Wachtel Award Honors Two Innovative Cancer Researchers

Neville Sanjana (left), Tom Misteli, Omer Yilmaz, Yevgeniya Nusinovich, and AAAS CEO Rush Holt at the Wachtel Awards ceremony at the National Institutes of Health. | Joseph Cariz/ AAAS

Neville Sanjana and Omer Yilmaz have received the 2018 AAAS Martin and Rose Wachtel Cancer Research Award for their work on genetic screening that uncovers the basis of cancer evolution and research elucidating the dietary origins of intestinal cancers, respectively.

Sanjana, a core faculty member at the New York Genome Center and assistant professor at New York University, and Yilmaz, a member of the Koch Institute for Integrated Cancer Research and assistant professor at the Massachusetts Institute of Technology, wrote essays on their work that were published in the August 8 issue of Science Translational Medicine. Both scientists also presented lectures on their prize-winning research at an award ceremony on August 10 at the U.S. National Institutes of Health.

"Dr. Sanjana's research uses high-throughput screening methods to identify new genes and noncoding elements that promote various hallmarks of cancer, such as metastasis and immune evasion," said Yevgeniya Nusinovich, a senior editor at Science Translational Medicine.

Yilmaz is focused on the influence of diet on intestinal cancers. He has spent much of his career examining the effects of normal, low-, and high-calorie diets on the behavior of intestinal stem cells — which give rise to mature gut cells — and the changes in the intestinal system that promote tumor development.

His work has granted researchers a new understanding of these processes that, "may eventually enable the development of better tolerated therapeutic diets or other alternatives for cancer prevention," said Nusinovich.

Each year, the AAAS Martin and Rose Wachtel Cancer Research Award honors early-career scientists who have made outstanding contributions to cancer research within 10 years of completing their Ph.D. or M.D. degree. Sanjana and Yilmaz will both receive a cash award of $12,500 funded by an endowment bequeathed by Martin L. Wachtel.

"Early-career scientists are a critical part of every investigational program, and they represent the future of biomedical research," said Tom Misteli, director of the Center for Cancer Research at the National Institutes of Health.

Harnessing technologies for large-scale DNA synthesis and gene editing, Sanjana has devised new screening approaches to analyze the genetic basis of tumor evolution, metastasis and therapy resistance in various human cancers. His work has allowed other researchers to gather new insights into these fields without needing large amounts of tumor samples.

The human genome is vast, containing 20,000 genes and additional regions of DNA that don't harbor genes but are critical for gene regulation. Probing this massive space for clues into the causes of cancer has often proved difficult for researchers, according to Sanjana.

"Cancer is a disease of the genome and it can mutate and hijack many different genes to trigger unfavorable outcomes like metastasis and drug resistance," he said. "It can be quite a pain to have to dig through each gene in the genome individually and test it for a possible role in cancer growth."

Cancer-associated genes, depicted here on soup cans, are the focus of the 2018 Wachtel Cancer Research Award. | Christian Stolte, New York Genome Center. Image derived from artwork © 2018 The Andy Warhol Foundation for the Visual Arts, Inc.

To address this hurdle, his lab has harnessed the power of CRISPR — a revolutionary technology that allows scientists to rapidly and easily edit genes — to screen multiple genes at once on a genome-wide scale. Using "libraries" of CRISPR genetic material, the researchers have been able to identify genes that make cancers such as melanoma resistant to drug treatments, he said.

His group has recently zeroed in on uncovering the genetic factors that allow cancers to become resistant to immunotherapy, and whether these factors are also present in cancer patients who don't respond to immunotherapy treatments.

"One ongoing project in our lab is to understand how these mutations influence patients who are treated with immunotherapy," Sanjana said. "That is, do some of the same genes identified in the CRISPR screen as drivers of drug resistance also result in similar therapeutic resistance when we see them in the clinic?"

So far, Sanjana and his colleagues have uncovered a large degree of overlap between these genes, and Sanjana now aims to integrate CRISPR screens and other genetic assays more closely with patient care. Ultimately, this approach could one day allow caretakers to quickly select which treatments might be best for a particular patient and their cancer, he said.

The researchers also plan to develop CRISPR screens to target not only genes but other elements of the human genome. They are particularly interested in demystifying how genes are regulated and if any of the key regions outside the genome can drive cancer development.

Yilmaz focuses on how diet and nutrients can affect stem cells in the small and large intestines. These cells can either create more stem cells or differentiate into a myriad of mature intestinal cell types. Previous research has indicated cancers frequently arise from stem cells because they persist for life and accumulate genetic mutations, he said.

His group recently discovered that in mouse models of obesity induced by high-fat diets, intestinal stem cells become more active and divide more frequently. Furthermore, high-fat diets induce non-stem cells in the intestines to take on some characteristics of stem cells, a change that "augments the pool of cells in the intestine that can contribute to intestinal cancers," he said.

Yilmaz's research has also explored the other side of dietary extremes: caloric restriction. His lab has found that low calorie diets also enhance the activity of intestinal stem cells, especially during old age. However, low calorie diets don't increase the formation of the cancer, a finding that they plan on investigating further in the future.

"Because stem cells play a significant role in not only tumor formation but also in tissue regeneration, deciphering their response to dietary factors is of the utmost importance for the treatment of degenerative conditions," Yilmaz said.

"Ultimately, we hope to design diet-based strategies to maximize regenerative and therapeutic impact while minimizing the risk of cancer development."