Small molecule targets B cell lymphoma

April 12, 2010

Scientists are one step closer to developing a targeted therapy for lymphoma. New research, published by Cell Press in the April 13th issue of the journal Cancer Cell, identifies a specific small-molecule inhibitor that was nontoxic in animal experiments and could kill human lymphoma cells.

BCL6 is the most commonly involved oncogene in diffuse large B cell lymphomas (DLBCL). Previous work has shown that BCL6 is required for survival of lymphoma cells and that blockade of the gene potently kills DLBCL cells. However, although BCL6 it a very attractive therapeutic target, it has not been considered to be particularly amenable to targeting with small molecules.

"Like many oncogenes, BCL6 is a transcription factor," says senior study author Dr. Ari Melnick from Weill Cornell Medical College in New York. "Transcription factors like BCL6 usually exert their actions through extensive interactions with other proteins. In general, small molecule inhibitors with the potential to become drug candidates have been considered not likely to effectively disrupt protein-protein interactions."

Dr. Melnick and colleagues used structure-based strategies to determine where the best point of attack would be to disrupt the activity of BCL6. Using computer-aided drug design combined with functional assays, the researchers identified small molecule compounds that specifically interacted with BCL6 at an exposed groove within the BCL6 BTB domain. The researchers were interested in this specific part of BCL6 because it is the binding site of cofactors required for BCL6 to carry out its cancer-causing functions.

One of the compounds that they identified, called 79-6, bound specifically to the BTB groove and effectively killed BCL6-positive DLBCL cell lines. Further, 79-6 markedly reduced BCL6-dependent tumors in mice that had received transplants of human lymphoma cells and specifically killed primary human DLBCL cells.

"Our work demonstrates that oncogenic transcriptional repressors can be therapeutically targeted with small molecules and presents a rationally designed therapy approach for treatment of lymphomas," concludes Dr. Melnick. "Future efforts will be taken to systematically improve the therapeutic potential of these compounds with the goal of developing BCL6 targeted therapy for DLBCL."
-end-
The researchers include Leandro C. Cerchietti, Weill Cornell Medical College, Cornell University, New York, NY; Alexandru F. Ghetu, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada; Xiao Zhu, University of Maryland, Baltimore, MD; Gustavo F. Da Silva, University of Maryland, Baltimore, MD; Shijun Zhong, University of Maryland, Baltimore, MD; Marilyn Matthews, University of Maryland, Baltimore, MD; Karen L. Bunting, Weill Cornell Medical College, Cornell University, New York, NY; Jose M. Polo, Albert Einstein College of Medicine, Bronx, NY; Christophe Fares, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada; Cheryl H. Arrowsmith, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada, University of Toronto, Toronto, Canada; Shao Ning Yang, Weill Cornell Medical College, Cornell University, New York, NY; Monica Garcia, Weill Cornell Medical College, Cornell University, New York, NY; Andrew Coop, University of Maryland, Baltimore, MD; Alexander D. MacKerell, Jr., University of Maryland, Baltimore, MD; Gilbert G. Prive, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada, University of Toronto, Toronto, Canada; and Ari Melnick, Weill Cornell Medical College, Cornell University, New York, NY.

Cell Press

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.