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A five-year $5 million grant from the Leukemia & Lymphoma Society will help Columbia and Memorial Sloan-Kettering investigators test an experimental lymphoma drug in clinical trials and also determine how the cancers develop. Dr. Riccardo Dalla-Favera, the Uris Professor of Pathology, professor of genetics and development, and director of the Institute for Cancer Genetics at Columbia, is leading the research.

Lymphomas – solid cancers of the lymph nodes – are the fifth most common cancers in the United States but the most common cancer in people between 30 and 40 years old. Most of the cancers stem from mutations in B cells, which originate from the node's germinal centers where the cells are selected for their ability to produce antibodies against foreign invaders. There are multiple types of B cell lymphoma and prognosis varies widely depending on the type.

New findings about lymphoma made in the past two years by Dr. Dalla-Favera's lab have shown that the cancers develop with a mechanism unique to B cells, but that they are also vulnerable to some new experimental drugs. The grant supports four projects –spanning basic to clinical research – that focus on the most common form of lymphoma, B cell diffuse large-cell lymphoma (DLCL). The overall goal is to identify new gene alterations and develop therapies targeted to the products of those altered genes.

One project will follow up on the recent finding that DLCL can be foiled by a new class of experimental drugs. Dr. Dalla-Favera and Dr. Wei Gu, assistant professor of pathology in the Institute for Cancer Genetics, found that the drugs work by targeting an oncogene that is active in most types of B cell lymphoma. The gene, BCL6, is necessary for the normal growth of germinal center B cells but must be turned off for the B cells to mature and become plasma cells. In lymphoma, BCL6 stays on, causing the cells to remain in the germinal center and develop into cancer.

Drs. Dalla-Favera and Gu have shown that the gene can be turned off by a process called acetylation and that drugs, known as histone deacetylase inhibitors, lead to the accumulation of inactive BCL6 and cell death. The grant will allow Dr. Gu to further explore the mechanism and optimize drugs that lead to BCL6 inactivation.

Based on this finding, Dr. Andrew Zelenetz, chief of the lymphoma service at Memorial Sloan-Kettering, will test a histone deacetylase inhibitor called SAHA in clinical trials with B cell lymphoma patients. Initial studies indicate intravenous SAHA is safe and shows some activity against DLCL tumors in people. Because the initial trials showed prolonged use of SAHA is probably necessary, Dr. Zelenetz is developing an oral form of the drug, which will be tested with support from the grant.

BCL6 is not the only thing to go awry in lymphoma and the grant's researchers will also look at a potential cancer-causing mechanism unique to B cell cancers. During the life of a normal B cell, point mutations pepper the cells' antibody genes to evolve into harder fighting B cells with stronger affinity for their antigens. But the normal hypermutation process can also misfire and hit other genes.

Two years ago, Dr. Dalla-Favera and Dr. Laura Pasqualucci, assistant professor of clinical pathology, discovered that hypermutation misfires in about half of all DLCL tumors, creating mutations in up to four different genes associated with lymphoma. How those mutated genes contribute to lymphoma development is still unknown, and the researchers hope to answer the question with funds from the new grant. Hypermutation's bad aim is also likely to hit other genes important for lymphoma development, and Dr. Dalla-Favera's lab will look for those still unknown genes. Finding these genes may also help the researchers explain the large difference in clinical outcomes among DLCL tumors.

DLCL also can evolve from another type of B cell cancer called follicular lymphoma. The last project in the grant will look for changes that cause most cases of follicular lymphoma to progress and transform into a particularly malignant form of DLCL. Dr. Ragu Chaganti, chief of the cytogenetics service at Memorial Sloan-Kettering, will lead the research.

—Susan Conova


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