Medical Science Discovery Helps Shrink Brain Tumors

 

Patients with glioblastoma, a type of malignant brain tumor, usually survive fewer than 15 months following diagnosis. Since there are no effective treatments for the deadly disease, University of California, San Diego researchers developed a new computational strategy to search for molecules that could be developed into glioblastoma drugs.

In mouse models of human glioblastoma, one molecule they found shrank the average tumor size by half. The study is published October 30 by Oncotarget.

The molecule — SKOG102 — wedges itself in a temporary interface between two proteins whose binding is essential for the tumor’s survival and growth. The study is the first to demonstrate successful inhibition of this type of protein, known as a transcription factor.

"Most drugs target stable pockets within proteins, so when we started out, people thought it would be impossible to inhibit the transient interface between two transcription factors," said Igor Tsigelny, a research scientist at UCSD Moores Cancer Center.

Transcription factors control which genes are turned "on" or "off" at any given time. For most people, transcription factors labor ceaselessly in a highly orchestrated system. In glioblastoma, one misfiring transcription factor called OLIG2 keeps cell growth and survival genes "on" when they shouldn't be, leading to quick-growing tumors.

n order to work, transcription factors must buddy up, with two binding to each other and to DNA at same time. If any of these associations are disrupted, the transcription factor is inhibited.

In this study, Tsigelny and team aimed to disrupt the OLIG2 buddy system as a potential treatment for glioblastoma. Based on the known structure of related transcription factors, study co-author Valentina Kouznetsova, PhD, associate project scientist at UC San Diego, developed a computational strategy to search databases of 3D molecular structures for those small molecules that might engage the hotspot between two OLIG2 transcription factors.

The team used the Molecular Operation Environment (MOE) program produced by the Chemical Computing Group in Montreal, Canada and high-performance workstations at the San Diego Supercomputer Center to run the search.

With this approach, the researchers identified a few molecules that would likely fit the OLIG2 interaction. They then tested the molecules for their ability to kill glioblastoma tumors in the Moores Cancer Center lab of the study's senior author, Santosh Kesari, MD, PhD. The most effective of these candidate drug molecules, called SKOG102, shrank human glioblastoma tumors grown in mouse models by an average of 50 percent.

The scientists said a few more years of study are needed to make sure medication based on the molecule would work and not be poisonous to patients.

Researchers with The Scripps Research Institute, Harvard Medical School and Brigham and Women's Hospital in Massachusetts contributed to the study, which was funded, in part, by the National Institutes of Health, Voices Against Brain Cancer Foundation, Christopher and Bronwen Gleeson Family Trust and American Brain Tumor Association Drug Discovery Grant.