Drug Prevents Cancer by Targeting Both Tumor Cells and the Tumor Microenvironment

Researchers at Michigan State University say they are testing a drug that may stop a gene associated with obesity from triggering breast and lung cancer, as well as prevent these cancers from growing. Their findings are based on two studies (“Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762”) and (“A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation”) published in Cancer Prevention Research.

“Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Due to limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies,” write the investigators.

“I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extra-terminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors.

“Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3 and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment.”

The preclinical study, led by Karen Liby, Ph.D., an associate professor in the department of pharmacology and toxicology, demonstrated that the drug, I-BET-762, is showing signs of significantly delaying the development of existing breast and lung cancers by focusing on how a cancerous gene, called c-Myc, acts.

“I-BET-762 works by targeting DNA so that this gene can’t be expressed,” Dr. Liby said. “It does this by inhibiting a number of important proteins – both in cancer and immune cells – ultimately reducing the amount of cancer cells in mice by 80%.”

These proteins are important because they play a critical role in what occurs between cells. For example, a particular protein, known as pSTAT3, can become activated in immune cells and stop them from doing their job, such as fighting off an invading cancer. The offending protein also can become overproduced in cancer cells and act as a shield, ultimately protecting the tumor.

“In our study, the drug decreased pSTAT3 levels by 50% in both types of cells,” noted Dr. Liby.

The second study, led by Jamie Bernard, Ph.D., an assistant professor of pharmacology and toxicology, applied Dr. Liby’s findings to precancerous cells.

“We looked directly at the effect I-BET-762 had on human cells that could become tumorigenic, but weren’t quite yet,” Dr. Bernard said. “We found that the drug prevented more than 50% of these cells from becoming cancerous.”

The c-Myc gene is induced by visceral fat, which is found around the inner organs of the body, as opposed to subcutaneous fat, which is located under the skin. This visceral fat is more dangerous to your health.

“Almost half a million of all new cancers have been linked to obesity,” explains Dr. Bernard. “There is evidence that visceral fat and high-fat diets can increase cancer risk; and while current cancer treatments have helped to lower cancer mortality, the number of obesity-associated cancers continues to climb.”

Due to the limited success in reducing high mortality rates of breast and lung cancer, new approaches for prevention are desperately needed, continued Dr. Bernard.

Drugs that act similarly to I-BET-762 also are being tested in clinical trials for the treatment of a variety of other cancers, including leukemia, lymphoma, brain tumors and myeloma. Drs. Liby and Bernard hope I-BET-762 will increase breast and lung cancer patients’ chances of survival.

“The goal is our findings will clarify what needs to be targeted and, therefore, can be used to prevent cancer in high-risk patient populations,” Dr. Bernard said.