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October 5, 2018
Wachtel Awardees Discuss Advances in Cancer Genomics

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Dr. Neville Sanjana

It’s an exciting time to be a young scientist, as new technology keeps opening new doors to scientific discovery. Two NIH early-career investigators recently discussed their research on cancer genomics, made possible by the latest genetic and analytic tools.

“Early-career investigators are the future of our institution and of biomedical research,” said Dr. Tom Misteli, director of NCI’s Center for Cancer Research, at the recent CCR Grand Rounds in Lipsett Amphitheater. “We have reached a point where we actually do understand many of the basic principles and mechanisms [underlying cancer] with sufficient detail, so we can use that knowledge to translate it to the clinic.”

Misteli introduced the two researchers who recently received the Martin & Rose Wachtel Cancer Research Award, splitting the $25,000 prize from the Wachtel endowment. Dr. Neville Sanjana of New York University and the New York Genome Center and Dr. Omer Yilmaz of the Koch Institute for Integrated Cancer Research at MIT, who both teach biology, described their findings at the AAAS-sponsored Wachtel Lecture, co-hosted by NCI.

Sanjana’s lab is using gene-editing technologies to pinpoint genetic variants that contribute to cancer growth and therapeutic resistance.

“How do we take the human genome, with its 3 billion bases, and find that needle in a haystack?” he asked. “As we get this huge number of variants from tumor sequencing, it’s becoming more and more difficult to understand which of these variants cause the disease, which ones drive tumor evolution and drug resistance and which ones might just be passengers along for the ride.”

In analyzing cancer mutations, much attention is focused on protein-coding genes of the genome. But they make up only a small fraction of the entire human genome — less than 2 percent. Sanjana is particularly interested in the noncoding regions, which comprise 98 percent of the genome. Using CRISPR nucleases like Cas9, his lab is able to knock out thousands of genes and noncoding regions to help find mutations that drive drug resistance in melanoma. His gene- editing approach using pooled screens does not rely on making a single mutation at a time but instead harnesses libraries that can test thousands of mutations in parallel.

BRAF is the most commonly mutated gene in melanoma and a common treatment for BRAF-mutant melanoma is the FDA-approved drug vemurafenib. Most melanoma patients go into remission for a time after receiving the drug, but then resistance sets in and the prognosis worsens. By editing human melanoma cells and exposing them to the drug or a placebo, Sanjana and his colleagues have identified novel genes and noncoding regions of the genome that drive vemurafenib resistance.

Dr. Omer Yilmaz
Dr. Omer Yilmaz

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“Even though we already have all these assays of noncoding function,” said Sanjana, “the functional screens add another layer on top of those assays that’s directly connected with an important phenotype, the drug resistance itself that we see in patients.”

Another study in Sanjana’s lab is identifying mutations that prevent immunotherapy from working. This collaborative work with NCI’s [Dr. Nicholas] Restifo’s lab uses genome-wide screens to pinpoint tumor mutations that result in immunotherapy failure across genetically diverse melanomas and also other cancers where immunotherapy is currently being deployed in the clinic.

One gene they identified, the apelin receptor, hadn’t previously been associated with immunotherapy response. But in a mouse melanoma model, tumor cells without the apelin receptor significantly decreased the efficacy of immunotherapy in terms of tumor volume and survival.

Said Sanjana, “We’re moving slowly toward a future with precision medicine where we could, in advance of a patient receiving a T-cell immunotherapy, be able to predict whether their tumor is a good candidate for this kind of therapy or whether it should be [used in combination with, or in lieu of] another therapy.”

The second Wachtel awardee, Yilmaz, discussed dietary origins of intestinal cancer. In many cases, low-calorie diets delay the incidence and inhibit the progression of different cancers, he said, whereas high-fat diets and obesity are found to accelerate cancers.

“Many tissues in the body are maintained by stem cells that integrate environmental cues like different types of nutrients and circulating hormones to coordinate tissue homeostasis and regeneration,” said Yilmaz.

Adult intestinal stem cells (ISCs) respond to these cues by interacting with their microenvironment, made up of support or “niche” cells, which include Paneth cells. Under normal dietary conditions, Yilmaz explained, ISCs are adjacent to their Paneth cell niche. But in a high-fat diet, ISCs proliferate and become uncoupled from this niche. It is possible that these changes enhance intestinal tumor formation in high-fat diets.

In one study, mice were fed an extremely high-fat diet for 18 months and became obese. These mice had at least triple the risk of developing spontaneous intestinal cancers, Yilmaz reported.

“Obesity is a modifiable risk factor for cancer,” he said. “Human patients with a body mass index of more than 30 have a modest, but significant, likelihood of developing and dying from colorectal cancer.”

RNA sequencing revealed a pathway called PPAR-delta that drives a fatty acid oxidation program enabling cells to utilize fat as an energy source. Interestingly, synthetic activation of the PPAR-delta pathway emulates many aspects that a high-fat diet has on intestinal stem cells: ISCs become uncoupled from their Paneth niche and these ISCs and their more differentiated daughter cells are better able to initiate intestinal tumors.

“We believe this high-fat diet PPAR-delta program contributes to intestinal tumorigenesis,” said Yilmaz.

Currently, his lab is studying reversibility, that is, the effects of a person quitting a high-fat diet and returning to a healthier diet and weight. They’re also studying whether fatty oxidation helps restore stem cell functionality and what other mechanisms might contribute to tumorigenesis.

Ultimately, Yilmaz hopes to create diet-based interventions that improve regenerative function while minimizing the risk of developing cancer. Sanjana looks forward to the next wave of analytic tools to help understand how tumor mutations affect cancer progression as well as therapeutic resistance. Then, he concludes in a recent article in Science Translational Medicine, we might “precisely tailor treatments from which cancers cannot escape.”

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