Cigall Kadoch's innovative work tracing how gene-regulating machines trigger the onset of rare forms of cancer has earned her the 2019 AAAS Martin and Rose Wachtel Cancer Research Award.
In her career, Kadoch, an assistant professor at the Dana-Farber Cancer Institute and Harvard Medical School, has focused on elucidating the role of chromatin remodeling machines — which control the architecture of the human genome — and how they can become perturbed in rare malignancies. By teasing apart the complicated landscape of chromatin regulation, her research has yielded insight into cancer genetics and could inform the development of novel therapeutics for hard-to-treat cancers.
Kadoch penned an essay on her work that was published in the July 17 issue of Science Translational Medicine and presented a public lecture on her research at an awards ceremony at the National Institute of Health on July 19.
"Dr. Cigall Kadoch was selected as the winner of this year's award based on her groundbreaking work on chromatin remodeling in cancer," said Yevgeniya Nusinovich, a senior editor at Science Translational Medicine. "Dr. Kadoch has become a leader in her field, and her lab is continually providing new biological insights that could help improve the treatment of numerous cancer types."
The annual AAAS Martin and Rose Wachtel Cancer Research Award recognizes early-career scientists who have made outstanding contributions to cancer research within 10 years of receiving their Ph.D. or M.D. degree. Kadoch will receive a cash award of $25,000 supported by an endowment bequeathed by Martin L. Wachtel.
"It's been an incredible journey over the past five or so years in establishing my young cancer research lab," said Kadoch. "To receive this award after a culmination of a lot of that work is quite meaningful to me and my entire research lab."
Kadoch's lab studies one type of chromatin remodeling complexes, which are molecular machines that essentially orchestrate which genes are turned on and off at different times. Recent sequencing studies have shown that mutations in chromatin remodeling genes occur in over 20% of human cancers, according to Kadoch.
Despite their relevance to cancer research, chromatin remodeling complexes have typically been difficult to study and characterize. They can be assembled in hundreds of different ways from their constituent molecular parts, which has complicated efforts to pin down or target any cancer-driving mutations.
"Because the complexes are so diverse, it's hard to isolate any one that's relevant to a mutation," she said. "No one had really taken a step back to understand why and how these complexes are put together."
Her group therefore undertook a large-scale effort to define, for the first time, how chromatin remodeling machines are pieced together and assembled.
One of her chief contributions was the discovery of a link between chromatin remodeling machines and a rare form of cancer called synovial sarcoma, which typically affects the joints of the knee. Her team found that in every case they studied, patients had a chromosomal abnormality (in the form of an extra protein) that "dragged" the chromatin complexes to new sites in the genome where they shouldn't have been, resulting in abnormally high stem cell and genetic activity.
"This was really exciting, the idea that if you add a piece to this complex you can get completely new cancer-specific positioning of this complex on the genome," said Kadoch.
This initial discovery coincided with a wave of DNA sequencing studies that began to analyze tumors for their genetic makeup. The mutations being identified in these studies pointed to a major role for chromatic remodeling machines in a variety of cancers, she said. "That was quite unexpected for the field, as before this we would have thought chromatin remodeling machines play more maintenance roles in the cell, helping to maintain cellular architecture."
Since then, her lab has examined chromatin remodeling mutations in other rare diseases such as malignant rhabdoid tumors, an aggressive cancer of soft tissue that primarily affects children. Kadoch believes that studying rare cancers offers unique advantages to molecular biologists, as these diseases are often caused by fewer pathways than more common and complicated cancers such as melanoma.
Kadoch notes that as sequencing methods have advanced, she has been able to uncover even more potential contributors to rare cancers. She stressed how focusing on human genetics has led her team to identify other mutations and proteins that drive rare cancers.
"Under every rock we've found a new mechanism or another way these complexes can be hijacked," she said. "We've always used human genetics as a guide, because it's so powerful. It's the compass that tells us where to go, if we're on a hunt it tells us where to hunt."
By understanding the role of chromatin remodeling machines in rare cancers, Kadoch's work has also yielded insights into the genetic origins of common cancers. For example, studying a hallmark mutation that causes a rare form of ovarian cancer has allowed her lab to draw conclusions about the larger role of the mutated complex in human health.
Kadoch added that her lab will continue to work on comprehensively understanding the structure and organization of chromatin remodeling complexes. Her ultimate goal is to use these insights as a springboard for developing cancer therapies that can target regions of remodeling machines that contribute to disease.
"There are currently no targeted biologics that can address any of these mutations for rare cancers like synovial sarcoma," she said. "There is a very major unmet medical need for patients with these remodeling mutations."