The National Cancer Institute (NCI) has awarded four Dana-Farber Cancer Institute researchers with Outstanding Investigator Awards (OIA) for ongoing progressive research within their respective areas of study. William Kaelin, MD, A. Thomas Look, MD, Kimberly Stegmaier, MD, and Jean Zhao, PhD, are all cancer researchers that were nominated by Dana-Farber and served as principal investigators on an NCI grant for the last five years and have demonstrated outstanding cancer research productivity. The OIA provides funding of up to $600,000 in direct costs per year for seven years to advance each researcher’s respective investigations.
“These awards are directly funding investigations into the deadliest and most difficult diseases that we face in modern medicine,” said Laurie Glimcher, president & CEO, Dana-Farber. “We are seeing encouraging results in new cancer therapies, such as immunotherapy, across several disease centers. The critical next step is to dig further into these advancements so that they become more widely attainable for patients, and this NCI funding is an integral part of that mission.”
Kaelin is professor of medicine at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, and investigator at the Howard Hughes Medical Institute. He has a longstanding interest in treating particular cancers, such as kidney cancer, based on an understanding of the genes that are altered in those cancers and the specific vulnerabilities created by those alterations.
Most drugs work by binding to specific proteins (referred to as their targets) and inactivating them. Unfortunately, many of the overactive proteins that cause specific forms of cancer lack potential drug-docking sites and are therefore considered “undruggable.” Kaelin and Benjamin L. Ebert, MD, PhD, Professor of Medicine, Brigham and Women’s Hospital and Harvard Medical School independently worked to recently discover that the drug thalidomide, which has emerged as an important drug for a form of bone marrow cancer called multiple myeloma, acts by targeting two myeloma-causing proteins that would have otherwise been considered “undruggable” for destruction.
This OIA grant is helping Kaelin’s team to apply this paradigm more broadly by looking for chemicals that will directly or indirectly target other “undruggable” cancer-causing proteins for destruction. The grant also allows expedited research into gene editing technique, called CRISPR/Cas9, to build better cancer models in mice and to rapidly identify specific therapeutic vulnerabilities in particular cancers that can eventually be translated into new patient therapies.
Look is a senior molecular biologist and principal investigator in the Department of Pediatric Oncology at Dana-Farber Cancer Institute and professor of pediatrics at Harvard Medical School. He is interested in one of the most puzzling problems in cancer biology - how genes that function well under normal conditions can acquire properties enabling them to take over the cell's machinery and impose a malignant cancerous state. These so-called “oncogenes” depend on many regulators of gene expression to boost their potency. One group of such elements, termed “enhancers,” operate over large molecular distances on the chromosome to escalate oncogene activity and maintain this output at high levels for the life of the cell. Enhancers that perform this task with exceptional potency are known as “super-enhancers.” Attempts to understand the basis of enhancer and super-enhancer regulation have become a high priority in cancer research, with several groups in the United States emerging as leaders in this relatively new field, including Look.
Using this NCI award, Look plans to clarify the molecular details of how cancer cells exploit a broad spectrum of regulatory elements – not only transcription factors but also specific DNA sequences and epigenetic readers, writers and erasers – to ensure that the transformed cell attains the exact oncoprotein levels needed to maintain a malignant environment. This proposed work is a logical outgrowth of research performed by Dr. Look at Dana-Farber, with the most immediate precursor being a report published in 2014 (Science346: 1373) by Look, Marc Mansour, Richard Young and others. In it, the authors demonstrate how very subtle inserted sequences in a non-protein-coding region of the genome can recruit a number of powerful transcription factors to that site, leading to the creation of super-enhancers able to support and sustain T-cell acute lymphoblastic leukemia cells. Look is hopeful that larger-scale studies of this type have the potential to generate an enormous shift in the understanding of enhancers in the origins of human cancer and the roles of enhancer-associated proteins as therapeutic targets.
Stegmaier is a Ted Williams investigator, vice-chair for pediatric oncology research, and co-director of the Pediatric Hematologic Malignancies Program at Dana-Farber Cancer Institute and is an associate professor of pediatrics at Harvard Medical School. She is focused on researching acute myeloid leukemia (AML), the most common cause of acute leukemia in adults and the second most common cause in children. A defining feature of AML is a failure of AML cells to mature and become normal white cells, a process called differentiation. Stegmaier’s laboratory had previously focused on the discovery of new approaches to induce AML differentiation by chemical screening (gene signature screening) and functional genomic (shRNA) screening; this prior work formed the basis of the NCI Outstanding Investigator application. Her OIA research is integrating innovative, powerful functional (CRISPR) and chemical genomic approaches to decipher the mechanisms underlying AML and to inform new therapeutics for children and adults with this disease. Specifically, her team is focusing on the application of these transforming approaches to identify new dependencies in high-risk subtypes of acute myeloid leukemia (AML). The ultimate goal of this work is to translate the findings to clinical trials for patients suffering from this disease.
Zhao is a professor of cancer biology at Dana-Farber and professor of Biological Chemistry & Molecular Pharmacology at Harvard Medical School, and co-leader of the Breast Cancer Program at Dana-Farber/Harvard Cancer Center. She has been focusing on investigating molecular mechanisms of signal transduction in cancer, in particular, the Phosphatidylinositol 3-Kinase (PI3K) signal pathway, in breast cancer. Patients suffering from metastatic breast cancer frequently face a dismal prognosis, with only limited and often ineffective treatment strategies available to them. Her research aims to deliver on the promise of precision medicine by developing novel targeted therapies in combination with immunotherapy in cancer. If successful, the results from this study have the potential to dramatically affect the lives of many patients suffering from metastatic breast cancer by providing effective and safer therapeutic options.
“The NCI Outstanding Investigator Award addresses a problem that many cancer researchers experience: finding a balance between focusing on their science while ensuring that they will have funds to continue their research in the future,” said Dinah Singer, Ph.D., director of NCI’s Division of Cancer Biology. “With seven years of uninterrupted funding, NCI is providing investigators the opportunity to fully develop exceptional and ambitious cancer research programs.”