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Spring 2014 issue (pdf)

Linda Resar, MD ’86Linda Resar, MD ’86

Taking the power out of cancer’s punch. That’s the goal of Linda Resar, MD ’86, Associate Professor of Medicine, Oncology and Pediatrics, and affiliate in the Institute for Cell Engineering at The Johns Hopkins University School of Medicine.

Dr. Resar studies the high mobility group A1 (HMGA1) gene, which is turned on by growth factors in cells. Her lab’s early research found that the gene has potent oncogenic (causing tumor development) activities, and recently discovered that the HMGA1 protein functions as a key molecular switch required by cancer cells to invade and metastasize to distant sites.

“The HMGA1 gene is overexpressed in all aggressive tumors studied to date, and high expression correlates with poor outcomes in diverse tumor types,” she said. “We found that silencing this so-called master regulator results in dramatic changes in cancer cells, including halting uncontrolled growth and altering cell shape and behavior to prevent cancer cells from spreading.”

This discovery may hold the key to developing agents that block the gene, or pathways or processes that it affects. Dr. Resar’s team is taking a multipronged approach in its search for effective treatments.

“One approach is to block expression of the HMGA1 gene itself, and we are working on developing nanoparticles to deliver vectors capable of silencing this gene in preclinical tumor models,” Dr. Resar said. “Another is to block pathways induced by this gene and protein, and we have studied inhibitors to pathways downstream of HMGA1. A third is to develop small molecules, called aptamers, to block HMGA1 binding to DNA.  Finally, we are also looking for regulatory microRNAs that could repress expression of this gene.”

Dr. Resar has been studying high mobility group genes for two decades. Her passion for research began nearly 30 years ago at the Medical College of Wisconsin.

“I had the opportunity to work in the Physiology Department in the laboratory of Dr. William Stekiel, who was a thoughtful and enthusiastic mentor,” she said. “Dr. Herbert Swick also was an amazing role model and pediatric neurologist, who taught me not only about pediatrics and neurology but also about how to ask the right questions to develop a thorough understanding of disease and treatment options for my patients.”

Dr. Resar initially became interested in investigating blood diseases and therapies to benefit her patients with sickle cell anemia. As it turned out, the gene she chose to study is not only an important stem cell gene, but also a critical cancer-causing gene. Today, she is returning to her original area of interest, in addition to continuing her cancer research.

“We know that the HMGA1 gene is also overexpressed in developing embryos and in stem cells,” she said. “Recent work from our lab suggests that it plays a fundamental role in stem cell function.”

Dr. Resar is studying pathways related to HMGA1 that could be used to increase fetal hemoglobin production in blood cells in patients with sickle cell disease. High levels of fetal hemoglobin ameliorate symptoms and improve outcomes for patients with sickle cell disease.

With her research coming full circle, she reflects on those who inspired her along the way: “I had the opportunity to learn with an outstanding group of students who motivated me and also taught me a great deal. In fact, my husband was a student at MCW, and we were married one week after I graduated.” 

Jon R. Resar, MD ’85, is Associate Professor of Medicine and Director of Interventional Cardiology at Johns Hopkins. The Resars have four children; their oldest daughter is studying pre-medicine and literature in college.

Dr. Linda Resar attends in the Hematology Clinic at The Johns Hopkins Hospital. She has published over five dozen papers in her field and is on the editorial board for Current Molecular Medicine. She has been continuously funded by the National Institutes of Health for 21 years.

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