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The body of knowledge on cancer genomics is massive and ever-expanding. But this wealth of potentially critical information is far less likely to be of help to patients if it is inaccessible to the doctors who treat them.

Researchers at Washington University School of Medicine in St. Louis have developed an online “knowledgebase” intended for the gathering and organization of this information so that clinicians have improved chances of identifying important mutations in a patient’s tumor and potentially connecting genetic errors with drugs known to target them.

The online resource, called CIViC, is described Jan. 30 in Nature Genetics.

CIViC stands for Clinical Interpretations of Variants in Cancer, and the researchers liken it to a Wikipedia of cancer genetics. Anyone can create an account and contribute information. That information is then curated by editors and moderators who are experts in the field.

“It’s relatively easy now to sequence the DNA of tumors — to gather the raw information — but there’s a big interpretation problem,” said senior author Obi L. Griffith, PhD, an assistant professor of medicine. “What do these hundreds or thousands of mutations mean for this patient? There are a lot of studies being done to answer these questions. But oncologists trying to interpret the raw data are faced with an overwhelming task of plumbing the literature, reading papers, trying to understand what the latest studies tell them about these mutations and how they may or may not be important.”

The CIViC knowledgebase is an attempt to solve this problem. While the investigators said this is one of many efforts to collect and interpret such information, CIViC is the only one that is entirely open access, to their knowledge. Anyone is free to contribute and use the content as well as the source code.

“We are committed to keeping this resource open and available to anyone who wants to contribute or make use of the information,” said Malachi Griffith, PhD, an assistant professor of medicine. “We would like it to be a community exercise and public resource. The information is in the public domain. There are no restrictions on its use, academic or commercial.”

Obi and Malachi Griffith, who are twin brothers, are assistant directors of the university’s McDonnell Genome Institute.

Though anyone can submit a new piece of information or suggest edits to existing data, at least two independent contributors must agree that the new information should be incorporated, and one of those users must be an expert editor. Expert editors are not permitted to approve their own submissions. Information on the CIViC website provides details about how new users may be promoted to expert editors and administrators.

To date, the site has seen over 17,500 users from academic institutions, governmental organizations and commercial entities around the world. Since CIViC’s launch, 59 users have volunteered their time to contribute their knowledge to CIViC, including descriptions of the clinical relevance of 732 mutations from 285 genes for 203 types of cancer, all gleaned from reviewing 1,090 scientific and medical publications.

Despite the fact there are many groups attempting to collect and interpret genomic variants in cancer, the investigators said the sheer volume of information has resulted in relatively little overlap in data gathered so far.

“While we believe this is the only such open-access knowledgebase, there are other large research centers with similar resources,” Malachi Griffith said. “We did an analysis to compare the big ones. Even though we all have access to the same published literature, if you look at the overlap of the information mined by each of these resources, it’s remarkably small. We’re all approaching the same problem and just by chance — and probably because of the amount of information out there — we haven’t duplicated our efforts very much yet.”

Obi and Malachi Griffith said finding a way to combine these resources is the primary goal of an international group they are helping lead called the Variant Interpretation for Cancer Consortium, which is a part of the Global Alliance for Genomics and Health (GA4GH).

“We’re just scratching the surface of the potential this holds for precision medicine,” Obi Griffith said. “There’s a lot of work to do.”

This work was supported by the National Institutes of Health (NIH), grant numbers U01CA209936, U54HG003079, K99HG007940, K22CA188163 and K08CA166229; by the German Federal Ministry of Education and Research, grant numbers 031L0030E and 031L0023B; by the Spanish Ministry of Economy and Competitiveness; and by the European Regional Development Fund, grant number SAF2015-74072-JIN.

Griffith M*, Spies NC*, Krysiak K*, McMichael JF, Coffman AC, Danos AM, Ainscough BJ, Ramirez CA, Rieke DT, Kujan L, Barnell EK, Wagner AH, Skidmore ZL, Wollam A, Liu CJ, Jones MR, Bilski RL, Lesurf R, Feng Y, Shah NM, Bonakdar M, Trani L, Matlock M, Ramu A, Campbell KM, Spies GC, Graubert AP, Gangavarapu K, Eldred JM, Larson DE, Walker JR, Good BM, Wu C, Su AI, Dienstmann R, Margolin AA, Tamborero D, Lopez-Bigas N, Jones SJM, Bose R, Spencer DH, Wartman LD, Wilson RK, Mardis ER, Griffith OL. CIViC is a community knowledgebase for expert-crowdsourcing the clinical interpretation of variants in cancer. Nature Genetics. Jan. 30, 2017. *These authors contributed equally to this work.

Conventional wisdom holds that the loss of cells that secrete acid in the stomach leads to a condition that eventually can develop into stomach cancer.

But new research at Washington University School of Medicine and Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis indicates otherwise. Researchers found that damage to acid-secreting cells alone doesn’t jump-start the transformation of healthy cells into precancerous cells — at least in a mouse model.

Their research is published online in the journal Gastroenterology.

“We believe it’s easier to stop cancer from starting than to treat it after it occurs, so our goal has been to find ways to stop this cascade before it begins,” said first author and doctoral candidate Joseph Burclaff. “But the first steps in the process that leads to cancer, however, are different than what we had assumed, so to prevent cancer, we’ll need to identify the real culprit.”

Burclaff works in the laboratory of Jason C. Mills, MD, PhD, a professor of medicine in the Division of Gastroenterology. Like other scientists in the field, they had concluded long ago that damage to acid-secreting cells in the stomach leads directly to a precancerous condition called metaplasia. But studying a mouse model of that condition, the researchers learned that the conventional wisdom was wrong.

“We thought we had this process figured out, but when we selectively destroyed only these acid-secreting cells in the stomachs of mice, the animals didn’t develop metaplasia,” Mills said.

The precancerous process causes cells in adult organs to change in response to inflammation or injury. Those changes may help cells respond more effectively to particular types of injury. The problem, said Mills, who also is a professor of developmental biology and of pathology and immunology, is that when the process continues over many years, it greatly increases cancer risk.

The two main causes of the precancerous condition are bacterial infections — particularly with H pylori, the microbe associated with stomach ulcers — and inflammation caused by the body’s own immune system.

In this study, Burclaff and Mills inserted a human gene into acid-secreting cells in the stomachs of mice. Then, by exposing the animals to a toxin that affects human cells but not mouse cells, they were able to kill the acid-secreting cells without damaging any other cells in the animals. But, surprisingly, the mice did not go on to develop the precancerous condition.

“We had thought the dying cells might signal other cells, sort of like a 911 call,” Burclaff said. “If there was such a signal, we could work to block it before it led to cancer. But these experiments demonstrate that if such signals exist, they must be coming from someplace else.”

Burclaff and Mills now believe whatever is contributing to the precancerous condition also may be causing the acid-secreting cells to die.

“These experiments suggest the loss of the acid-secreting cells and metaplasia may occur through different mechanisms,” Mills said. “Ultimately, the cause may be the same, for example infection with H pylori, but simply damaging or destroying the cells isn’t sufficient to launch this cascade. The more we can learn about what actually causes the precancerous condition, the more likely we’ll be able to interrupt the cascade and prevent stomach cancer.”

For the first time ever, investigators are studying immunotherapy for patients with newly diagnosed endometrial cancer. The trial uses pembrolizumab, a programmed death receptor-1 (PD-1) inhibitor. The drug is currently approved by the Food and Drug Administration for treatment of advanced melanoma and metastatic non-small-cell lung cancer.

“Pembrolizumab has been studied in patients with relapsed endometrial cancer, but our trial is the first to use it as an initial treatment for the disease,” says Katherine Fuh, MD, PhD, a gynecologic oncologist at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

Investigators plan to enroll nine patients with type 2 endometrial cancer. Unlike patients with type 1 endometrial cancer, those with type 2 disease have a poor prognosis and a high risk of recurrence.

“The large majority of endometrial cancers are type 1, which is thought to be caused by excess estrogen, often in obese women,” says gynecologic oncologist Premal Thaker, MD, the trial’s principal investigator. “These cancers are most often detected early because the excess estrogen leads to vaginal bleeding.” Thaker notes that patients with type 2 endometrial cancer usually don’t have obesity or diabetes, or other comorbidities, and may not have a long period of bleeding. “They tend to be thin, otherwise healthy women, and their cancer has commonly spread outside the uterus by the time it is discovered,” Thaker says.

Endometrial cancers have high tumor-mutational burden. “These mutations can generate a novel protein sequence that will be recognized as foreign by the immune system,” Fuh says. “The new protein sequences, or neo-antigens, potentially can elicit an immune response against the cancer—a situation that informs our rationale for this trial.” Pembrolizumab, Fuh says, works by inhibiting tumors from evading the immune response and allowing the immune system to do its job.

Study participants will receive two cycles of intravenous pembrolizumab three weeks apart before undergoing surgery to remove the cancer. They will then receive standard treatment—usually a combination of chemotherapy and radiation—followed by four additional cycles of pembrolizumab as a maintenance therapy.

“Immunotherapy for gynecological cancers is still in its infancy,” Thaker says. “But lots of women are dying of advanced-stage endometrial cancers, and immunotherapy has the potential to prevent that.”

Investigators will compare the study participants’ outcomes to those of historical controls. They also will take two biopsies from each patient’s uterus—one before the initial pembrolizumab dose and a second at the time of surgery. By comparing the samples, they can determine whether the drug affects the cancer.

“There aren’t many other disease sites that lend themselves to getting multiple biopsies easily,” Thaker says. “But because we can, we have the ability to understand how this treatment impacts the tumor microenvironment. That is part of what makes this trial novel, and hopefully it ultimately will make an impact for patients.”

For decades, scientists have tried to halt cancer by blocking nutrients from reaching tumor cells, in essence starving tumor cells of the fuel needed to grow and proliferate. Such attempts often have disappointed because cancer cells are nimble, relying on numerous backup routes to continue growing.

Now, scientists at Washington University School of Medicine in St. Louis have exploited a common weak point in cancer cell metabolism, forcing tumor cells to reveal the backup fuel supply routes they rely on when this weak point is compromised. Mapping these secondary routes, the researchers also identified drugs that block them. They now are planning a small clinical trial in cancer patients to evaluate this treatment strategy.

The research is published Jan. 24 in Cell Reports.

Studying human cancer cells and mice implanted with patients’ tumor samples, the researchers demonstrate that a double hit — knocking out the weak point and one of the tumor cells’ backup routes — shows promise against many hard-to-treat cancers. Though present in multiple cancer types, the weak point is particularly common in sarcomas — rare cancers of fat, muscle, bone, cartilage and connective tissues. Doctors treat sarcomas primarily with traditional surgery, radiation and chemotherapy, but such treatments often are not effective.

“We have determined that this metabolic defect is present in 90 percent of sarcomas,” said senior author Brian Van Tine, MD, PhD, an associate professor of medicine. “Healthy cells don’t have this weakness. We have been trying to create a therapy that takes advantage of the metabolic defect because, in theory, it should target only the tumor. Basically, the defect allows us to force the tumor cells to starve.”

To grow and proliferate, tumor cells must have basic building materials. The researchers’ strategy relies on the fact that the vast majority of sarcomas have lost the ability to manufacture their own arginine, a protein building block that cells need to make more of themselves. Lacking this ability, the cells must harvest arginine from the surrounding environment. The supply of arginine in the blood is abundant, and cancer cells have no trouble scavenging it. But remove this environmental supply of arginine and the cells have a problem.

“When we use a drug to deplete arginine in the blood, the cancer cells panic because they’ve lost their fuel supply,” Van Tine said. “So they rewire themselves to try to survive. In this study, we used that rewiring to identify drugs that block the secondary routes.”

Unlike most cancer therapies, depleting arginine in the blood does not affect healthy cells. Normal cells don’t rely on external sources of arginine because they don’t have the cancer’s metabolic defect. They continue to make their own arginine, so there is no induced starvation in normal cells even when there is no arginine in the blood. Van Tine said this strategy is based on the properties of a tumor — it shuts down tumor metabolism specifically and nothing else.

Unable to make or obtain external arginine, the tumor cells’ fuel supply routes are forced inward. The cells must begin to metabolize their internal supply of arginine in a process called autophagy, or “self-eating.” In the case of sarcomas, this state slows or pauses cancer growth but does not kill the cell. During this period, tumor cells appear to be buying time to find yet another internal work-around.

“Cancer doesn’t die when you halt its primary fuel supply,” Van Tine said. “Instead, it turns on all these salvage pathways. In this paper, we identified the salvage pathways. Then we showed that when you drug them, too, you kill cells. Our study showed that tumors actually shrink under these conditions. This is the first time tumors have been shown to shrink using just metabolism drugs and no other anti-cancer strategies.”

The arginine-depleting drug is currently in clinical trials investigating its safety and effectiveness against liver, lung, pancreatic, breast and other cancers. But so far, it has been ineffective likely because it has activated the salvage pathways allowing cancer growth to continue. The researchers said the drug may yet become a vital metabolic therapy for cancer as long as it is used in combination with other drugs targeting the backup pathways.

Van Tine and the study’s first author, Jeff C. Kremer, a PhD student in Van Tine’s lab, explained that when cancer cells with this metabolic defect are deprived of environmental arginine, they are forced to shift from a system that burns glucose to a system that burns a different fuel called glutamine. They showed that adding a glutamine inhibitor to the arginine-depleting drug is lethal to the cells. Eliminating arginine from the blood also rewires serine biology, another backup fuel, so adding serine inhibitors also causes cell death.

This strategy could be applied beyond rare sarcoma tumors because the metabolic defect is often present in other cancers, including certain types of breast, colon, lung, brain and bone tumors, the researchers said. The new study includes data showing similar anti-tumor responses in cell lines from these cancer types. Van Tine also pointed out that all of the drugs used in the study are either already approved by the U.S. Food and Drug Administration for other conditions or in ongoing clinical trials investigating cancer drugs.

Based on this study and related research, Van Tine and his colleagues at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine are planning a clinical trial of the arginine-depleting drug in patients with sarcomas.

“We will start with a baseline trial testing the arginine-depleting drug against sarcomas with this defect, and then we can begin layering additional drugs on top of that therapy,” Van Tine said. “Unlike breast cancer, for example, sarcomas currently have no targeted therapies. If this strategy is effective, it could transform the treatment of 90 percent of sarcoma tumors.”