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Lurie Cancer Center Scientists Receive NCI Outstanding Investigator Awards

Scientists from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University have been awarded seven-year, $6.4 million grants from the National Cancer Institute (NCI) to embark on projects that have unusual potential to advance cancer research.

Marcus Peter, PhD, professor of Medicine in the Division of Hematology/Oncology and Leader of the Translational Research in Solid Tumors Program at the Lurie Cancer Center, Navdeep Chandel, PhD, David W. Cugell Professor of Medicine & Cell Biology and Leader of the Membranes, Organelles and Metabolism Program at the Lurie Cancer Center,  and Ali Shilatifard, PhD, chair and Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine, were chosen to receive the NCI’s R35 Outstanding Investigator Awards.

In addition to Peter and Shilatifard, Maciej Lesniak, MD, chair of Neurological Surgery at Northwestern Medicine as of November 1, was also chosen to receive an NCI Outstanding Investigator Award while a professor at the University of Chicago. In research he will continue at the Lurie Cancer Center, he plans to develop therapies for malignant brain tumors by targeting stem cells.

The new NCI program, which is completing its inaugural round of funding this year, was established to support experienced and exceptional investigators.  Award recipients are encouraged to use the grant to be more adventurous and to take greater risks so that they can break new ground in their lines of inquiry.

“Three of the first 30 NCI Outstanding Investigator Awards are carried by Lurie Cancer Center members, a reflection of Northwestern's innovative cancer research efforts,” said Leonidas Platanias, MD, PhD, director of the Lurie Cancer Center. “It also reflects our increasing depth and strength as one of the leading cancer programs in the country.”

“There are thousands of cancer researchers. The idea is to let a few of us play with completely crazy ideas that could have tremendous payoffs,” Peter said. “My lab is doing exactly the opposite of what most others are doing. Instead of focusing on oncogenes to kill cancer cells, we’re targeting tumor suppressors.”

While much research is devoted to developing therapies that target the specific genetic mutations that cause various forms of cancer, Peter’s strategy applies to all solid cancers because it concentrates on the roots rather than the manifestations of cancer.

“We are trying to turn on powerful cancer-destructive mechanisms designed by evolution to prevent cancer,” Peter said. “By the time a patient presents to the clinic with a tumor, some cancer surveillance mechanisms have already failed.” 

Last year, he published a study showing that removing the death receptor CD95, or Fas, kills cancer cells, but not normal cells. The molecule’s day-to-day function is to trigger apoptosis to get rid of potentially harmful cells, including those that drive malignant tumor growth. But mutations can hit every gene, including those responsible for this tumor suppressor. Peter believes that a network of sensors in cells recognizes when mutations will stop CD95 from doing its job and the cells commit suicide as a failsafe mechanism. Eliminating CD95 in cancer cells may induce the same mechanism.

“This self-destruct program has to be a very tightly controlled, very efficient process, otherwise none of us would be here,” Peter said. “We believe we’ve tapped into this program.”

Over the next seven years, Peter will pursue eight projects to understand the signals and pathways that surround CD95, other tumor suppressors and CD95 removal, which Peter has termed “death induced by CD95 receptor or ligand elimination” or DICE for short. With the NCI grant, he can do this without worrying about imminent grant renewal.

“During the last decade not enough attention has been given to very basic science that could eventually result in a completely new way of attacking the cancer problem,” Peter said. “This grant is perfect for us, because that is exactly what we do.”

Cancer forms because genetic mutations can cause cells to lose control of self-regulation and multiply rapidly. For nearly 20 years, Shilatifard has explored how chromatin – genetic material that encompasses DNA, RNA and proteins – and the process of transcription play a role in this cancer pathogenesis.

This research led to the identification of a protein complex he named COMPASS, a signaling pathway of H3K4 methylases that activates gene expression. Importantly, mutations in COMPASS are hidden within a broad array of cancers, from leukemia to brain tumors to liver cancer.

“This grant gives me the opportunity and time to think comprehensively and ask, what are the most fundamental biological questions in the field that have not yet been answered?” Shilatifard said. “Why are COMPASS family mutations associated with so many different forms of cancer? And what is the molecular mechanism of this process?”

In several recent manuscripts published in Science, Cell and Nature, Shilatifard and colleagues provided molecular clues on how misregulation of gene expression through transcription factor mutations can function in cancer. With the new award, Shilatifard aims to fully characterize the molecular and biochemical properties of the six members of the COMPASS family that his lab previously identified in multiple model systems.

“The better molecular understanding we have of this epigenetic process, the better chance we’ll have of developing targeted therapeutics, such as a small molecule that turns off COMPASS function or something that augments its activity depending on whether the mutation causes cancer through loss or gain of function,” he said. “Without having to worry about grant renewal for our COMPASS studies, we can really focus on making substantial, meaningful discoveries.”

Though the results of their funded projects are uncertain, each of these scientists has the potential to improve treatment options in areas where new ideas – and time to investigate them – are critically needed.

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