Article Category: Research

Light-triggered nanoparticles show promise against metastatic cancer

A new anti-cancer strategy wields light as a precision weapon. Unlike traditional light therapy — which is limited to the skin and areas accessible with an endoscope — this technique can target and attack cancer cells that have spread deep inside the body, according to researchers at Washington University School of Medicine in St. Louis. 

Light emitted as part of traditional cancer-imaging techniques, to locate metastatic tumors, also can trigger light-sensitive drugs, according to the new study. In addition, the research shows that when such drugs are packaged into nanoparticles that target lit-up cancer cells, the light-sensitive drug produces toxic free radicals that kill the tumor cells. The researchers showed that the technique worked effectively in mice with multiple myeloma, a cancer of white blood cells, and aggressive metastatic breast cancer.

The study is published online in Nature Communications.

“Cancer that has spread remains the major reason patients die,” said senior author Samuel Achilefu, PhD, the Michel M. Ter-Pogossian Professor of Radiology at the School of Medicine. “Our study shows that this phototherapeutic technology is particularly suited to attacking small tumors that spread to different parts of the body, including deep in the bone marrow.” 

The technology harnesses a chemotherapy drug called titanocene. As a chemotherapy agent alone, titanocene has not worked well in clinical trials, even at relatively high doses. But when exposed to the radiation emitted by visible light, titanocene produces reactive particles that are toxic to cells, even at low doses. 

Achilefu and his colleagues packaged low doses of titanocene inside nanoparticles they targeted to proteins known to sit on the surface of cancer cells. They found that when the nanoparticles make contact with cancer cells, their membranes fuse together, releasing the titanocene into the cells. 

The investigators then deliver a common cancer imaging agent called fluorodeoxyglucose (FDG), a type of sugar. Energy-hungry cancer cells take up the FDG at high rates, causing tumors to glow in a positron emission tomography (PET) scan. This glow also triggers the titanocene, releasing free radicals and killing the cells.

Since the titanocene and the light-emitting FDG are targeted to the same place at the same time only in tumors, the technique is believed to be less toxic than standard radiation and chemotherapy. Research also shows that the body rids itself of titanocene through the liver, while FDG is cleared through the kidneys. That the two components are disposed of separately minimizes damage to other organs. When separated, the two components are not toxic, according to the investigators. 

Mice with multiple myeloma were treated using this strategy once a week for four weeks. In the weeks following, the treated mice had significantly smaller tumors and survived longer than the control mice. Fifty percent of treated mice survived at least 90 days. Of the control mice, 50 percent survived 62 days. The mice with breast cancer also showed an anti-tumor effect when treated using this strategy, though less pronounced than in those with multiple myeloma, likely due to the extreme aggressiveness of the breast cancer cell line, according to the researchers. The investigators also found that certain types of multiple myeloma surprisingly were resistant to this technique. They determined that the resistant multiple myeloma cells lacked the surface proteins used to target the titanocene-loaded nanoparticles.

“This is an opportunity to learn because it’s similar to what is seen in patients — some of the cells become dormant but don’t die after treatment,” said Achilefu, who also is a research member at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “When we looked closer at the cells that were resistant to our phototherapy, we saw that the surface protein we are targeting was not there. So next, we want to find out if we can pinpoint another surface protein to target and kill these resistant cells along with the myeloma cells that did respond to the original therapy, which could lead to complete remission.”

Achilefu envisions doctors being able to one day use this type of technology to prevent cancer from recurring. 

“We are interested in exploring whether this is something a patient in remission could take once a year for prevention,” Achilefu said. “The toxicity appears to be low, so we imagine an outpatient procedure that could involve zapping any cancerous cells, making cancer a chronic condition that could be controlled long-term.”

Study prompts new ideas on cancers’ origins

Rapidly dividing, yet aberrant stem cells are a major source of cancer. But a new study suggests that mature cells also play a key role in initiating cancer — a finding that could upend the way scientists think about the origins of the disease.

Researchers at Washington University School of Medicine in St. Louis have found that mature cells have the ability to revert back to behaving more like rapidly dividing stem cells. However, when old cells return to a stem cell-like status, they can carry with them all of the mutations that have accumulated to date, predisposing some of those cells to developing into precancerous lesions.

The new study is published online in the journal Gastroenterology.

“As scientists, we have focused a good deal of attention on understanding the role of stem cells in the development of cancers, but there hasn’t been a focus on mature cells,” said senior investigator Jason C. Mills, MD, PhD, a professor of medicine in the Division of Gastroenterology. “But it appears when mature cells return back into a rapidly dividing stem cell state, this creates problems that can lead to cancer.”

The findings, in mice and in human stomach cells, also raise questions about how cancer cells may evade treatment.

Most cancer therapies are aimed at halting cancer growth by stopping cells from rapidly dividing. Such treatments typically attack stem cells but would not necessarily prevent mature cells from reverting to stem cell-like status.

“Cancer therapies target stem cells because they divide a lot, but if mature cells are being recruited to treat injuries, then those therapies won’t touch the real problem,” said first author Megan Radyk, a graduate student in Mills’ laboratory. “If cancer recurs, it may be because the therapy didn’t hit key mature cells that take on stem cell-like behavior. That can lead to the development of precancerous lesions and, potentially, cancer.”

Studying mice with injuries to the lining of the stomach, the researchers blocked the animals’ ability to call on stem cells for help in the stomach. They focused on the stomach both because Mills is co-director of Washington University’s NIH-supported Digestive Disease Center and because the anatomy in the stomach makes it easier to distinguish stem cells from mature cells that perform specific tasks. Even without stem cells, the mice developed a precancerous condition because mature stomach cells reverted back to a stem cell state to heal the injury.

Analyzing tissue specimens from 10 people with stomach cancer, the researchers found evidence that those same mature cells in the stomach also had reverted to a stem cell-like state and had begun to change and divide rapidly.

The Mills lab is working now to identify drugs that may block the precancerous condition by preventing mature cells from proliferating and dividing.

“Knowing these cells are leading to increased cancer risk may allow us to find drugs to keep mature cells from starting to divide and multiply,” Mills said. “That may be important in preventing cancer not only in the stomach and GI tract but throughout the body.”

Undaunted explorer

Timothy Ley, MD, the Lewis T. and Rosalind B. Apple ­Professor of Medicine, has been investigating leukemia, particularly acute myeloid leukemia (AML), for decades. A glimpse of his research over just the past 10 to 15 years — featured in ­journals like Nature, Cell, the New England ­Journal of Medicine and ­Journal of the American Medical Association — illustrates how challenging the journey has been, yet it also showcases the resolve that he and his ­colleagues continue to display in their quest for answers and ultimately cures for this terrible disease.

After the human genome was sequenced in 2003 (after nearly 13 years of research and more than $2 billion in ­funding), Ley ­proposed an audacious plan to find all the ­mutations ­associated with AML, which is a heterogeneous set of diseases with many ­subtypes. He approached Rick Wilson, then ­director of the ­university’s Genome ­Sequencing Center (now the ­McDonnell Genome Institute­), with the idea, and they both knew it would be too daunting and too expensive to do at the time.

Yet they prepared for a day when the cost of sequencing would go down and speed would go up. Banking the right samples from people with AML, and tracking their disease to identify all the laboratory and clinical features, Ley and John DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine and chief of the Division of Oncology, and their colleagues laid the groundwork for research to come. In 2007, a technical breakthrough — next-generation ­sequencing — dropped the cost of sequencing a genome by nearly ­1,000-fold and allowed them to proceed.

Cobbling together funding from various sources, the team from the Genome Sequencing Center and the oncology division ­began the initial sequencing work. But funding ran short, and none of the usual sources were willing to pitch in at the time. The work was new, unproven, expensive and risky. Soon thereafter, however, they received a visionary gift from Alvin Siteman to conduct whole genome sequencing on two patients with AML; these were the first cancer genomes to be sequenced in the world. The aim was to begin to define AML-specific mutations that could identify who would do poorly and who would do well after therapy. Each AML sample had about 1,000 mutations, but only 10 to 15 were in genes. This work catapulted their efforts into the national spotlight and was featured on the front page of The New York Times.

These findings created a blueprint for cancer genome ­sequencing and allowed the team to acquire major long-term funding from the National Cancer Institute. The WashU team then collaborated with The Cancer Genome Atlas to sequence hundreds of AML cases. This work led to the discovery of nearly all the genes mutated in AML patients and provided the foundation for a new understanding of the disease.

“The grand idea was that by retrospectively ­analyzing banked samples (from patients whose outcomes were known), we would be able to recognize ­mutations that would better predict who was going to do well and who wasn’t. We could then reclassify our patients and tailor therapy for each person. But it didn’t work out that way,” says Ley, associate director of the ­McDonnell Genome ­Institute. “It turned out to be far more complicated than it had looked to be on first blush.”

Their early studies of AML, however, led to an important understanding of the problem: clonal heterogeneity, which, ­according to Ley, is now at the center of all cancer genomics.

In short, when cancer cells are placed under therapeutic ­bottlenecks — when treated with drugs that try to kill them — some will adapt in response, “kind of like Roundup-resistant weeds in soybean fields,” while others will be resistant up-front.

“AML tumors turned out to be clonally complex even before therapy, which was a great surprise to us,” Ley says. “Every AML has a founding clone and also unique subclones (each with a unique set of mutations). It turned out that our existing therapies often eliminate only some AML subclones in a particular patient, and the resistant ones rise again to cause a relapse.”

This finding has been extrapolated to most other ­cancer types in adults and represents one of the greatest ­challenges in cancer therapeutics. “Regardless of how difficult this problem is, it is important that we discovered the truth about it,” Ley says.

Thinking about how to clinically address the clonal ­heterogeneity problem, the team used each ­patient’s own AML cells to assess how different subclones respond to initial therapy. They sequenced AML samples from patients at presentation and then again after their initial therapy to see whether the ­mutations were cleared by the treatment. Surprisingly, about half of the patients — who were thought to be in remission ­using standard methods — had not cleared all of their mutations, and they relapsed a year earlier than the ­patients who did clear all ­measurable disease. This study has moved forward to a prospective trial to determine whether serial ­sequencing can help assign risk and help clinicians pick the least toxic and most effective therapy for each intermediate-risk AML patient who seeks ­treatment at Siteman Cancer Center.

The same serial-sequencing approach was also recently used by the group to define which patients were responding to a less toxic form of therapy with a drug called decitabine, which is often used in older AML patients who cannot tolerate the ­aggressive therapies used in younger, more fit patients. This study provided yet another surprise: Patients with the most ­lethal form of AML, harboring mutations in a gene called TP53, all responded favorably to this milder form of therapy. Again, these results have led to the development of new clinical trials using this therapy earlier for patients with this mutation, which truly represents the central goal of precision medicine: ­matching the mutation to the right drug.


In the 60 percent of AML patients who have an ­intermediate risk of relapse, some respond well to conventional treatments, while others do very poorly. “When we started these ­studies, the mutations associated with this kind of AML were not ­understood. These patients represented the ­biggest therapeutic conundrum in the field,” Ley says. After years of ­research, Ley and his team now understand the initiating events for most of these cases, including the 35 percent who have mutations in the gene DNMT3A, which was discovered in the first AML genome the team sequenced. “The discovery of the major initiating ­mutations for this kind of AML was crucial,” Ley says, “because it has ­allowed us to begin to think about new approaches to target these ­mutations.”

Currently, the only AML-initiating mutation that can be ­targeted specifically is a fusion gene that causes one subtype of AML, called acute promyelocytic leukemia (APL), which ­comprises about 10 percent of cases. APL patients are now ­routinely treated with drugs that destroy the protein that initiates the ­disease — without traditional chemotherapy — and nearly 95 ­percent are cured. “This is the poster child for what we want to do for all AML cases: find drugs that eradicate cells harboring the ­initiating mutations. And now that we know what these ­mutations are for nearly all patients, we have new hope that we’ll find novel ways to target them,” Ley says.

Ley admits that his team still has a lot of work to do, but they at least know the face of the enemy. “We don’t have everything solved,” he says, “but we now have a sound understanding of the problem: the mutations that we need to go after ­aggressively, the ones we can go after less aggressively, the nature of the ­mutations that need to be targeted and why patients relapse.”

[Note: According to Timothy Ley, this ongoing work has been a team effort. In the Division of Oncology, in addition to Ley and John DiPersio, key members of the team have included the following: Daniel Link, MD, the Alan A. & Edith L. Wolff Professor of Medicine; Timothy Graubert, MD; Matthew Walter, MD, professor medicine; Michael Tomasson, MD; John Welch, MD, assistant professor of medicine; Lukas Wartman, MD, assistant professor of medicine; Peter Westervelt, MD, professor of medicine; Jeffrey Klco, MD, PhD; David Spencer, MD, assistant professor of medicine; Matthew Christopher, MD; Michael Rettig, MD, associate professor of medicine; Eric Duncavage, MD, associate professor of pathology & immunology; Jacqueline Payton, MD, assistant professor of pathology & immunology; Mark Watson, MD, associate professor of pathology & immunology; Sharon Heath and Jack Baty. At the McDonnell Genome Institute, key contributors have included Richard Wilson, PhD; Elaine Mardis, PhD; Li Ding, PhD; Chris Miller, PhD; Malachi Griffith, PhD; Obi Griffith, PhD; Allegra Petti, PhD; David Larson, PhD; Michelle O’Laughlin, Catrina Fronick, Bob Fulton and Lucinda Fulton. Numerous others have also made important contributions to this body of work. Finally, none of the work could have been done without the willing participation of the patients and families who participated, who are also team members in the truest sense of the word.]

$6 million supports leukemia research

John F. DiPersio, MD, PhD, of Washington University School of Medicine in St. Louis, has received a $6 million outstanding investigator award from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) to support research aimed at improving therapies for leukemia.

DiPersio, the Virginia E. and Sam J. Golman Professor of Medicine in Oncology, is also deputy director of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. He is a leading expert in understanding and treating leukemia, a cancer of the blood-forming cells in the bone marrow. Along with chemotherapy, the standard of care for leukemia is a stem cell transplant, commonly referred to as a bone marrow transplant.

“One of our major goals is to optimize stem cell transplantation — both in making the process of donating stem cells faster and more efficient and in finding ways to control the potentially damaging side effects of the transplant,” DiPersio said. “A stem cell transplant is often the only curative therapy for these types of blood cancers. But the transplant itself can be life-threatening if the donor’s stem cells begin to attack the patient’s vital organs. If we can control and prevent these side effects, it could have a significant impact on patients.”

The NCI’s outstanding investigator award recognizes physician-scientists who have a long history of successful research and are deemed likely to make major gains in the cancer field with the support of continuous funding for seven years.

The grant will support three major areas of research in DiPersio’s lab. One area is focused on improving the effectiveness of standard chemotherapy and in making stem cell donation faster and more efficient. DiPersio and Michael P. Rettig, PhD, an associate professor of medicine, are seeking better ways to force cancerous cells that hide in the bone marrow to move into the bloodstream, where they are more vulnerable to chemotherapy. In addition, boosting this movement of blood stem cells also helps speed the process of harvesting healthy stem cells from a donor, for use in a stem cell transplant. Today, that process can take up to two weeks. DiPersio said he and his colleagues are testing strategies that have the potential to reduce the time to minutes or hours.

A second area of focus for DiPersio’s lab is to prevent graft-versus-host disease, a major and sometimes life-threatening complication of bone marrow transplantation. Graft-versus-host disease occurs when the donor immune cells that kill cancer begin inadvertently to attack a patient’s organs. Researchers in DiPersio’s lab, led by Jaebok Choi, PhD, an assistant professor of medicine, are investigating a class of drugs called JAK inhibitors — approved by the Food and Drug Administration to treat rheumatoid arthritis. These drugs have been shown in animal models and in small clinical trials to reduce graft-versus-host disease while maintaining the anti-cancerous effect against the leukemia.

A third area of focus is to develop new immunotherapies to treat acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL) and T-cell non-Hodgkin lymphoma (T-NHL). The grant will support developing antibodies and engineered T cells, called CAR-T cells, capable of targeting multiple proteins on AML, T-ALL and T- NHL. Also, to pursue targeted therapies for T-ALL, the grant will support the use of CRISPR gene-editing technology to design T-cells that can attack cancer without harming healthy cells.

“Tumor cells make proteins that distinguish these cells from healthy cells,” DiPersio said. “We can now genetically program immune cells to target these proteins, taking what an immune cell does normally, every day, to protect us from infection and directing it at a specific type of cancerous cell. It’s a bit like giving a dog a scent. You’re telling the immune cells what to look for, sensitizing them to the target.”

In this approach, the gene-editing technology also is used to remove the cellular machinery that triggers graft-versus-host disease while still allowing these genetically edited CAR-T cells to track down and kill the T-ALL cells. Using this approach, the DiPersio lab will be able to use T-cells obtained from any donor without relying on the patient’s own T cells, which are “sick” and hard to separate from the patient’s malignant T-ALL, among other challenges.

DiPersio’s novel approach has been dubbed “off-the-shelf” CAR-T cell therapy because the T-cells could be donated by anyone and prepared ahead of time. This is in contrast to a traditional stem cell transplant, in which the potential donors are restricted to a patient’s close relatives or a person with similar immune characteristics. Efforts in this third research area are led by Matthew L. Cooper, PhD, an instructor in medicine.

In addition to his research program, DiPersio also directs the Division of Oncology at the School of Medicine and was the founding director of the adult bone marrow and stem cell transplant program, which he led for many years. One of the largest such programs worldwide, it currently is led by Peter Westervelt, MD, PhD, a professor of medicine. The program performs almost 500 transplants per year and recently performed its 7,500th transplant.

How cells detect, mend DNA damage may improve chemotherapy

The busy world inside a cell is directed by its DNA blueprint. When the blueprints are altered, cells can sicken, die or become cancerous. To keep DNA in working order, cells have ways to detect and mend damaged DNA.

Now, researchers at Washington University School of Medicine in St. Louis report that they have found a previously unknown way that cells sense a kind of damage induced by certain chemotherapy drugs. The findings, published Nov. 8 in the journal Nature, could have important implications for treating cancer.

Some of the oldest chemotherapy drugs are known as alkylating agents because they kill cancer cells by adding groups of carbon and hydrogen atoms to – or alkylating – DNA. The extent of the alkylation damage overwhelms the cells’ ability to heal themselves via their DNA repair pathways. And some tumors are abnormally dependent on proteins involved in DNA repair, such that knocking out those proteins kills the tumor cells.

“We found that human cells can sense alkylation damage and mobilize a repair complex specifically suited to repair this kind of injury,” said senior author Nima Mosammaparast, MD, PhD, an assistant professor of pathology and immunology, and co-leader of the DNA Metabolism and Repair Working Group at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “Knocking out this complex may be a way to increase the potency of certain chemotherapy drugs, or to specifically target tumor cells that have become dependent on the repair complex.”

Alkylation can happen naturally, which is why cells have this repair system in the first place. Also, certain chemotherapy drugs force it to happen. Busulfan, used to treat leukemia, and temozolomide, prescribed for brain tumors, alkylate many spots along DNA. It is difficult for the genetic blueprint to be copied accurately where DNA has been alkylated, so such alkylation damage kills the cells.

Studying cells treated with alkylating chemotherapy drugs or with drugs that lead to other kinds of DNA damage, the researchers determined how cells try to mend DNA damage caused specifically by alkylating agents. They identified a group of proteins that clustered near the spots on the DNA that had been alkylated. Cells that lacked a key member of this protein complex were more likely to die if they were treated with alkylating drugs than cells that had the protein, indicating the importance of the protein complex in repairing DNA. Lacking the key protein made no difference when the DNA was damaged in other ways.

These findings suggest that sensing alkylation damage is a major primary defense against chemotherapy drugs such as busulfan and other alkylating agents. Interfering with this repair complex could amplify the killing power of such drugs and potentially even avert or undermine drug resistance. After a successful course of chemotherapy, tumors sometimes recur tougher than before, having become resistant to the drugs from the first round of treatment.

“There’s some evidence now that overexpressing components of this signaling pathway may be how some tumors become resistant to chemotherapy,” Mosammaparast said. “Blocking this pathway could be a way to make resistant tumors sensitive again.”

Recurrent tumors are not the only ones that may have high levels of DNA repair proteins. Some tumors that have never encountered alkylating chemotherapy drugs have high levels of key alkylation-repair proteins. And when they do, it portends poorly for the patients.

“In some kinds of pancreatic, prostate and lung cancer, overexpressing components of this pathway indicates a significantly worse prognosis,” Mosammaparast said.

There is a possible silver lining, though. Tumors that have high levels of key alkylation repair proteins are often dependent on them, meaning that if those proteins were somehow inhibited, the cells would die.  Normal cells are not dependent on this alkylation repair pathway to the same degree. Other repair systems can handle the level of alkylating DNA damage typically encountered by a healthy cell.

“That could be an opening for a chemotherapy drug,” Mosammaparast said. “We may be able to design a drug that is toxic to tumors but not to normal cells by targeting this alkylation repair pathway.”

The drug olaparib, approved in 2014 to treat hereditary ovarian cancer, exploits a similar vulnerability. It targets tumors that are unusually dependent on a repair pathway that stitches DNA back together after it has been cut into pieces. Olaparib blocks that pathway, and without it, the cancerous cells die.

Chemo-loaded nanoparticles target breast cancer that has spread to bone

Breast cancer that spreads often infiltrates bone, causing fractures and intense pain. In such cases, chemotherapy is ineffective because the environment of the bone protects the tumor, even as the drug has toxic side effects elsewhere in the body.

Now, scientists at Washington University School of Medicine in St. Louis have developed a nanoparticle that can deliver chemotherapy directly to tumor cells that have spread to bone. In mice implanted with human breast cancer and exposed to circulating cancer cells likely to take up residence in bone, the researchers showed the treatment kills tumor cells and reduces bone destruction while sparing healthy cells from side effects.

The study is available online in the journal Cancer Research.

“For women with breast cancer that has spread, 70 percent of those patients develop metastasis to the bone,” said senior author Katherine N. Weilbaecher, MD, a professor of medicine. “Bone metastases destroy the bone, causing fractures and pain. If the tumors reach the spine, it can cause paralysis. There is no cure once breast cancer reaches the bone, so there is a tremendous need to develop new therapies for these patients.”

In the study, the researchers showed that breast cancer cells that spread to bone carry molecules on their surface that are a bit like Velcro, helping tumor cells stick to the bone. These adhesion molecules also sit on the surface of cells responsible for bone remodeling, called osteoclasts.

“In healthy bones, osteoclasts chew away old, worn out bone, and osteoblasts come in and build new bone,” said Weilbaecher, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But in cancer that spreads to bone, tumors take over osteoclasts and essentially dig holes in the bone to make more room for the tumor to grow.”

Weilbaecher said she and her colleagues were surprised to find that the same adhesive molecule on the surface of osteoclasts also is present in high levels on the surface of the breast tumors that spread to bone. The research showed that the molecule — called integrin αvβ3 — was absent from the surfaces of the original breast tumor and from tumors that spread to other organs, including the liver and the lung. The researchers confirmed that this pattern also was true in biopsies of human breast tumors that had spread to different organs.

A collaboration with co-senior author Gregory M. Lanza, MD, PhD, a professor of medicine and of biomedical engineering, then led to the design of a nanoparticle that combines the bone-adhesion molecules with a form of the cancer drug docetaxel, which is used to treat breast cancer as well as other tumors. The adhesive molecules allow the nanoparticle to penetrate the otherwise protective environment of the bone matrix in a way that, in essence, mimics the spreading of the tumor cells themselves. The result is a delivery method that keeps the chemotherapy drug contained in the nanoparticle until the adhesion molecules make contact with the tumor cell, fusing the nanoparticle with the cell surface and releasing the drug directly into the cancer cell.

“When we gave these nanoparticles to mice that had metastases, the treatment dramatically reduced the bone tumors,” Weilbaecher said. “There was less bone destruction, fewer fractures, less tumor. The straight chemo didn’t work very well, even at much higher doses, and it caused problems with liver function and other toxic side effects, which is our experience with patients. But if we can deliver the chemo directly into the tumor cells with these nanoparticles that are using the same adhesive molecules that the cancer cell uses, then we are killing the tumor and sparing healthy cells.”

Surgery for early prostate cancer may not save lives

A major 20-year study provides further evidence that prostate cancer surgery offers negligible benefits to many men with early-stage disease. In such men, who account for most cases of newly diagnosed prostate cancer, surgery did not prolong life and often caused serious complications such as infection, urinary incontinence and erectile dysfunction.

The study, by a national research team including Washington University School of Medicine in St. Louis, was led by the Minneapolis Veterans Administration Health Care System. It is published July 13 in The New England Journal of Medicine.

In men with early prostate cancer, the study compared surgery with observation. With the latter, men only were treated if they developed bothersome symptoms, such as urinary difficulty or bone pain. Such symptoms may indicate progression of the cancer. Many men in the observation group received no treatment at all because early-stage prostate cancer often grows slowly and rarely causes symptoms.

“The findings will go a long way in helping to improve prostate cancer care,” said co-author Gerald L. Andriole, MD, director of Washington University’s Division of Urologic Surgery. “About 70 percent of patients newly diagnosed with prostate cancer cases are in the early stages, meaning the cancer is confined to the prostate gland, and they have nonaggressive tumors. As such, these patients have an excellent prognosis without surgery. This study confirms that aggressive treatment usually is not necessary. We hope the findings will steer doctors away from recommending surgery or radiation to their patients with nonaggressive early-stage prostate cancer and patients away from thinking it’s necessary.”

The American Cancer Society ranks prostate cancer as the second most common cancer in men and the third-leading cause of cancer deaths among men, after lung and colorectal cancer. In 2017, about 161,360 men will be diagnosed with prostate cancer, and 26,730 will die from it.

The study, known as the Prostate Cancer Intervention Versus Observation Trial, or PIVOT, is one of the largest and longest involving cancer patients. It got underway in 1994 just as the prostate-specific antigen blood test for prostate cancer became routine. With many more men diagnosed with prostate cancer, the standard treatment for all prostate cancers became surgery or radiation, with the thinking that removing or irradiating the tumor would increase survival. But over the next decade, reports of treatment-related complications raised concerns, as did data indicating that most early-stage cancers grew so slowly they were unlikely to cause health problems.

To evaluate any potential benefits of surgery, the researchers randomly assigned 731 men in the U.S. with localized prostate cancer to receive either surgery or observation at one of 44 Department of Veteran Affairs Health Care Centers or eight academic medical centers, including Washington University.

The average age of men in the study was 67 at the time of enrollment.

Of the men who had prostate cancer surgery, 223 (61 percent) died of other causes after up to 20 years of follow-up, compared with 245 men (66 percent) in the observation group – a difference that is not statistically different. Further, 27 (7 percent) men in the surgery group died of prostate cancer, compared with 42 men (11 percent) in the observation group, but that difference also is not statistically significant.

However, the data show that surgery may have a mortality benefit in some men, particularly those with a long life expectancy and intermediate-risk prostate cancer. (Such men generally have PSA scores of 10-20 ng/ml and a Gleason score of seven. The latter score signifies tumor aggressiveness.)

“It would be a disservice to dismiss surgery as a viable option for patients with intermediate-risk prostate cancer,” said Andriole, the School of Medicine’s Robert K. Royce Distinguished Professor of Urologic Surgery. He treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. “For these patients, and for some men with high-risk prostate cancer, surgery is often beneficial, as are other other treatments such as radiation.”

Technology has advanced since the study began, allowing physicians to more accurately classify tumors and avoid overtreating patients who have prostate cancer.

Of the 364 men treated with surgery, 53 (15 percent) suffered from erectile dysfunction, and 63 (17 percent) reported having incontinence. Another 45 developed other complications.

“The benefits of surgery also need to be balanced against the negative long-term consequences of surgery that occur early and often,” said senior author Timothy Wilt, MD, a physician-researcher with the Center for Chronic Disease Outcomes Research at the Minneapolis VA Health Care System and a professor of medicine at the University of Minnesota. “Our results demonstrate that for the majority of men with localized prostate cancer, selecting observation for their treatment choice can help them live a similar length of life, avoid death from prostate cancer and prevent harms from surgical treatment. Physicians can use information from our study to confidently recommend observation as the preferred treatment option for men with early prostate cancer.”

Zika virus kills brain cancer stem cells

While Zika virus causes devastating damage to the brains of developing fetuses, it one day may be an effective treatment for glioblastoma, a deadly form of brain cancer. New research from Washington University School of Medicine in St. Louis and the University of California San Diego School of Medicine shows that the virus kills brain cancer stem cells, the kind of cells most resistant to standard treatments.

The findings suggest that the lethal power of the virus – known for infecting and killing cells in the brains of fetuses, causing babies to be born with tiny, misshapen heads – could be directed at malignant cells in the brain. Doing so potentially could improve people’s chances against a brain cancer – glioblastoma – that is most often fatal within a year of diagnosis.

“We showed that Zika virus can kill the kind of glioblastoma cells that tend to be resistant to current treatments and lead to death,” said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine and the study’s co-senior author.

The findings are published Sept. 5 in The Journal of Experimental Medicine.

Each year in the United States, about 12,000 people are diagnosed with glioblastoma, the most common form of brain cancer. Among them is U.S. Sen. John McCain, who announced his diagnosis in July.

The standard treatment is aggressive – surgery, followed by chemotherapy and radiation – yet most tumors recur within six months. A small population of cells, known as glioblastoma stem cells, often survives the onslaught and continues to divide, producing new tumor cells to replace the ones killed by the cancer drugs.

In their neurological origins and near-limitless ability to create new cells, glioblastoma stem cells reminded postdoctoral researcher Zhe Zhu, PhD, of neuroprogenitor cells, which generate cells for the growing brain. Zika virus specifically targets and kills neuroprogenitor cells.

In collaboration with co-senior authors Diamond and Milan G. Chheda, MD, an assistant professor of medicine and of neurology at Washington University School of Medicine, and Jeremy N. Rich, MD, of UC San Diego, Zhu tested whether the virus could kill stem cells in glioblastomas removed from patients at diagnosis. They infected tumors with one of two strains of Zika virus. Both strains spread through the tumors, infecting and killing the cancer stem cells while largely avoiding other tumor cells.

The findings suggest that Zika infection and chemotherapy-radiation treatment have complementary effects. The standard treatment kills the bulk of the tumor cells but often leaves the stem cells intact to regenerate the tumor. Zika virus attacks the stem cells but bypasses the greater part of the tumor.

“We see Zika one day being used in combination with current therapies to eradicate the whole tumor,” said Chheda, Siteman Cancer Center neurologist and research member. 

To find out whether the virus could help treat cancer in a living animal, the researchers injected either Zika virus or saltwater (a placebo) directly into the brain tumors of 18 and 15 mice, respectively. Tumors were significantly smaller in the Zika-treated mice two weeks after injection, and those mice survived significantly longer than the ones given saltwater.

If Zika were used in people, it would have to be injected into the brain, most likely during surgery to remove the primary tumor. If introduced through another part of the body, the person’s immune system would sweep it away before it could reach the brain.

The idea of injecting a virus notorious for causing brain damage into people’s brains seems alarming, but Zika may be safer for use in adults because its primary targets – neuroprogenitor cells – are rare in the adult brain. The fetal brain, on the other hand, is loaded with such cells, which is part of the reason why Zika infection before birth produces widespread and severe brain damage, while natural infection in adulthood causes mild symptoms.

The researchers conducted additional studies of the virus using brain tissue from epilepsy patients and showed that the virus does not infect noncancerous brain cells.

As an additional safety feature, the researchers introduced two mutations that weakened the virus’s ability to combat the cell’s defenses against infection, reasoning that the mutated virus still would be able to grow in tumor cells – which have a poor antiviral defense system – but would be eliminated quickly in healthy cells with a robust antiviral response.

When they tested the mutant viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent, but that the mutant strain also succeeded in killing the cancerous cells.

“We’re going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading,” said Diamond, who also is a professor of molecular microbiology, and of pathology and immunology. “Once we add a few more changes, I think it’s going to be impossible for the virus to overcome them and cause disease.”

New imaging technique aims to ensure surgeons completely remove cancer

Of the quarter-million women diagnosed with breast cancer every year in the United States, about 180,000 undergo surgery to remove the cancerous tissue while preserving as much healthy breast tissue as possible.

However, there’s no accurate method to tell during surgery whether all of the cancerous tissue has been successfully removed. The gold-standard analysis takes a day or more, much too long for a surgeon to wait before wrapping up an operation. As a result, about a quarter of women who undergo lumpectomies receive word later that they will need a second surgery because a portion of the tumor was left behind.

Now, researchers at Washington University School of Medicine in St. Louis and California Institute of Technology report that they have developed a technology to scan a tumor sample and produce images detailed and accurate enough to be used to check whether a tumor has been completely removed.

Called photoacoustic imaging, the new technology takes less time than standard analysis techniques. But more work is needed before it is fast enough to be used during an operation.

The research is published May 17 in Science Advances.

“This is a proof of concept that we can use photoacoustic imaging on breast tissue and get images that look similar to traditional staining methods without any sort of tissue processing,” said Deborah Novack, MD, PhD, an associate professor of medicine, and of pathology and immunology, and a co-senior author on the study.

The researchers are working on improvements that they expect will bring the time needed to scan a specimen down to 10 minutes, fast enough to be used during an operation. The current gold-standard method of analysis, which is based on preserving the tissue and then staining it to make the cells easier to see, hasn’t gotten any faster since it was first developed in the mid-20th century.

For solid tumors in most parts of the body, doctors use a technique known as a frozen section to do a quick check of the excised lump during the surgery. They look for a thin rim of normal cells around the tumor. Malignant cells at the margins suggest the surgeon missed some of the tumor, increasing the chances that the disease will recur.

But frozen sections don’t work well on fatty specimens like those from the breast, so the surgeon must finish a breast lumpectomy without knowing for sure how successful it was.

“Right now, we don’t have a good method to assess margins during breast cancer surgeries,” said Rebecca Aft, MD, PhD, a professor of surgery and a co-senior author on the study.  Aft, a breast cancer surgeon, treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

Currently, after surgery a specimen is sent to a pathologist, who slices it, stains it and inspects the margins for malignant cells under a microscope. Results are sent back to the surgeon within a few days.

To speed up the process, the researchers took advantage of a phenomenon known as the photoacoustic effect. When a beam of light of the right wavelength hits a molecule, some of the energy is absorbed and then released as sound in the ultrasound range. These sound waves can be detected and used to create an image.

“All molecules absorb light at some wavelength,” said co-senior author Lihong Wang, PhD, who conducted the work when he was a professor of biomedical engineering at Washington University’s School of Engineering & Applied Science. He is now at Caltech. “This is what makes photoacoustic imaging so powerful. Essentially, you can see any molecule, provided you have the ability to produce light of any wavelength. None of the other imaging technologies can do that. Ultrasound will not do that. X-rays will not do that. Light is the only tool that allows us to provide biochemical information.”

The researchers tested their technique by scanning slices of tumors removed from three breast cancer patients. For comparison, they also stained each specimen according to standard procedures.

The photoacoustic image matched the stained samples in all key features. The architecture of the tissue and subcellular detail such as the size of nuclei were clearly visible.

“It’s the pattern of cells – their growth pattern, their size, their relationship to one another – that tells us if this is normal tissue or something malignant,” Novack said. “Overall, the photoacoustic images had a lot of the same features that we see with standard staining, which means we can use the same criteria to interpret the photoacoustic imaging. We don’t have to come up with new criteria.”

Having established that photoacoustic techniques can produce usable images, the researchers are working on reducing the scanning time.

“We expect to be able to speed up the process,” Wang said. “For this study, we had only a single channel for emitting light. If you have multiple channels, you can scan in parallel and that reduces the imaging time. Another way to speed it up is to fire the laser faster. Each laser pulse gives you one data point. Faster pulsing means faster data collection.”

Aft, Novack and Wang are applying for a grant to build a photoacoustic imaging machine with multiple channels and fast lasers.

“One day we think we’ll be able to take a specimen straight from the patient, plop it into the machine in the operating room and know in minutes whether we’ve gotten all the tumor out or not,” Aft said. “That’s the goal.”

Wong TTW, Zhang R, Hai P, Zhang C, Pleitez MA, Aft RL, Novack DV, Wang LV. Fast label-free multilayered histology-like imaging of human breast cancer by photoacoustic microscopy. Science Advances. May 17, 2017

This work was supported by the National Institutes of Health, grant number DP1 EB016986 and R01 CA186567, and by Washington University’s Siteman Cancer Center’s 2014 Research Development Award.

New insight into origin of stomach cancer

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.”