Localized genetic mutations may serve as a biomarker for a wide range of cancers

A team of Northwestern Medicine researchers successfully located new molecular mechanisms behind a genetic mutation found in a wide range of cancers, which could serve as a biomarker to improve patient stratification and treatment, according to results published in Proceedings of the National Academy of Sciences.

“It is very rewarding to be able to work on a project at the molecular level for many years and relate the results to the clinical stratification of patients with cancer, particularly bladder cancer in this case, and to further develop therapies “targeted drugs for the treatment of bladder cancer that can be applied to other forms of cancers such as lung, colon and other solid tumors,” said Zibo Zhao, Ph.D., assistant professor of biochemistry and of molecular genetics and lead author of the study.

Ali Shilatifard, Ph.D., Robert Francis Furchgott Professor and Chair of Biochemistry and Molecular Genetics, was the lead author of the study.

Mutations in the MLL4 gene, which belongs to a set of genes known as the Complex of Proteins Associated with Set1 (COMPASS) family, are seen in patients with a myriad of cancer types, including bladder cancer. , colorectal cancer, esophageal cancer, endometrial cancer and acute cancer. lymphocytic leukemia, among others.

In previous work from the Shilatifard laboratory, published in the Journal of Clinical InvestigationResearchers found that cancer cells containing MLL4 mutations were more sensitive to an inhibitor of purine synthesis, which inhibited cancer cell growth, findings that further highlight MLL4’s potential as a therapeutic target.

In the current study, researchers used CRISPR gene editing to identify precise molecular mechanisms in cancer cell lines with MLL4 mutations. By applying immunohistochemistry techniques to tissue samples from bladder cancer patients, scientists discovered that MLL4 mutations localize to the cytoplasm of cancer cells.

The team then used a metabolic inhibitor called Lomètrexol 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 stratify patients based on expected sensitivity to targeted therapies such as lomètrexol.

“About one-third of bladder cancer patients have a mutation in MLL4,” said Joshua Meeks, MD ’05, PhD ’03, GME ’06 2011, Edward M. Schaeffer, MD, PhD ’11. Professor of urology, associate professor of biochemistry and molecular genetics and co-author of the study. “Lomètrexol works like methotrexate, which is part of our chemotherapy regimen for bladder cancer. This study may explain why the drug is only effective in about half of patients.”

The study suggests that cytoplasmic MLL4 mutations could serve as a biomarker to improve patient stratification and treatment outcomes, according to the authors.

“The cytoplasmic change in MLL4 could be a simple but powerful biomarker to better predict response to methotrexate regimens. Unfortunately, there is a shortage of methotrexate, so it would be ideal to continue lometrexol in this setting. I am incredibly excited about the collaborations that bring the world together- teaching science at our hospital,” Meeks said.

The results could also inform the development of new targeted therapies that restore MLL4 function in different cancers and diseases.

“This paper represents a way to stratify bladder cancer patients based on the presence of MLL4 in the cytoplasm, and those who have MLL4 in the cytoplasm could be excellent candidates for this metabolic therapy that we have identified,” said Shilatifard, who is also director of the Simpson Querrey Institute for Epigenetics and head of the Cancer Epigenetics and Nuclear Dynamics Program at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center.