Powerful screening technique suggests targeting cancer stress response

Researchers from Case Western Reserve University School of Medicine and Cleveland Clinic Lerner Research Institute have developed a new method to screen brain tumor cells and identify potential drug targets missed by traditional methods. The team successfully used their technique to find a new drug target in glioblastoma that, when inhibited, significantly extended survival in preclinical mouse models.

In the new study published in Nature, the team implanted human glioblastoma cells from patients to form human tumors inside mouse brains, closely mimicking the natural tumor environment. They simultaneously screened hundreds of genes in these tumors to understand which genes were important for cancer cell survival. They compared these screening results in the brain with those from a parallel screening they conducted in the patients’ cells grown in the laboratory. What they found was surprising: 57 genes required for the cancer cells to grow in a functional tumor environment in the brain were not required when the cells were grown in the laboratory.

“There was very little overlap of the targets identified in the new in vivo screening method and the traditional cell culture screen,” said Jeremy Rich, one of the senior authors of the study, formerly of the Department of Stem Cell Biology & Regenerative Medicine at Cleveland Clinic Lerner Research Institute and Taussig Cancer Institute. “This means the field has been missing a number of potential therapeutic targets that may actually improve patient outcomes and prolong survival.”

Rich is now a professor at University of California San Diego.

Glioblastoma is the most aggressive type of brain tumor and the median survival for patients is only 15 months, even with current therapies, according to the American Brain Tumor Association. The high-throughput screening technique revealed new vulnerabilities in glioblastoma tumors that could be targeted by drug developers. Of the 57 genes identified, 12 were all related to a single process—how cancer cells respond to stress. The researchers inhibited a number of these stress response genes in the implanted tumors and the mice survived longer. However, inhibiting the gene in cells grown in traditional laboratory culture dishes did not alter glioblastoma cell growth or survival.

“Our study found that in a natural environment, tumor cells are more susceptible to inhibition of their stress response mechanisms,” Tyler Miller, first author on the study and medical student in the CWRU Medical Science Training Program and Cleveland Clinic Lerner Research Institute. “Current chemotherapies all target proliferating, or dividing cells. We know that type of therapy doesn’t work for glioblastoma. Our findings suggest that targeting the stress response may be better at slowing tumor growth than targeting cell proliferation, which opens up a new avenue for therapeutic development.”

According to the researchers, their approach could be used to screen other types of cancers for potential therapeutic targets.

“Prior attempts at discovering therapeutic targets have generally been done in cell culture, that is, patient cells on plastic dishes in artificial media to help them grow,” said Paul Tesar, the other senior author of the study, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and associate professor of genetics and genome sciences at Case Western Reserve University School of Medicine and the Case Comprehensive Cancer Center. “The hope is that systems like ours that more closely mimic the natural tumor environment will identify new targets that better translate into effective therapies for patients.”

Joining Miller, Tesar and Rich in this research effort were co-authors Lisa Wallace, Qi Xie, Deobrat Dixit, Lian Wu, Stephen Mack and Christopher Hubert of Cleveland Clinic Lerner Research Institute; Andrew Morton, Daniel Factor, Leo Kim, James Morrow and Peter Scacheri of Case Western Reserve University School of Medicine; Brian Liau, Shawn Gillespie, William Flavahan, Rohit Thummalapalli and Bradley Bernstein of Harvard Medical School and Massachusetts General Hospital; Thomas Hoffman and Johannes Zuber of the Research Institute of Molecular Pathology in Vienna, Austria; Michael Hemann of the Koch Institute for Integrative Cancer Research at MIT; Patrick Paddison of the Fred Hutchinson Cancer Research Center; and Craig Horbinski of Feinberg School of Medicine, Northwestern University.