Archives: News and Blog

Belly fat affects the odds of women surviving kidney cancer but not men, according to a new study by researchers at Washington University School of Medicine in St. Louis.

Half of female kidney cancer patients with substantial abdominal fat at the time of diagnosis died within 3 1/2 years, while more than half of women with little belly fat were still alive 10 years later, the researchers found. For men, the amount of abdominal fat appeared to make no difference in how long they survived.

The findings suggest that kidney cancer may develop and progress differently in women than men.

“We’re just beginning to study sex as an important variable in cancer,” said senior author Joseph Ippolito, MD, PhD, an instructor in radiology at Mallinckrodt Institute of Radiology at the School of Medicine. “Men and women have very different metabolisms. A tumor growing in a man’s body is in a different environment than one growing inside a woman, so it’s not surprising that the cancers behave differently between the sexes.”

The study is available online in the journal Radiology.

Excess weight is a major risk factor for the development of kidney cancer, but it does not necessarily portend a poor outcome. Rather, the new study suggests that how long a patient survives after diagnosis is linked not to total fat but to the distribution of body fat, at least for women.

Most methods of estimating body fat rely on just a person’s height and weight. But not all fat is the same. The kind you can squeeze – called subcutaneous fat – seems to be mostly harmless. But visceral fat, which lies within the abdomen and encases internal organs, has been associated with diabetes, heart disease and many kinds of cancer.

Visceral fat sits too deep inside the abdomen to be measured accurately with a tape measure around a person’s waist. Instead, Ippolito and colleagues analyzed cross-sectional CT scans, which are routinely performed on people newly diagnosed with kidney cancer to measure the size of tumors and to look for metastases. Subcutaneous and visceral fat are located in different areas of the body on a CT scan, making it possible to calculate the proportion of each.

The researchers analyzed images from 145 men and 77 women with kidney cancer. The scans were drawn from The Cancer Imaging Archive, a collection of demographic, clinical and imaging data on hundreds of cancer patients.

The researchers found that half of the women with high visceral fat died within 3 ½ years of diagnosis, while more than half of the women with low visceral fat were still alive after 12 years. Women often gain visceral fat after menopause, but the link still held after correcting for age.

For men, there was no correlation between visceral fat and length of survival.

“We know there are differences in healthy male versus healthy female metabolism,” Ippolito said. “Not only in regard to how the fat is carried, but how their cells use glucose, fatty acids and other nutrients. So the fact that visceral fat matters for women but not men suggests that something else is going on besides just excess weight.”

That “something else” could lie in the tumor cells themselves. Tumor cells prefer sugar as a fuel source, but some have more of a sweet tooth than others. A sugar-hungry tumor typically spells trouble for patients.

Using data from The Cancer Genome Atlas, the researchers analyzed the gene expression profiles of tumors from 345 men and 189 women diagnosed with kidney cancer. Both men and women were less likely to survive if their tumor cells had switched on the genes associated with consuming sugar, or glycolysis. Men whose tumor cells exhibited low glycolysis survived an average of 9 ½ years, whereas those with high-glycolysis tumors survived for only six years on average.

The researchers found 77 women with matched imaging and gene expression data, so they combined their analyses of visceral fat and glycolysis.

About a quarter of the women had a high amount of visceral fat and tumors whose glycolysis genes were significantly active. Those women survived only two years after diagnosis on average. Strikingly, of the 19 women who fell into the low visceral fat and low glycolysis category, none died before the end of the study, which covered a span of 12 years. There was no group of men with a similarly rosy prognosis.

“We found there’s a group of women that’s doing really poorly relative to everyone else, and a group that’s doing really well,” Ippolito said. “Our data suggest that there is a potential synergy between the patient’s visceral fat and the metabolism of their tumor. That can be a starting point to figure out how to better treat women with kidney cancer. We would not have discovered this if we had been looking at men and women together.”

Researchers nationwide have reached a major milestone in describing the genetic landscape of cancer. Scientists at Washington University School of Medicine in St. Louis and other institutions have completed the genetic sequencing and analyses of more than 11,000 tumors from patients, spanning 33 types of cancer — all part of The Cancer Genome Atlas (TCGA) project, funded by the National Cancer Institute and National Human Genome Research Institute, both of the National Institutes of Health (NIH).

Altogether, the researchers identified about 300 genes that drive tumor growth. And, remarkably, just over half of all tumors analyzed carry genetic mutations that could be targeted by therapies already approved for use in patients.

TCGA was launched in 2005 to pursue the genetic basis of cancer. The results appear April 5 in a series of studies published in Cell Press journals.

“For the 10,000 tumors we analyzed, we now know — in detail — the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” said leading TCGA scientist Li Ding, PhD, an associate professor of medicine and director of computational biology in the Division of Oncology at Washington University. “This is the first definitive summary of the genetics behind 33 major types of cancer.”

Ding, also an assistant director of  The McDonnell Genome Institute at Washington University, is a major author of six papers published April 5 in the journals Cell, Cell Reports and Cell Systems, detailing the genetic mutations underlying cancer.

Genomic studies over the past decade have demonstrated that cancer is a disease of errors in genes rather than particular organs.

“This project is the culmination of more than a decade of groundbreaking work,” said NIH Director Francis S. Collins, MD, PhD. “This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better-informed clinical trials and future treatments.”

Ding said the new analyses have revealed that the genetic errors of cancer result in specific molecular signatures that could guide treatment.

“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” Ding said. “We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases. But studying their molecular features, we now know such cancers are closely related. Cancers originating in, for example, epithelial cells that line various organs are similarly closely related, regardless of their location.”

According to Ding, the research supports the idea that tumors of any type with high numbers of mutations — which often are resistant to chemotherapy — are susceptible to immunotherapy drugs called checkpoint inhibitors. Highly mutated tumors produce comparatively more misshapen proteins that can trigger an immune response. But as a safeguard against autoimmunity, the body often puts the breaks on such an immune response. Still, to treat aggressive tumors, checkpoint inhibitors can remove those breaks, letting the immune system fight the tumor more effectively.

The studies also provide further clarity on the significance of certain mutations in the BRCA1 gene that drive breast and ovarian cancer. Specific mutations in this gene are known to significantly increase the risk of certain types of cancer. But the consequences of many other mutations in this gene were unknown, making it difficult to predict cancer risk.

“We have known for a long time that BRCA1 is an important gene in cancer development,” said Ding, who has a research affiliation with Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But it’s very hard to tease out which specific mutations in BRCA1 are actually driving the cancer and which mutations are harmless. Our paper on cancer-causing variants in inherited mutations provides new clarity on the BRCA1 mutations actually driving tumor growth. We found 21 disease-causing BRCA1 and BRCA2 variants in breast cancer, three in cervical cancer, one in colorectal cancer, one in glioblastoma and 38 in ovarian cancer.”

Ding said she is particularly excited about the prospect of using these analyses to re-examine data from past clinical trials. Many times, a small proportion of patients in a given trial did well on an experimental therapy, but many others did not respond to the treatment at all, and researchers didn’t understand why. Perhaps a drug was not approved for, say, lung cancer because of such results, but some patients with certain cancer mutations may benefit.

“Most earlier trials were not designed with genomics in mind,” Ding said. “We know how these patients responded. Now, we can sequence the tumor samples from patients enrolled in those trials with our latest software tools. We can look for correlations between the patients’ genomics and how they responded to the treatments. If we do this for many past trials, we will have tremendous statistical power to identify reasons why drugs work for some patients and not others. So even negative trials that might have been a disappointment at the time can become powerful tools to design better treatments in the future.”

In this way, a drug that might have failed as a treatment for lung cancer might be re-examined as a potential therapy for, say, squamous cell carcinoma, again, regardless of location.

“Even after genomic sequencing, sometimes we still can’t explain what is going on,” Ding said. “This is why we are planning to expand beyond studies of the tumor cells to include the entire tumor ecosystem — the immune cells that infiltrate the tumor and the supporting tissue that creates the tumor’s microenvironment.”

Added Eric Green, MD, PhD, director of the National Human Genome Research Institute, “These TCGA publications effectively showcase how genomics has brought transformative advances to the study of cancer. Central to these advances has been the development and use of new and increasingly more powerful technologies and approaches for genome sequencing.”

TCGA is a collaborative effort involving more than 20 institutions. The McDonnell Genome Institute and many researchers at Washington University have made major contributions to this national project. In the latest batch of seminal papers, Kuan-lin Huang, Matthew H. Bailey, Reyka G. Jayasinghe, Qingsong Gao, Song Cao, Wen-Wei Liang, Steven M. Foltz and others from Ding’s lab are primary authors. Within Washington University, Ding has collaborated with a number of investigators, including Feng Chen, PhD, an associate professor of medicine and a co-senior author of two of these papers.

An investigational drug in clinical trials for rheumatoid arthritis prevents a common, life-threatening side effect of stem cell transplants, new research from Washington University School of Medicine in St. Louis shows. Studying mice, the researchers found the drug prevented what’s known as graft-versus-host disease, a debilitating, sometimes lethal condition that develops when transplanted stem cells attack the body’s own organs or tissues.

About half of patients receiving donor stem cells develop graft-versus-host disease, which can linger for months or years after their transplants. In some cases, patients die not from their cancer but from the complication itself. Current treatments are not effective.

The study is online in the journal Leukemia.

In past work, this research team defined the role of molecules called JAK1/2 kinases and their signaling pathways in immune cell activation and graft-vs-host disease. In the new study, these same researchers evaluated ruxolitinib and baricitinib, and found baricitinib to be the superior of the two drugs in reducing and preventing graft-versus-host-disease in mice. Both drugs belong to a class of pharmaceuticals called JAK inhibitors that are known for dialing down inflammation.

“Transplanted donor stem cells — and more specifically, the T cells in the donor stem cell product — are particularly good at fighting off leukemia, but these cells can go haywire, unfortunately, and attack the patient’s healthy tissues, causing graft-versus-host disease,” said senior author John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine in Oncology. “The typical ways we can reduce the effects of the disease also tend to weaken the T cells’ ability to attack the cancer. We’re looking for a treatment strategy that stops the disease without shutting down T cells’ assault on the cancer.”

Surprisingly, baricitinib did more than shut down graft-versus-host disease. It actually boosted the ability of the donor T cells to fight the cancer.

“We don’t know yet exactly how this happens, but we’re working to understand it,” said first author Jaebok Choi, PhD, an assistant professor of medicine. “We think at least part of the explanation is the drug strips the leukemia cells of their immune defenses, making them more vulnerable to attack by the donor T cells. At the same time, the drug also stops the donor T cells from being able to make their way to important healthy tissues, such as the skin, liver and gastrointestinal tract, where they often do the most damage.”

In other words, the drug appears to stop graft-versus-host disease by simply keeping the donor T cells circulating in the bloodstream, away from vital organs. Simultaneously, the drug makes the leukemia cells more vulnerable to immune attack from the donor T cells, which are now mostly confined to the bloodstream, where the cancer is.

The drug also appeared to boost levels of specific immune cells that put the brakes on a runaway immune response that can make graft-versus-host disease worse. These apparently independent effects are specific to baricitinib and may explain why other JAK inhibitors did not work as well, according to DiPersio, who is also deputy director of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

The researchers emphasized the finding that the drug not only prevented graft-versus-host disease from developing in the mice but reversed established disease, suggesting possible options for patients already affected by it.

“We were surprised to achieve 100 percent survival of mice with the most severe model of graft-versus-host disease,” Choi said. “We are now studying the multi-pronged ways this drug behaves in an effort to develop an even better version for eventual use in clinical trials.”

Because of the drug’s broad effectiveness in preventing inflammatory disorders, DiPersio said he and his colleagues are beginning to explore whether it could be used to prevent organ rejection in patients undergoing solid organ transplantation. Such a strategy might reduce the need to give these patients powerful immune-suppressing drugs that increase the risk of infection.

Last year, the Food and Drug Administration approved the first cellular immunotherapies to treat cancer. These therapies involve collecting a patient’s own immune cells — called T cells — and supercharging them to home in on and attack specific blood cancers, such as hard-to-treat acute lymphoblastic leukemia and non-Hodgkin lymphoma.

But so far, these T cell immunotherapies — called CAR-T cells — can’t be used if the T cells themselves are cancerous. Even though supercharged T cells can kill cancerous T cells, they also can kill each other because they resemble one another so closely.

Scientists at Washington University School of Medicine in St. Louis now have used the gene-editing technology CRISPR to engineer human T cells that can attack human T cell cancers without succumbing to friendly fire.

The study evaluating the approach in mice appears online in the journal Leukemia.

The researchers also engineered the T cells so any donor’s T cells could be used. A “matched” donor with similar immunity is not required and neither are the patient’s own T cells, which is important for the obvious reason: Many of the patient’s own T cells are cancerous.

“Cancerous T cells and healthy T cells have exactly the same protein — CD7 — on their surfaces,” said senior author John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine in Oncology.

DiPersio’s team first generated a novel CAR-T strategy targeting CD7, allowing for the targeting and killing of all cells with CD7 on the surface.

“But if we program T cells to target CD7, they would attack the cancerous cells and each other, thus undermining this approach,” DiPersio said. “To prevent this T cell fratricide, we used CRISPR/Cas9 gene editing to remove CD7 from healthy T cells, so they no longer carry the target.”

DiPersio, who treats patients at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital, and his colleagues also used CRISPR gene editing to simultaneously eliminate the therapeutic T cells’ ability to see healthy tissues as foreign.

To do this, they genetically deleted the T cell receptor alpha (TCRa) subunit. This way, T cells from any normal donor can be used without risk of life-threatening toxicities such as graft-versus-host disease, in which T cells attack the organs of the recipient, sometimes resulting in death. This new approach also may have broad implications for the CAR-T field, allowing for use of therapeutic T cells from any healthy donor. Healthy T cells could be collected in advance and stored for any patient with a relapsed T cell malignancy.

“We have genetically modified these T cells so they are unable to cause graft-versus-host disease but can still kill cancerous cells,” said first author Matthew L. Cooper, PhD, an instructor in medicine. “One additional benefit of this approach is that a patient could receive this therapy much more quickly after diagnosis. We wouldn’t need to harvest the patient’s own T cells and then modify them, which takes time. We also wouldn’t have to find a matched donor. We could collect T cells from any healthy donor and have the gene-edited T cells ready in advance, a strategy termed ‘off-the-shelf’ CAR-T cell therapy.”

The researchers demonstrated that this approach is effective in mice with T cell acute lymphoblastic leukemia (T-ALL) taken from patients. Mice treated with the gene-edited T cells targeted to CD7 survived 65 days, compared with 31 days in a comparison group that received engineered T cells targeting a different protein. The researchers also found no evidence of graft-versus host disease in mice that received T cells lacking the molecular machinery that sees healthy tissues as foreign. They also found that the therapeutic T cells remained in the blood for at least six weeks after the initial injection, suggesting it could ramp up again to kill cancerous T cells if they return.

“T cell malignancies represent a class of devastating blood cancers with high rates of relapse and death in children and adults with the disease,” Cooper said. “In an effort to develop the first clinically viable targeted therapy for this type of cancer, we are scaling up the manufacturing of our gene-edited CAR-T cells for clinical trials, which we hope to complete at Siteman Cancer Center.”

A new study shows that higher doses of radiation do not improve survival for many patients with prostate cancer, compared with the standard radiation treatment. The analysis, which included 104 radiation therapy oncology groups across North America, was led by researchers at Washington University School of Medicine in St. Louis.

Past studies have shown that gradually escalating the radiation dose resulted in improved cancer control, such as slower tumor growth and lower levels of prostate-specific antigen (PSA), an indicator of cancer growth. The new study, published March 15 in JAMA Oncology, is the first that is large enough to examine whether these improved measurements translate into longer survival for patients.

“Our goal is to improve survival, but we didn’t see that despite advances in modern radiotherapy,” said first author Jeff M. Michalski, MD, the Carlos A. Perez Distinguished Professor of Radiation Oncology. “But we did see significantly lower rates of recurrence, tumor growth and metastatic disease — tumors that spread — in the group that received the higher radiation dose. Still, that didn’t translate into better survival. The patients in the trial did better than we anticipated, and part of that may have been because of improvements in metastatic cancer therapy over the 10 years of the trial.”

The study included about 1,500 patients with intermediate-risk prostate cancer, the risk category in which most patients fall. To be classified in this risk category, patients generally have PSA scores of 10-20 ng/ml and a Gleason score of seven, the latter of which is a measure of tumor aggressiveness. Both treatment groups received external beam radiation. The standard group received a radiation dose of 70.2 gray delivered over 39 treatment visits. The investigational group received increasing doses up to 79.2 gray delivered over 44 visits. (A gray is the standard measure of radiation a material has absorbed.)

Of the 748 men receiving standard treatment, 75 percent were still alive after eight years of follow-up. Of the 751 men receiving the dose-escalation treatment, 76 percent were alive at the eight-year mark — a difference that is not statistically significant. These overall survival rates include deaths for any cause, not just those due to prostate cancer. Over the course of the study, 51 patients died of prostate cancer, which is 3.4 percent of all patients enrolled. At the eight-year mark, the death rate due to prostate cancer for patients receiving standard treatment was 4 percent compared with 2 percent for patients receiving the escalating dose. These rates also were not statistically different.

While there was no difference in overall survival numbers, Michalski pointed out some differences in side effects and in whether further treatment was needed later. Such differences could help doctors and patients in deciding the best treatment course.

Patients in the standard dose group were more likely to undergo further therapies to control tumors that had grown larger or that had spread to another site in the body. But patients in the escalating dose group experienced more side effects — such as urinary irritation or rectal bleeding — sometimes years after treatment.

During the 10 years it took to enroll enough patients in the trial, Michalski said, at least six new therapies were approved for recurrent or metastatic prostate cancer, and these therapies have been shown to improve survival. It is possible the patients in the standard treatment arm — who were shown to need more follow-up therapies — would not have done as well as the group receiving the escalating dose had these new therapies not become available.

“If there is a difference between standard and escalating doses, it’s hard to show it when the patients who later develop recurrent cancer can have their lives extended through the use of additional therapies,” said Michalski, who treats patients at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. “Of course, these additional therapies have their own side effects, as does the higher initial dose of radiation therapy. In addition, the selective use of androgen withdrawal therapy has been shown to improve survival in men treated with radiation therapy. This treatment can be combined with either standard or higher dose radiation therapy.”

“If we can safely deliver the higher dose of radiation, my opinion is to do that,” Michalski added. “It does show lower risk of recurrence, which results in better quality of life. But if we can’t achieve those ‘safe’ radiation dose goals, we shouldn’t put the patient at risk of serious side effects down the line by giving the higher dose. If we can’t spare the rectum or the bladder well enough, for example, we should probably back off the radiation dose. It’s important to develop treatment plans for each patient on a case-by-case basis.”

Recent research at Washington University School of Medicine in St. Louis demonstrated that mature cells in the stomach sometimes revert back to behaving like rapidly dividing stem cells. Now, the researchers have found that this process may be universal; no matter the organ, when tissue responds to certain types of injury, mature cells seem to get younger and begin dividing rapidly, creating scenarios that can lead to cancer.

Older cells may be dangerous because when they revert to stem cell-like behavior, they carry with them all of the potential cancer-causing mutations that have accumulated during their lifespans. However, because mature cells in the stomach, pancreas, liver and kidney all activate the same genes and go through the same process when they begin to divide again, the findings could mean that cancer initiation is much more similar across organs than scientists have thought. That could support using the same strategies to treat or prevent cancer in a variety of different organs.

The findings about how mature cells begin dividing again — a process the researchers have named paligenosis — are reported Feb. 15 in The EMBO Journal.

“When we began the war on cancer in the 1970s, scientists thought all cancers were similar,” said senior investigator Jason C. Mills, MD, PhD, a professor of medicine in the Division of Gastroenterology and a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “It turned out cancers are very different from one organ to another and from person to person. But if, as this study suggests, the way that cells become proliferative again is similar across many different organs, we can imagine therapies that interfere with cancer initiation in a more global way, regardless of where that cancer may appear in the body.”

Studying cells from the stomach and pancreas in humans and mice, as well as mouse kidney and liver cells, and cells from more than 800 tumor and precancerous lesions in people, the researchers found when tissue is injured by infections or trauma, mature cells can revert back to a stem-cell state in which they divide repeatedly. And along the way, those cells all activate the same genes to break down the mature cells and help them begin to divide again.

“First, we saw a massive increase in the activity of genes associated with cell degradation,” said first author Spencer G. Willet, PhD, a research associate in the Mills lab. “Then, the cell’s growth pathway senses that degradation and releases nutrients that then activate cell growth pathways and allow the mature cells we studied to proliferate.”

Paligenosis, Mills explained, appears similar to apoptosis — the programmed death of cells as a normal part of an organism’s growth and development — in that it seems to happen the same way in every cell, regardless of its location in the body.

“Nature has provided a way for mature cells to begin dividing again,” Mills said, “and that process is the same in every tissue we’ve studied.”

Willet, Mills and their colleagues believe the discovery that cells in different organs go through the same process to become proliferative could lead to new potential targets for cancer treatment because the factors that initiate tumors could be the same in multiple organs.

“If you were to compare this reprogramming of cells to tearing down a building and putting something new in its place, the slow way to go would be to remove and then replace each brick, one at a time,” Mills said. “What we’re seeing is that nature is smarter than just running the building program in reverse. Instead, there is a wrecking ball program: When an old cell begins to divide again, a program runs to clear things out and then rebuild, and the same program runs in every tissue we’ve analyzed.

Cancer therapies have improved — in some cases dramatically — over the past two decades, but treatment for cervical cancer has remained largely unchanged. All patients receive radiation and chemotherapy, yet despite the aggressive approach, the regimen fails in about one-third of patients with cervical cancer that has spread beyond the cervix but not outside the pelvis.

Now, researchers at Washington University School of Medicine in St. Louis have shown that cervical tumors that don’t respond to radiation may be vulnerable to therapies that also attack the cancer’s fuel supply. Studying mice implanted with human cervical cancer cells, the investigators wiped out many of the animals’ tumors with a combination of radiation and three drugs that target tumor metabolism. They chose drugs that cut off the cancer’s ability to burn glucose and shut down protective processes that help cancer cells survive.

The study is published online in the journal Cancer Research.

“Cancer cell metabolism is a little bit peculiar,” said senior author Julie K. Schwarz, MD, PhD, an associate professor of radiation oncology. “Tumor cells take up glucose faster and in higher amounts than normal tissues. In past imaging studies, my colleagues and I noticed that cervical tumors that took up a lot of glucose prior to radiation treatment tended to be more resistant to radiation therapy than other tumors. If consuming a lot of sugar makes them resistant, we wondered what happens if we inhibit their sugar uptake.”

Schwarz and her colleagues used three different drugs, alone and in combination, to deprive cervical tumors of glucose and block downstream metabolic pathways that help protect cancer cells from building up toxic free radicals. Two of the drugs are investigational and approved by the Food and Drug Administration (FDA) for use in people as part of clinical trials; the third drug is FDA-approved to treat rheumatoid arthritis.

The researchers tested the drug combinations against four different human cervical cancer cell lines. One of the cell lines was vulnerable to being cut off from glucose alone, but the others needed more interference. All four cancer cell lines responded significantly to radiation plus the three-drug combination. One cell line was wiped out entirely. Schwarz and her team noted that the mice did not show obvious negative side effects of this therapy, likely because healthy cells don’t rely on one fuel production pathway.

When Schwarz and her colleagues cut off glucose, they force a cancer cell to scavenge for an alternative fuel. With the tumor in this vulnerable state, the researchers strike again by shutting down the cell’s ability to mitigate the toxic stew it creates from its own deranged metabolism. The treatment essentially forces the cell to drown in its own toxicity, according to the researchers.

“In many cases, when you cut off glucose alone, the cancer cells find ways to compensate,” said first author Ramachandran Rashmi, PhD, a staff scientist in radiation oncology. “But if you then hit their metabolic pathways in two more ways at the same time, the cell can’t recover from that. The stress from the toxic free radicals will escalate, eventually overwhelming the cell.”

Schwarz said that historically, cervical cancer is difficult to study in the lab because most cases are caused by human papillomavirus (HPV), and there is no equivalent infection in mice.

“Ninety to 95 percent of cervical cancer cases are HPV-related, and there are very few studies of this type of cancer in mice because HPV is a human virus,” said Schwarz who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “It’s very difficult to produce a mouse model of a solid tumor of the type we see in most women who are diagnosed with cervical cancer. Even though this is a relatively rare cancer, we know HPV is important in a number of other tumors, including those of the head and neck. We believe what we learn from studying cervical cancer will help improve treatments for any HPV-driven 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.”