July 27, 2001

Khan combats cancer with $1 million grant

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Wasif Khan, Ph.D., will use the grant to study the signaling pathways that control immune cell growth. (photo by Dana Johnson)

Khan combats cancer with $1 million grant

Wasif N. Khan, Ph.D., assistant professor of Microbiology & Immunology, has received one of the largest American Cancer Society research grants ever awarded to an individual investigator at Vanderbilt. With the four-year, $1 million grant, Khan and colleagues will study the signaling pathways that control immune cell growth, and what goes wrong to lead to immune cell cancers like Hodgkin’s lymphoma.

Khan’s studies stem from his fascination with the regulatory controls that limit multicellular organisms and their organs to a defined size. Tumors, he said, manage to escape these controls and grow to unlimited sizes, so understanding the normal controls should provide new clues for improved cancer treatments. Khan focuses on cells of the immune system, because it is the body’s most dynamic “organ,” he said.

“Our bone marrow produces millions and millions of immune cells everyday, and only a small percentage of these live because the system has to maintain its normal size and cell number,” Khan said. “The immune system is ideal as a model for understanding cell growth and cell death.”

Khan’s research focuses on B cell – the group of immune system cells that produce antibodies to fight against infections. These cells, in particular, provide a good analogy to tumors, he said. When a B cell recognizes an infectious agent such as a bacterial cell or virus, that single B cell gives rise to a whole population of identical B cell clones that produce antibodies to fight the infectious agent. Similarly, a tumor gets its start from a single cell, Khan said.

“In the immune system, a process of massive expansion of one cell clone can happen everyday,” he said. “And when the infection is gone, these cells are eliminated by an active program of cell death to return the system to its normal state. Why can we regulate cell growth and death in this system, but not in the case of a tumor?”

Khan believes the answers to this question lie in understanding the complex signaling networks inside cells. “That’s where the biochemical key is to how cells regulate growth,” he said.

Although it is clear that genes are the critical determinants of size control, Khan said, “we have just begun to understand how genes are regulated in response to environmental cues.” In the B cell, signals from infectious agents outside the cell activate biochemical signaling networks that lead to changes in gene expression. Understanding these networks is essential to efforts to develop therapeutic strategies for the treatment of immune cell pathologies, Khan said.

Khan and colleagues have already identified several of the signaling proteins that participate in a key B cell signaling pathway. “We know the identity of these components,” he said, “but we have yet to understand the interplay between them.”

Abnormalities in this key signaling pathway can have two extreme consequences – loss or absence of B cells at one extreme, malignant overgrowth of cells at the other.

Absent B cells result in immunodeficiency diseases; the first such disease discovered in humans, X-linked agammaglobulinemia, is caused by the loss of a tyrosine kinase that appears to function as a central switch for the signaling pathway Khan studies.

Hodgkin’s lymphoma, a blood cancer that will affect about 7,500 Americans this year according to the Leukemia & Lymphoma Society, recently was linked to continuous over-activity of the same pathway. Khan hypothesizes that some of the proteins in this signaling pathway are responsible for Hodgkin’s lymphoma and could serve as new drug targets. “We do not have a certain molecular target right now,” Khan said, “but we are paving the way towards the discovery of new drugs.” Strategies aimed at turning off the over-active biochemical signals hold definite promise for the treatment of patients with Hodgkin’s lymphoma, he said.

Khan’s American Cancer Society grant was highly ranked in a competitive field – it was number two out of 50 reviewed proposals. Khan credits his lab members, Ben Petro, Jamshedur Rahman, and Nicholas Shinners, and co-investigator Dean W. Ballard, Ph.D., professor of Microbiology & Immunology, for the proposal’s success. The early results from these studies have been selected for presentation at an international immunology conference in Stockholm this month. “Our work is being recognized by both immunology and cancer investigators at many levels,” Khan said.