that at the site of a heart attack, stroke, or organ transplant—recruit stem cells hibernating in the bone marrow as the source of their new blood vessels. By the time the stem cells arrive, they have begun to differentiate into two types of cells: a specialized white blood cell and the maturing endothelial progenitor cell, which work together to create the lining of the new vessels that fuel the growth of tumors or new or regenerating tissue. Similarly, he has shown that molecular and cellular collaboration between vascular and organ-specific stem cells is essential for the generation of functional tissue, such as bone marrow, heart, and muscle tissues.
Rafii has discovered specific types of mobilizing factors that wake up the stem cells in bone marrow and move them to vascular niches, where new blood vessels are formed, dramatically speeding up restoration of the blood cells destroyed by chemotherapy or radiation. The same factors may increase the supply of stem cells that rush in to repair or regenerate tissue.
Rafii has demonstrated that interfering with the migration of stem cells from the bone marrow can halt tumor growth. He and colleagues have also harnessed the selective homing mechanism of stem cells to deliver toxic payloads to the "tumor vascular niches" by loading the stem cells with cancer-killing agents.
Scientists once believed that a new class of experimental cancer drugs targeting the molecules needed for blood vessel growth, or angiogenesis, would only be useful in halting solid tumors by depriving them of oxygen and nutrients. But Rafii has found that angiogenic endothelial cells are also crucial to promote the growth of hematological malignancies, including myelomas, leukemias, and lymphomas, as they release growth factors that fuel proliferation and invasion. Now, clinical trials are under way to test antiangiogenic agents to treat hematological malignancies.