Article Category: Research

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.”

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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.

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.”

Patients with the most lethal form of acute myeloid leukemia (AML) – based on genetic profiles of their cancers – typically survive for only four to six months after diagnosis, even with aggressive chemotherapy. But new research indicates that such patients, paradoxically, may live longer if they receive a milder chemotherapy drug.

Treatment with the less intensive drug, decitabine, is not a cure. But surprisingly, AML patients whose leukemia cells carried mutations in a nefarious cancer gene called TP53 consistently achieved remission after treatment with decitabine. Their median survival was just over a year.

The study, by a team of scientists at Washington University School of Medicine in St. Louis, is published Nov. 24 in The New England Journal of Medicine.

In AML, treatment involves intensive chemotherapy to try to kill the patient’s leukemia cells and put the cancer into remission. If successful, a follow-up bone-marrow transplant can offer a possible cure, but this course of treatment is recommended only for patients with a high risk of relapse because the procedure can cause severe complications, even death.

“What’s really unique here is that all the patients in the study with TP53mutations had a response to decitabine and achieved an initial remission,” said the study’s senior author, Timothy J. Ley, MD, the Lewis T. and Rosalind B. Apple Professor of Medicine, noting that in AML, TP53 mutations have been correlated with an extremely poor prognosis. “With standard aggressive chemotherapy, we only see about 20 to 30 percent of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.

“The findings need to be validated in a larger trial,” Ley added, “but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates.”

In an accompanying editorial, Elihu Estey, MD, an AML expert at the University of Washington Medical Center and Fred Hutchinson Cancer Research Center in Seattle, noted that AML is not one disease but many, each driven by different genetic mutations. The results of the current trial, he said, point to the inevitable need to replace large cancer clinical trials evaluating homogeneous drug treatments with smaller trials that involve subgroups of patients, with treatments targeted to their specific mutations.

The current study involved 116 patients treated with decitabine at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital, and at the University of Chicago. The patients either had AML – a cancer of the bone marrow – or myelodysplastic syndrome (MDS), a group of blood cancers that often progresses to AML. This year, an estimated 20,000 people living in the U.S. will be diagnosed with AML, and at least 11,000 deaths will be attributed to the disease.

Decitabine often is given to older patients with AML or MDS because it is less toxic than standard chemotherapies. But fewer than half of patients who get the drug achieve an initial remission, so the researchers wanted to determine whether specific mutations in the patients’ cancer cells could predict their responses to treatment.

To find out, they sequenced all the genes in patients’ cancer cells or analyzed select cancer genes. They also conducted standard tests to look for broken, missing or rearranged chromosomes. Then, the researchers correlated these molecular markers with treatment response to identify subgroups of patients likely to benefit from decitabine.

Among the patients in the study, 46 percent achieved a remission with decitabine. But, remarkably, all 21 patients whose leukemia cells carriedTP53 mutations went into remission.

Patients also were likely to respond to decitabine if they were deemed to have an “unfavorable risk” prognosis based on extensive chromosomal rearrangements in their cancer cells; many of these patients also hadTP53 mutations. Indeed, 66 percent of patients with an unfavorable risk achieved remission, compared with 34 percent of patients who had more favorable prognoses.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said co-author Amanda Cashen, MD, an associate professor of medicine who led an earlier clinical trial of decitabine in older patients with AML. “The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

First author John Welch, MD, PhD, an assistant professor of medicine, added: “It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging. We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon.”

Responses to decitabine are usually short-lived, however, with remissions typically lasting for about a year. Decitabine does not completely clear all the leukemia cells that carry TP53 mutations, and these cells invariably become resistant to the drug, leading to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Ley explained. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or two and with a good quality of life, because the chemotherapy is not too toxic.”

Roughly 10 percent of AML patients carry TP53 mutations in their leukemia cells. Among patients in the study with such mutations, median survival was 12.7 months – which is not significantly different from the 15.4 months’ survival seen in patients without the mutations – and is longer than the typical four- to six-month survival observed in such patients treated with more aggressive therapies.

Decitabine was approved by the FDA in 2006 as a treatment for MDS, but oncologists often prescribe it off-label as a treatment for AML, particularly in older patients. AML typically strikes in a person’s mid-60s; the average age of people in the current study was 74.

“We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations,” Welch said. “It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

While a particular metabolic pathway shows potential to slow down the aging process, new research indicates a downside: That same pathway may drive brain cancer.

The pathway, known as the nicotinamide adenine dinucleotide (NAD+) pathway, is overactive in a deadly form of brain cancer known as glioblastoma, according to a study by researchers at Washington University School of Medicine in St. Louis. Glioblastoma is the most common and aggressive brain cancer in adults. Over 70 percent of patients with glioblastoma die within two years of diagnosis.

The new research showed that glioblastoma patients with high expression of an NAD+ pathway gene known as NAMPT died sooner. Tumors with elevated expression of the same gene grew rapidly when they were implanted in mice and shrank when NAMPT was inhibited.

The study, published Dec. 5 in Proceedings of the National Academy of Sciences, suggests that inhibiting the NAD+ pathway may improve the outlook for glioblastoma patients but also may affect other biological processes, such as aging.

NAMPT produces a molecule known as nicotinamide mononucleotide (NMN) that has been shown to reduce signs of aging in mice. While its safety in people has yet to be determined – a clinical trial is ongoing in Japan – NMN and other molecules along the NAD+ pathway are being marketed as anti-aging supplements.

“There’s a lot of buzz about taking NAD+ precursors for their anti-aging effects, which is based on a lot of great science,” said Albert H. Kim, MD, PhD, an assistant professor of neurological surgery and the senior author on the study. “We didn’t directly demonstrate that taking NAD+ precursors makes tumors grow faster, but one implication of our work is that if you want to take anti-aging NAD+ precursors, you might want to keep in mind that we don’t yet understand all the risks.”

Using human glioblastoma cells, Kim, postdoctoral researcher Amit Gujar, PhD, and colleagues showed that NAMPT helped cancerous stem cells survive and proliferate, fueling the growth of existing tumors, while inhibiting NAMPT reduced the ability of the cancer stem cells to renew themselves.

Furthermore, the scientists found that glioblastoma cells responded to radiation therapy – a standard therapy used to treat the disease in people – by increasing expression of NAD+ pathway genes, and that inhibiting NAMPT before dosing the cells with radiation made them easier to kill.

“If you target the NAD+ pathway, you can disrupt the ability of the cancer stem cells to self-renew, and you can also make them more sensitive to radiation treatment,” said Kim, who also treats patients with brain tumors at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. “In a patient, that could mean that if you suppress the pathway, the same dose of radiation may be more effective at destroying the tumor.”

The NAD+ pathway involves many different genes and proteins, and its very complexity may be the key to having it both ways. Kim believes it may be possible to carefully modulate the pathway so as to suppress cancer without accelerating aging or interfering with other important biological processes.

“The question we are considering now is, ‘How do we make an NAD+ strategy that is specific for cancer?’” Kim said. “Maybe there are some cancer-specific regulators, and we can disrupt those. Maybe we can change the expression of some key NAD+ pathway genes only in cancer cells, not healthy cells. There are many ways to look at this, and that’s why we want to dig deeper into how this pathway works in glioblastoma.”

New research shows that excess weight increases the risk that a benign blood disorder will progress into multiple myeloma, a cancer of the blood.

The study, by a team at Washington University School of Medicine in St. Louis, is published Nov. 18 in the Journal of the National Cancer Institute.

Being overweight or obese has been known to increase the risk of multiple myeloma, a cancer of the plasma cells in the blood and bone marrow that develops more often after age 60. Multiple myeloma is preceded by a blood disorder called monoclonal gammopathy of undetermined significance (MGUS) in which abnormal plasma cells produce many copies of an antibody protein. This precancerous condition does not cause symptoms and often goes undiagnosed.

“But our findings show that obesity can now be defined as a risk factor for developing multiple myeloma through this condition,” said the study’s first author, Su-Hsin Chang, PhD, an assistant professor of surgery in the Division of Public Health Sciences at Washington University.  “For patients diagnosed with MGUS, maintaining a healthy weight may be a way to prevent the progression to multiple myeloma, if further confirmed by clinical trials.”

The researchers analyzed data from a U.S. Department of Veterans Affairs database, identifying 7,878 patients, predominately men, diagnosed with MGUS from October 1999 through December 2009.

Among these patients, 39.8 percent were overweight and 33.8 percent were obese. The researchers then tracked whether the patients developed multiple myeloma. They found that 4.6 percent of overweight patients (followed for a median of 5.75 years) and 4.3 percent of obese patients (followed for a median of 5.9 years) developed multiple myeloma, compared with 3.5 percent of people at normal weight (followed for a median of 5.2 years) – a difference that is statistically significant.

Overweight and obese MGUS patients had a 55 percent and 98 percent higher risk of progression to multiple myeloma, respectively, than normal-weight MGUS patients.

African-American men also were more likely than their Caucasian counterparts to experience a progression from MGUS to multiple myeloma.

MGUS is caused by elevated levels of an antibody protein, known as M protein, that is found in 3 percent of people over age 50. By itself, MGUS is difficult to diagnose and often does not warrant treatment.

“The diagnosis is usually by accident, often driven by tests performed for the diagnosis or management of other conditions,” Chang said. “Although our study does not directly suggest screening for MGUS, regular check-ups can help physicians monitor whether MGUS is progressing to other disorders, including multiple myeloma.”

Multiple myeloma is the third most common type of blood cancer. An estimated 30,330 new cases of the cancer will be diagnosed in 2016, and 12,650 deaths will be attributed to the disease, according to the American Cancer Society.

“Based on our finding that being overweight or obese is a risk factor for multiple myeloma in MGUS patients, and since extra weight is a modifiable risk factor, we hope that our results will encourage intervention strategies to prevent the progression of this condition to multiple myeloma as soon as MGUS is diagnosed,” Chang said. “Also, for black people diagnosed with MGUS, close monitoring of the disease progression, in addition to maintaining a healthy weight, should be prioritized.”

Future studies are planned by Chang and other School of Medicine researchers – including senior author Kenneth R. Carson, MD, PhD, an assistant professor of oncology, and Graham Colditz, MD, DrPH, a cancer expert who also is associate director of prevention and control at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

“In the future, we will look at whether healthy weight loss is inversely associated with the progression of multiple myeloma in MGUS patients or how weight change plays a role in the progression of MGUS to multiple myeloma,” Chang said.

A combination of two topical drugs that have been in use for years triggers a robust immune response against precancerous skin lesions, according to a new study. The research, from Washington University School of Medicine in St. Louis and Harvard Medical School, shows that the therapy activates the immune system’s T cells, which then attack the abnormal skin cells.

The study, which involved patients with actinic keratosis, a precursor to a type of skin cancer called squamous cell carcinoma, is published Nov. 21 in The Journal of Clinical Investigation.

“We looked at precancerous lesions on patients with sun-damaged skin,” said Washington University dermatologist and study co-author Lynn A. Cornelius, MD, director of the Division of Dermatology. “Most commonly found on the face, scalp and arms, these lesions appear abnormal by visual examination and under the microscope but are not full-blown skin cancers. But because these lesions have the potential to develop into a true skin cancer, they are commonly treated. Our study shows this combination therapy is more effective and better tolerated than current treatment practices.”

On average, the investigational therapy reduced the number of precancerous skin lesions on the face by almost 88 percent compared with a 26 percent reduction using the standard chemotherapy. While some side effects such as skin scaling and itching were similar with both treatments, patients receiving the investigational therapy reported more redness and increased burning sensations, which are consistent with the immune response it triggers. Interestingly, although not specifically measured, patients who had been treated previously with conventional therapies reported decreased pain and discomfort with the combination treatment, according to Cornelius, who is also the Winfred A. and Emma R. Showman Professor of Dermatology.

The investigational treatment combines a cream formulation of a chemotherapy drug called 5-fluorouracil with a synthetic form of vitamin D called calcipotriol. Topical 5-fluorouracil alone is prescribed to treat actinic keratosis. Calcipotriol is approved by the Food and Drug Administration (FDA) for treatment of psoriasis, an autoimmune disorder characterized by red, scaly patches of skin.

Past studies of mice prone to allergic inflammation, especially eczema rash on the skin, have shown that they also are resistant to developing skin cancer. These observations suggested that overreactive immunity triggered by damaged skin may have a beneficial side effect — a hyper-vigilant immune system that also attacks any cancerous cells that may form. Earlier work at Washington University by senior author Shadmehr Demehri, MD, PhD, now at Harvard Medical School, showed that a protein called TSLP in the skin activates the immune system’s T cells, which then attack tumor cells. Calcipotriol also was known to cause the skin to produce TSLP.

“The idea behind this study was to induce a heightened immune response in the skin using calcipotriol combined with the 5-fluorouracil that works to destroy the precancerous cells,” Cornelius said. “In so doing, the destroyed precancerous cells release cell proteins, or antigens, and facilitate the heightened immune system to respond. We compared the two-drug formulation to 5-fluorouracil alone over a shorter application period — four days as opposed to two to four weeks that is typical for the standard treatment of 5-fluorouracil alone.”

The current study involved 132 patients with actinic keratosis treated at Washington University School of Medicine in St. Louis. Sixty-five of these patients were randomly assigned to receive the investigational drug combination of 5-fluorouracil plus calcipotriol. The remaining 67 served as a control group and received the standard 5-fluorouracil plus Vaseline petroleum jelly. Patients applied the assigned cream twice daily for four days.

Patients in the investigational and control groups began the trial with similar numbers of precancerous lesions on each part of the body examined. At each body site evaluated, there were on average about 15 lesions on the face, 22 lesions on the scalp, 14 lesions on the right arm and 12 on the left arm. Following treatment, facial lesions were reduced by 88 percent in the investigational group versus 26 percent in the control group. On the scalp, lesions were reduced by 76 percent in the investigational group compared with about 6 percent for the control group. On the right arm, the reduction was 69 percent for the investigational treatment versus about 10 percent for the control. On the left arm, the precancerous lesions were reduced by 79 percent for the investigational treatment compared with 16 percent for the control.

“Because calcipotriol has been shown to induce an immune response, we are now interested in seeing if the anti-tumor immunity of the activated T cells can be recalled later to help prevent both precancerous and cancerous skin lesions,” Cornelius said. “We are now planning to re-contact our patients to determine whether there are differences in precancerous and skin cancer rates between the two treatment groups.”

Two scientists at Washington University School of Medicine in St. Louis and Siteman Cancer Center will receive a combined $300,000 in funding over two years for their innovative approaches to fighting cancer.

The awards, from the Alvin J. Siteman Cancer Research Fund, are meant to further promising early-stage science that because of its unconventional approach might not receive funding from traditional sources.

The recipients are:

• Nima Mosammaparast, MD, PhD, an assistant professor of pathology and immunology, who is studying how DNA is repaired, in hopes of identifying new ways to treat tumors. He will receive $200,000.

• James Janetka, PhD, an associate professor of biochemistry and molecular biophysics, who is working to develop inhibitors that have anticancer effects in breast, pancreas, lung, prostate and glioblastoma cell lines. He will receive $100,000.

Alvin J. Siteman, an emeritus Washington University trustee, chairman of Site Oil Co. and president of Flash Oil Co., established the Siteman Cancer Research Fund in 2010. Since then, the fund has provided about $7 million in funding to 11 projects at Washington University/Siteman Cancer Center. All projects are reviewed and recommended by an external review panel.

The National Cancer Institute (NCI) has awarded a $10.4 million, five-year grant to Washington University researchers and physicians at Siteman Cancer Center to lead a national group of experts in collaborative pancreatic cancer research.

The award, a prestigious Specialized Program of Research Excellence (SPORE) grant, will help scientists pursue new treatments for the deadliest form of the disease, pancreatic ductal adenocarcinoma, including development of more effective chemotherapies and a vaccine.

Partner institutions are the University of Rochester, the University of North Carolina at Chapel Hill and Johns Hopkins University.

“This grant addresses a huge need to improve therapies for pancreatic cancer patients,” said surgeon William Hawkins, MD, the Neidorff Family and Robert C. Packman Professor at Washington University and principal investigator of the grant. “With it, we are able to build on our already extensive knowledge of the disease and to further pursue a multipronged approach aimed at extending lives.”

The pancreas, an organ that lies between the stomach and spine, has two primary functions: making enzymes that are released into the small intestine to help digest food, and making insulin and other hormones that help control blood sugar levels.

While the lifetime risk of developing pancreatic cancer is low – about 1.5 percent for the average American – fewer than 8 percent of patients survive more than five years after they’re diagnosed, according to the NCI. This year, an estimated 53,070 people will be diagnosed with the disease in the U.S., including 1,080 in Missouri and 2,120 in Illinois, according to the American Cancer Society. Surgery, radiation and chemotherapy can extend survival and/or relieve symptoms, but they rarely serve as a cure.

The SPORE grant supports four new projects that involve:

• Altering the environment around the tumor to make it more susceptible to immunotherapy, which harnesses a patient’s own immune system to fight cancer. This research is led by David DeNardo, PhD, a Washington University assistant professor of medicine, who will work with David Linehan, MD, of the University of Rochester;
• Developing a more effective chemotherapy aimed at targeting pancreatic cancer and inducing tumor cell death. This work is led by Hawkins, who also sees patients at Barnes-Jewish Hospital and is the Neidorff Family and Robert C. Packman Professor;
• Evaluating for future clinical testing another potential chemotherapy that overcomes tumor resistance. This area of study is led by Andrea Wang-Gillam, MD, PhD, a Washington University associate professor of medicine, who will work with Channing Der, PhD, of the University of North Carolina at Chapel Hill;
• Conducting preclinical studies of a personalized pancreatic cancer vaccine. This work is led by William Gillanders, MD, a Washington University professor of surgery, who will work with Robert Schreiber, PhD, the Alumni Endowed Professor of Pathology and Immunology at Washington University, and Elizabeth M. Jaffee, MD, of Johns Hopkins University.

Three other Washington University faculty members are key partners: Ryan Fields, MD, an assistant professor of surgery; Graham Colditz, MD, DrPH, the Niess-Gain Professor of Surgery; and Albert Lockhart, MD, a professor of medicine.

The award is the second SPORE grant currently held by Washington University researchers. The other, a $11.3 million, five-year award given in 2013, is for leukemia research.

Quitting smoking improves health and lowers odds of developing lung cancer. But a new study shows that even among smokers with a genetic predisposition to smoking heavily and developing lung cancer at a young age, the benefits of quitting are significant.

An international study led by researchers at Washington University School of Medicine in St. Louis and the Siteman Cancer Center indicates that in these high-risk smokers, quitting smoking cuts lung cancer risk in half and delays the age at which the disease is diagnosed.

The findings suggest that in the future, doctors may request a DNA analysis from smokers to employ more effective therapies to help them quit. The new study is available online in the journal eBioMedicine.

The researchers analyzed data from 15 studies involving more than 12,000 current and former smokers.

They found that even those with DNA variations that elevated their cancer risk had better outcomes if they kicked the habit.

“When people with the risky gene variants quit smoking, it cuts their odds of getting lung cancer in half,” said first author Li-Shiun Chen, MD, an assistant professor of psychiatry. “We also found that although some patients will go on to develop lung cancer even after quitting, stopping smoking can delay their diagnosis by an average of seven years.”

The same research team previously had found that smokers with variations in a nicotine receptor gene were likely to continue smoking longer than those without the DNA variants. Those with the risky gene profile also were likely to be diagnosed with lung cancer about four years earlier than smokers without the risky variety of the gene, calledCHRNA5. The researchers also repeatedly have found that it’s more difficult to quit for people with the high-risk genetic profile.

But if they can manage it, Chen said, quitting can significantly lower their risk of lung cancer, on par with smokers who don’t have gene variations that make it harder to quit.

“Some people believe that genes determine everything,” Chen said. “They might think there’s no use in even trying to quit, but these findings directly contradict that myth. Although a person may be genetically vulnerable to conditions such as smoking, obesity or metabolic syndrome, the situation isn’t hopeless. Our health may be altered by certain genes, but we still can manage to make healthier choices, and if we do that, there can be big benefits.”

Lung cancer is the most common cancer in the world, making up about 13 percent of cancer cases worldwide and contributing to more than a quarter of all cancer-related deaths. About half of those diagnosed with lung cancer will die within a year of that diagnosis.

In past research, Chen and her colleagues have found that a risky genetic profile can make a smoker more likely to respond to nicotine-replacement therapy. Because those with high-risk genes are more likely to benefit from nicotine patches and other medications, Chen’s colleague, Laura Jean Bierut, MD, the Alumni Endowed Professor of Psychiatry, explained that doctors might want to identify smokers who have risky genetic variants. That, she explained, could make it possible to match smokers to therapies that are most likely to help them kick the habit.

“Normally, those with a risky genetic profile have difficulty quitting,” Bierut explained. “They are successful only about one-third as often as those who don’t have a risky gene profile. Because we also know they are more likely to respond to certain therapies, such as nicotine patches or lozenges, we should be able to use precision medicine therapies that match individual smokers to the treatments most likely to help them.”

Chen is studying smokers to learn what combinations of treatments work best in those with and without risky DNA variants. Her team is recruiting 720 smokers from the St. Louis area who are trying to quit.

Those in the study are randomly assigned to receive either counseling only or counseling and one of two smoking-cessation therapies. The researchers will try to determine which therapeutic strategies work best and how to match those therapies to an individual smoker’s DNA by comparing success in smoking cessation with the DNA of individual smokers.

For more information about that study, which is called the Genetically Informed Smoking Cessation Trial, contact study coordinator Nina Smock at 314-747-7849 or e-mail her at [email protected].