In a significant breakthrough published recently in Nature, researchers at Weill Cornell Medical College and the University of California, San Francisco, have been able to overcome resistance of a form of leukemia to targeted therapy, demonstrating complete eradication of the cancer in cell and animal studies.
The study shows that an investigational drug, RI-BPI, developed at Weill Cornell, in combination with the drug Gleevec shut down stem cells responsi ble for about one-third of acute lymphoblastic leukemia (ALL), a cancer of white blood cells that affects young children as well as older adults. This form of ALL has the so-called Philadelphia chromosome, which is also found in chronic myelogenous leukemia (CML). But while Gleevec has greatly improved survival in CML, it has had a less dramatic effect in ALL, and most patients still die within a relatively short time frame.
That prognosis may change given these results, says co-senior investigator Dr. Ari Melnick, associate professor of medicine and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, and a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. Dr. Melnick and his colleagues developed RI-BPI, and they have shown its potent effects in non-Hodgkin’s lymphoma (NHL) with no toxicity to normal cells. The drug targets the transcription factor BCL6, a master regulator of hundreds of genes that provides strong growth signals to NHL cells.
“I am surprised, and extremely glad, to see that RI-BPI has such strong activity in a leukemia. This opens up the possibility that the agent will have similar beneficial effects in other tumor types,” says Dr. Melnick.
Click here to read the press article describing the study results. Click here to read the published research paper.
Background on the development of RI-BPI at Weill Cornell Medical Center: Diffuse Large B ell lymphoma (DLBCL) is a common and aggressive subtype of lymphoma that is frequently associated with deregulation of the oncogene BCL6 (oncogene is a genetic material that carries the ability to induce cancer). Deregulated BCL6 activity keeps B cells in a rapidly proliferating (reproducing) state. The high levels of BCL6 expression in DLBCL coupled with the low or nil expression of BCL6 in normal cells have made BCL6 an attractive candidate for anti-cancer drug development.
Personalized lymphoma medicine offers the hope that by identifying lymphoma-causing mutations in critical regulatory genes, we can target these mutant proteins to cure lymphoma while limiting the side effects. A major roadblock to this has been the inability to find specific, drug-like inhibitors of nonenzymatic proteins, especially transcription factors. BCL6 is a transcription factor, a gene repressor with no enzymatic activity.
In 2004, the Melnick group at Weill Cornell Medical Center described the initial development of a research tool, a recombinant peptide, to inhibit BCL6. This molecule was a large peptide of 120 amino acids that worked by interfering with the ability of BCL6 to bind its critical partner proteins, NCOR and SMRT. We called this molecule BCL6 Peptide Inhibitor (BPI). While growth inhibition by BPI was highly specific, the major drawback of BPI was its instability that precluded its use in animal models.
After several years of peptide engineering, Dr. Melnick, Leandro Cerchietti, MD and collaborators reported the development of RI-BPI, an inverted, mirrored, small and stable BPI. RI-BPI was specifically designed to be use as an anti-cancer drug. RI-BPI has been shown to inhibit the growth of lymphoma in animal models alone or in combination with other drugs such as HSP90 inhibitors (PUH71) and HDAC inhibitors (SAHA). The finding of BCL6 in other tumor settings, such as leukemia cells, opened the possibility for using RI-BPI to treat several tumor types in addition to lymphomas.
New Developments in Lymphoma 