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Researchers identify 'Achilles heel' in metabolic pathway that could lead to new cancer treatment


Researchers at UT Southwestern Medical Center have found an "Achilles heel" in a metabolic pathway crucial to stopping the growth of lung cancer cells.

At the heart of this pathway lies PPARγ (peroxisome proliferation-activated receptor gamma), a protein that regulates glucose and lipid metabolism in normal cells. Researchers demonstrated that by activating PPARγ with antidiabetic drugs in lung cancer cells, they could stop these tumor cells from dividing.

This is Dr. Ralf Kittler.

Credit: UT Southwestern

"We found that activation of PPARγ causes a major metabolic change in cancer cells that impairs their ability to handle oxidative stress," said Dr. Ralf Kittler, Assistant Professor in the Eugene McDermott Center for Human Growth and Development, the Department of Pharmacology, the Harold C. Simmons Cancer Center and the Cecil H. and Ida Green Center for Reproductive Biology Sciences at UT Southwestern.

"The increased oxidative stress ultimately inhibits the growth of the tumor. We found that activation of PPARγ killed both cancer cells grown in a dish and tumors in mice, in which we observed near complete tumor growth inhibition," said Dr. Kittler, the John L. Roach Scholar in Biomedical Research of UT Southwestern's Endowed Scholars Program.

The study, published in the journal Cell Metabolism, builds on a large body of work showing that metabolism in cancer cells is altered when compared to normal cells. Changes in metabolism can make cancer cells more vulnerable to therapeutic agents, which make them a good target to investigate for cancer therapy. The new research also extends earlier observations made by Dr. Steven Kliewer, Professor of Molecular Biology and Pharmacology, who first identified that thiazolidinediones target PPARγ. Dr. Kliewer holds the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer Research.

Dr. Kittler and his team determined that PPARγ activation triggers changes in glucose and lipid metabolism that cause an increase in the levels of reactive oxygen species (ROS). ROS are highly reactive oxygen-containing molecules that damage cells when present at high levels, a phenomenon known as oxidative stress. It is this increase in ROS that eventually stops the cancer cells from dividing.

"The abnormal metabolism in cancer cells frequently causes increased oxidative stress, and any further increase can 'push' cancer cells over the cliff," said Dr. Kittler, UT Southwestern's first Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research.

The findings suggest that targeting PPARγ could be a promising new therapeutic approach for lung cancer and potentially other cancers. The researchers saw that activating PPARγ caused similar molecular changes in breast cancer cells.

"This is an important finding because the drugs that activate PPARγ include FDA-approved antidiabetic drugs that are relatively well tolerated compared to chemotherapy. Knowing their mechanism of action provides us with clues for selecting tumors that may be responsive to this treatment, for combining these drugs with anti-cancer drugs to make therapy more effective, and for developing markers to measure the response of tumors to these drugs in patients," said Dr. Kittler, Director of the McDermott Next-Generation Sequencing Core at UT Southwestern.

"Of course, further study will be required to determine the therapeutic effectiveness of PPARγ-activating drugs for lung cancer treatment," he added.


Other UT Southwestern researchers involved in the work include joint first authors Dr. Nishi Srivastava, postdoctoral researcher, and Rahul Kollipara, computational biologist; Dr. Dinesh Singh, research scientist; Jessica Sudderth, research associate; Dr. Zeping Hu, Assistant Professor at the Children's Research Institute at UT Southwestern; Dr. Hien Nguyen at the University of Massachusetts Medical School; Dr. Shan Wang, postdoctoral researcher; Caroline Humphries, senior research scientist; Ryan Carstens, student research assistant; Dr. Kenneth Huffman, research scientist; and Dr. Ralph DeBerardinis, Associate Professor with the Children's Medical Center Research Institute at UT Southwestern, the Eugene McDermott Center for Human Growth and Development, and the Department of Pediatrics, who holds the Joel B. Steinberg, M.D. Chair in Pediatrics and is the Sowell Family Scholar in Medical Research. The study was funded by the Cancer Prevention and Research Institute of Texas (CPRIT) and the National Cancer Institute (NCI).

UT Southwestern's Harold C. Simmons Cancer Center is the only National Cancer Institute-designated cancer center in North Texas and one of just 66 NCI-designated cancer centers in the nation. The Simmons Cancer Center includes 13 major cancer-care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevent cancer worldwide. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians.

The Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Site, a prestigious new designation by the NCI, and the only Cancer Center in North Texas to be so designated. The designation and associated funding is designed to bolster the cancer center's clinical cancer research for adults and to provide patients access to cancer research trials sponsored by the NCI, where promising new drugs often are tested.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 91,000 hospitalized patients and oversee more than 2 million outpatient visits a year.

Lori Sundeen Soderbergh | Eurek Alert!

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