Local gene mutations serve as biomarkers for multiple cancers

A Northwestern Medicine research team has successfully located a new molecular mechanism behind genetic mutations found in multiple cancers that could serve as biomarkers to improve patient stratification and treatment, according to findings published in the Journal of Northwestern Medicine . Proceedings of the National Academy of Sciences.

“It is very exciting to be able to work on a molecular program for many years and relate the findings to the clinical stratification of patients with cancer, specifically in this case bladder cancer, and to further develop targeted therapies to treat bladder cancer. “Exciting applications to other forms of cancer, such as lung cancer, colon cancer, and other solid tumors,” said Zibo Zhu, Ph.D., assistant professor of biochemistry and molecular genetics and lead author of the study.

Dr. Ali Shilatifard, the Robert Francis Furchgott Professor and Chair of Biochemistry and Molecular Genetics, is the study’s senior author.

The MLL4 gene belongs to a group of genes called the Set1-associated protein complex (COMPASS) family, and mutations have been found in patients with multiple cancer types, including bladder, colorectal, esophageal, endometrial, and acute uterine cancer. Endometrial cancer. Lymphocytic leukemia, etc.

Previous work from the Shilatifard lab was published in Journal of Clinical InvestigationResearchers found that cancer cells harboring mutations in MLL4 are more sensitive to inhibitors of purine synthesis, hindering cancer cell growth, a finding that further highlights MLL4’s potential as a therapeutic target.

In the current study, the researchers used CRISPR gene editing to identify the precise molecular mechanisms underlying cancer cell lines harboring MLL4 mutations. Using immunohistochemistry techniques on tissue samples from bladder cancer patients, scientists found that MLL4 mutations were localized in the cytoplasm of cancer cells.

The team then used a metabolic inhibitor called Lometrexol in a mouse model of bladder cancer, which significantly reduced tumor stage in mice with MLL4 mutations, suggesting that MLL4 mutations could be used to predict sensitization to targeted treatments such as Lometrexol. stratify patients.

“About one-third of patients with bladder cancer have MLL4 mutations,” says Joshua Meeks, ’05 MD, ’03 Ph.D., ’06 ’11 GME, Edward M. Schaeffer, MD, Ph.D., professor of urology. Associate Professor of Biochemistry and Molecular Genetics and a co-author of the study. “Lometrexole functions similarly to methotrexate, which is part of our chemotherapy regimen for bladder cancer. This study could explain why the drug only works in about half of patients.”

The authors stated that this study demonstrates that cytoplasmic MLL4 mutations may serve as biomarkers to improve patient stratification and treatment outcomes.

“Cytoplasmic changes in MLL4 may be a simple and powerful biomarker to better predict response to methotrexate treatment regimens. Unfortunately, there is a shortage of methotrexate, so seeking to Lometrexol would be ideal. I’m very passionate about collaborating to bring that to the world — to bring science into our hospitals,” Meeks said.

These findings may also inform the development of new targeted therapies to restore MLL4 function in different cancers and diseases.

“This paper proposes a way to stratify bladder cancer patients based on the presence or absence of MLL4 in their cytoplasm, and patients with MLL4 in their cytoplasm may be the best candidates for this metabolic therapy that we have identified,” Shilatifard said. “He is also director of the Simpson Querrey Institute for Epigenetics and director of the Cancer Epigenetics and Nuclear Dynamics Program at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center.