Two novel clinical trials for patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) are open and enrolling patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.

The clinical trials are utilizing a breakthrough whole-genome sequencing test, ChromoSeq, developed by researchers and cancer specialists at WashU and recently approved for reimbursement by the Centers for Medicare & Medicaid Services.

“One clinical trial is enrolling AML and MDS patients admitted to our inpatient service, and the second trial is for MDS patients who are being seen in outpatient settings,” says medical oncologist Meagan Jacoby, MD, PhD, principal investigator of the 2 studies.

The trials are designed to better pinpoint genetic mutations in the two blood cancers so that patients can be risk-stratified to optimal treatments. In addition, researchers are tracking how ChromoSeq is used by physicians to guide and/or change initial treatment recommendations.

“We published our initial findings on the ChromoSeq whole-genome sequencing test in the New England Journal of Medicine in 2021 showing that it can be more accurate than other tests currently in use to identify specific genetic mutations,” says David Spencer, MD, PhD, medical director of the Clinical Sequencing Facility in the McDonnell Genome Institute at WashU and the physician-scientist who led the team that developed and validated the ChromoSeq test. “As whole-genome sequencing gets even faster and less expensive, we believe it will become the routine way we test for mutations in cancer patients.”

Optimal treatment for both AML and MDS is guided by the diseases’ genetic mutations and overall aggressiveness. Currently, multiple tests are used to obtain this information and some of these can miss important mutations. In contrast, ChromoSeq identifies the full range of genetic mutations in cancer cells using a single test and, in some cases, can offer a more precise diagnosis of a patient’s cancer.

“All risk stratification tools require genetics to guide therapy,” notes Dr Jacoby. “The current tests give us multiple separate results that provide this information. With whole-genome sequencing, we get a complete look at the genetic components of a patient’s cancer with one approach. In some cases, we learn critical new information that can be difficult to find with conventional tests.”

Says Dr Spencer, “The third AML patient we sequenced with ChromoSeq had a rare mutation that is found in only about one percent of patients and is challenging to detect with conventional tests. The mutation is associated with poor response to chemotherapy and is one example of how ChromoSeq can benefit patients with this cancer.”

In a more recent example, Dr Jacoby says, a patient initially identified to be at intermediate risk for relapse was later determined to be at higher risk after reviewing the results of their ChromoSeq test. The finding altered treatment recommendations.

Consider ChromoSeq Testing for Your Patients

ChromoSeq research has been so promising with AML and MDS that Dr. Spencer and others are expanding research into its use with other cancers, including multiple myeloma and acute lymphoblastic leukemia (ALL), the most common form of childhood leukemia.

Currently, ChromoSeq testing is available only through Washington University Pathology Services for AML and MDS patients. The test is most beneficial when used to guide therapy at the time of diagnosis; however, it also can be used to determine next steps after relapse.

Physicians interested in obtaining a whole-genome sequencing test for their AML and MDS patients can submit samples of bone marrow or peripheral blood and fill out an order form at 

https://pathologyservices.wustl.edu/services-tests/chromoseq/

. Physicians will then receive a comprehensive report noting the percentage and type of gene mutations as well as risk stratification information.

“We give physicians the precise information they need to optimize treatment recommendations,” stresses Dr Spencer. “This can make a difference in patient care. Ultimately, we think it could improve outcomes. I think ChromoSeq is the latest example of precision medicine applications that are becoming a routine part of cancer care.”

For patient criteria information about open ChromoSeq clinical trials, contact our Patient Care Coordination Center at 314-747-3046 or

To view the full list of active clinical trials at Siteman, visit 

Articles

Two clinical trials for AML or MDS are open and enrolling at Siteman Cancer Center and Washington University School of Medicine in St. Louis.

Whole Genome Sequencing for AML/MDS Risk Stratification

Jumping Genes in Cancer Cells Open Door to New Immunotherapies: © SciePro - stock.adobe.com

Jumping genes are short sections of DNA that have been incorporated randomly into the human genome over the long course of evolution. Also called transposable elements, these pieces of DNA have been implicated in the development of cancer.

But new research from Washington University School of Medicine in St. Louis suggests that transposable elements in various cancers potentially may be used to direct novel immunotherapies to tumors that don’t typically respond to immune-based treatments.

The study is available online in the journal Nature Genetics.

Immunotherapy is often most effective in tumors with numerous mutations, such as skin and lung cancers. Mutations in DNA cause cancer cells to produce unusual proteins that distinguish tumor cells from normal cells and serve as targets — called tumor antigens — for immunotherapies, such as antibodies, vaccines and genetically engineered CAR-T cell therapies. But many tumor types don’t contain large numbers of mutations and are therefore harder for the immune system to identify as a threat.

“Immunotherapy is an extremely promising approach for cancer treatment, but current therapies don’t work in many tumor types in which the mutation burden is low,” said senior author 

, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine. “We are excited about this research, because it opens up an entirely new way to identify tumor antigens in types of cancer that have previously been invisible to immunotherapy.”

Jumping genes — believed to have possibly originated from viruses — usually are found in parts of the genome that are inactive in adult tissues. 

 showed that these transposable elements sometimes can function as hidden on switches, forcing a gene to be turned on all the time, even though it should not be. As these stealthy on switches drive cancer growth, they also can churn out unusual pieces of proteins that are unique to the tumor and not present in normal cells.

In an analysis of 33 tumor types from the National Cancer Institute’s The Cancer Genome Atlas Program, the researchers identified 1,068 transposable element-derived transcripts — or sections of RNA made by the cancer cells — with the potential to produce tumor antigens that could serve as targets for new immunotherapies.

Wang and his colleagues determined that these possible tumor antigens were present on the surfaces of cancer cells, making them ideal for targeting with immunotherapies. Importantly, they found that almost 98% of the more than 10,000 tumors analyzed had at least one potential antigen target arising from a transposable element. Most tumors had from two to 75 possible antigens.

In another important finding, the researchers showed that many of the candidate proteins that could serve as antigens were present in multiple tumors and, in some cases, across tumor types. Wang and his colleagues speculated that this raises the possibility of a universal antigen-based therapy that could treat multiple tumors with a single cocktail targeting several of the most common tumor antigens that arise from jumping genes. For example, the data suggest that a vaccine with a combination of 20 of the most common protein targets could cover about 75% of patients across 27 cancer types.

“With this analysis, we can envision the design of a cancer vaccine that targets the top five or top 10 most common tumor proteins that are caused by transposable elements,” said Wang, also a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “This type of vaccine is still just an idea, but we are excited about the potential, because these common targets could cover a large fraction of tumors. Much more work is necessary, but we are hopeful that this analysis can serve as a starting point for the development of effective immunotherapies across many more cancer types.”

Research from Washington University School of Medicine in St. Louis suggests that transposable elements in various cancers potentially may be used to direct novel immunotherapies to tumors that don’t typically respond to immune-based treatments.

Jumping Genes in Cancer Cells Open Door to New Immunotherapies

Patients with glioblastoma, a devastating brain cancer, receive treatment that frequently leads to the unfortunate side effect of low white blood cell counts that lasts six months to a year. The low numbers of white blood cells are associated with shorter survival — but the specific reason for the prolonged drop in white blood cells and the link with shorter survival has vexed scientists.

A new study led by Washington University School of Medicine in St. Louis reveals at least one cause of low white blood cell counts in patients treated for glioblastoma and demonstrates a potential treatment strategy that improves survival in mice.

The study is published in the journal Science Translational Medicine.

Patients with this cancer typically do not survive longer than 18 months. The standard treatment is radiation and chemotherapy, after which many patients develop severely low numbers of lymphocytes — a type of white blood cell — in the bloodstream. The cause of these low lymphocyte counts has been something of a mystery because the therapy does not target the bone marrow, where these cells originate, and not all patients experience the problem.

“We know patients who develop low lymphocyte counts do worse than average,” said co-corresponding author 

, an associate professor of radiation oncology and co-clinical director of the 

 at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “To improve their outcomes and extend their lives, we needed to understand what is causing these low levels of white blood cells and how it contributes to worse survival.”

Huang and his colleagues at Siteman led a study that collected and analyzed blood samples from glioblastoma patients. About half of the patients developed low white blood cell counts following treatment.

The researchers found a significant increase in what are called myeloid-derived suppressor cells — a type of cell known for suppressing the immune system — in those that developed low white blood cell levels. In mouse studies, the scientists then established a causal relationship between the increased myeloid-derived suppressor cells induced by irradiation of the tumor and the suppression of white blood cells.

“We wanted to find out if we could block these myeloid-derived suppressor cells using an inhibitor to improve treatment response to radiation,” said senior corresponding author Dinesh Thotala, PhD, who conducted this work at Washington University and is now with the University of Oklahoma Health Sciences Center. “We ended up testing two inhibitors separately with radiation and found a significant improvement in survival in multiple mouse models of this cancer.”

The researchers, including first author Subhajit Ghosh, PhD, a postdoctoral fellow who conducted this work in Thotala’s lab, first at Washington University and now at the University of Oklahoma, found that, on average, all of the mice with glioblastoma that received radiation alone died by day 40. Of the mice that received either inhibitor plus radiation, 50% to 60% were still alive at day 120, when the experiment ended.

One inhibitor, called CB1158, is in a class of drugs called arginase-1 inhibitors and is being investigated in a clinical trial for the treatment of solid tumors, including colorectal, lung and bladder cancers. The second drug is a phosphodiesterase-5 inhibitor called tadalafil, which is approved by the Food and Drug Administration to treat other conditions, including erectile dysfunction and pulmonary hypertension.

“The myeloid-derived suppressor cells have normal functions in the body,” said Huang, who develops clinical trials for glioblastoma patients. “During pregnancy, the body makes these cells to suppress the immune cells so it doesn’t attack the embryo or fetus. But glioblastoma takes this normal process and exploits it for its own purpose. Furthermore, radiating the tumor triggers the body to create massive quantities of these cells, leading to low white blood cell counts in our patients, sometimes for many months. Our work suggests that targeting those cells in combination with radiation may be a new, exciting strategy to improve the treatment of glioblastoma.”

To further confirm their findings, the researchers have conducted a small clinical trial that combined tadalafil with standard radiation for patients with glioblastoma. According to the researchers, they are finding encouraging results, with some patients responding well to the investigational treatment. This work is currently under review in another scientific journal. The researchers also are working toward developing new therapies with even more potential than these two inhibitors to block myeloid-derived suppressor cells.

A new study led by Washington University School of Medicine in St. Louis reveals at least one cause of low white blood cells.

Patients With Brain Cancer May Benefit From Treatment to Boost White Blood Cells

Regular postsurgical screening is critical for patients with lung cancer, the United States’ second most prevalent type of cancer and leading cause of cancer deaths. In cases involving early-stage non small cell lung cancer, up to half of patients will experience recurrence within the first two years after surgery.

For these reasons, guidelines by the National Comprehensive Cancer Network and other cancer groups recommend computed tomography (CT) scans every three to six months for patients who have had malignant lung tumors surgically removed. However, a new study by researchers at Washington University School of Medicine in St. Louis found no improvements in survival or recurrence rates among patients who followed the protocol, compared with those who were scanned every six months to one year.

“Our findings suggest that lung cancer treatment guidelines should consider less frequent surveillance imaging than current recommendations,” said the study’s senior author, 

, a thoracic surgeon and professor of surgery. “Annual surveillance would simplify guidelines and may result in better, easier postoperative care for early-stage patients.”

The study is published Nov. 28 in the Journal of the National Cancer Institute.

Non-small cell lung cancer accounts for 84% of all lung cancer cases, according to the American Cancer Society, and the overall five-year survival rate is 25%.

The researchers focused on the first two years after surgery since that is when the risk of lung cancer recurrence is highest. After two to three years, cancer organizations typically recommend annual scans until the end of life.

“Scanning too frequently can be associated with unnecessary anxiety for patients and increased health-care costs,” said Puri, also a research member of 

 at Washington University School of Medicine and Barnes-Jewish Hospital. “Patients who receive scans to check for recurrent cancer are understandably anxious, especially since it can take several days for results to be received. This phenomenon is sometimes called ‘scanxiety.’ It is obviously important to minimize scanxiety when it can be done safely.”

For the study, the researchers analyzed de-identified medical records in a database maintained by the U.S. Veterans Health Administration, the nation’s largest integrated health-care delivery system. The researchers examined information involving 6,171 patients with stage 1 non-small cell lung cancer who underwent surgery from Oct. 1, 2006, through Sept. 31, 2016. One patient group received scans every three to six months, and the other group every six to 12 months.

In all cases, more scans did not offer improved health, including among different tumor sizes, tumor stages and types of surgical procedures. Recurrence was observed in 22% of patients and did not differ based on the frequency of scanning. Similarly, overall survival remained the same between the two groups, with about 65% of patients surviving at least five years.

The average age of the patients was 67.5. The patients were predominantly male and white; however, statistical modeling controlled for different ages, genders and races.

“We found that certain patients had received more frequent CT scans, including patients who smoked and patients who had certain types of operations,” said the study’s first author, 

, a surgical resident and research fellow at Washington University. “Conversely, we found that African-American patients received less frequent scans, which is a potentially concerning health disparity that warrants further research. Nonetheless, we were encouraged to find that patient outcomes were generally equivalent regardless of scan frequency.”

Heiden continued: “The VA treats a unique patient population that consists mostly of males with significant smoking histories. Therefore, we believe that our findings are most applicable to veterans with lung cancer. However, prior studies examining non-VA patient populations have found similar results to ours, suggesting that the results may apply more broadly to the general population. More research is needed.”

A new study by researchers at Washington University School of Medicine in St. Louis found that undergoing more frequent computed tomography scans was not associated with improved outcomes following lung cancer surgery. 

More Frequent CT Scans Not Associated with Improved Outcomes After Lung Cancer Surgery

A type of chronic leukemia can simmer for many years. Some patients may need treatment to manage this type of blood cancer — called myeloproliferative neoplasms (MPN) — while others may go through long periods of watchful waiting. But for a small percentage of patients, the slower paced disease can transform into an aggressive cancer, called secondary acute myeloid leukemia, that has few effective treatment options. Little has been known about how this transformation takes place.

But now, researchers at Washington University School of Medicine in St. Louis have identified an important transition point in the shift from chronic to aggressive leukemia. They have shown that blocking a key molecule in the transition pathway prevents this dangerous disease progression in mice with models of the disease and in mice with tumors sampled from human patients.

The research appears Dec. 29 in the journal Nature Cancer.

“Secondary acute myeloid leukemia has a grim prognosis,” said senior author 

, an associate professor of medicine and co-director of the 

 at the School of Medicine. “Almost every patient who develops acute leukemia after a history of myeloproliferative neoplasms will die from the disease. Therefore, a major focus of our research is to better understand this conversion from chronic to aggressive disease and to develop better therapies and, hopefully, prevention strategies for these patients.”

The study suggests that inhibiting this key transition molecule — called DUSP6 — helps overcome the resistance that these cancers often develop to JAK2 inhibitors, the therapy typically used to treat them. JAK2 inhibitors are an anti-inflammatory therapy also used to treat rheumatoid arthritis.

“These patients are commonly treated with JAK2 inhibitors, but their disease progresses despite that therapy, so we’re also trying to identify how the disease is able to worsen even in the setting of JAK2 inhibition,” said Oh, who treats patients at Siteman Cancer Center at 

 and Washington University School of Medicine.

The researchers conducted a deep dive into the genetics of these tumors, both during the slow chronic phase and after the disease had transformed into the aggressive form while patients were taking JAK2 inhibitors. The DUSP6 gene stood out as highly expressed in the 40 patients whose tumors were analyzed in this study.

Using genetic techniques to delete the DUSP6 gene prevented the transition to aggressive disease in mice with models of this cancer. The researchers also tested a drug compound that inhibits DUSP6 and found that the compound — only available for animal research — stopped progression of the chronic disease to the aggressive disease in two different mouse models of the cancer and in mice with human tumors sampled from patients. Reducing DUSP6 levels both genetically and with a drug also reduced inflammation in these models.

Since the drug that inhibits DUSP6 is not available for human clinical trials, Oh and his colleagues are interested in exploring treatments that inhibit another molecule that they found is activated downstream of DUSP6 and that they showed is also required to perpetuate the negative effects of DUSP6. There are drugs in clinical trials that inhibit this downstream molecule, known as RSK1. Oh’s team is interested in investigating these drugs for their potential to block the dangerous transition from chronic to aggressive disease and address resistance to JAK2 inhibition.

“A future clinical trial might enroll myeloproliferative neoplasm patients who are taking JAK2 inhibitors and, despite that, show evidence of their disease worsening,” Oh said. “At that point, we might add the type of RSK inhibitor that’s now in trials to their therapy to see if that helps block progression of the disease into an aggressive secondary acute myeloid leukemia. A newly developed RKS inhibitor is in phase 1 clinical trials for patients with breast cancer, so we’re hopeful our work provides a promising foundation for developing a new treatment strategy for patients with this chronic blood cancer.”

A type of chronic leukemia can simmer for many years and for a small percentage of patients, the slower paced disease can transform into an aggressive cancer, called secondary acute myeloid leukemia, that has few effective treatment options. 


Study Reveals How Chronic Blood Cancer Transitions to Aggressive Disease

A single drug compound simultaneously attacks hard-to-treat prostate cancer on several fronts, according to a new study in mice and human cells. It triggers immune cells to attack, helps the immune cells penetrate the tumor, and cuts off the tumor’s ability to burn testosterone as fuel, according to new research from Washington University School of Medicine in St. Louis. The drug may offer a promising new strategy for treating patients whose tumors don’t respond to standard therapy.

Prostate cancer is notorious for eventually developing resistance to standard treatments that block or reduce testosterone, which fuels growth of these tumors. And like many solid tumors, prostate cancer also has proven stubbornly resistant to newer immunotherapies, which are intended to take the brakes off the immune system’s T cells to get them fighting cancerous invaders. Immunotherapies — most commonly, immune checkpoint inhibitors — can be extremely effective but only in certain cancers, such as melanoma.

“We need to develop better therapies for prostate cancer patients, because most of these tumors develop resistance to hormone-based therapies doctors rely on to treat these cancers,” said senior author 

, a professor of surgery. “Immunotherapy is the newest and most promising type of therapeutic for cancer right now, but even so, immune checkpoint inhibitors have failed to do much against most solid tumors, including prostate cancer. This study was surprising because we found that this drug activates anti-cancer T cells in a novel way, and it also increases the T cells’ ability to penetrate the tumor. This could lead to a more effective strategy for patients whose cancers are hard to treat.”

The drug, called (R)-9b, is a small molecule that blocks an oncogene, a gene that drives cancer. The researchers initially attributed the drug’s success in mouse studies to its ability to reduce or eliminate androgen receptors in the prostate cancer cells. These receptors bind to testosterone and use the hormone to fuel tumor growth. The drug’s ability to eliminate the androgen receptor differs from standard drugs that reduce the amount of testosterone in the body, and other drugs that block the androgen receptor’s function as a transcription regulator.

But because the new drug was so effective, Mahajan and his colleagues suspected something more was going on. The drug blocks a gene called 

. The researchers developed a strain of mice that totally lacked this gene in order to study what happens when it’s missing. At first, the researchers were baffled by these mice. Mice missing an entire gene often have obvious problems. But these mice seemed fine. And when the researchers looked for tumor growth, they found very little. It was difficult to model cancer in these animals.

“In most of these mice, when we introduced cancer cells as we typically do, there was no trace of a tumor,” said Mahajan, also a research member of Siteman Cancer Center at 

 and Washington University School of Medicine. “In the few that did develop tumors, the tumors were small compared to those of wild-type mice. This was the first clue that something important was happening in mice missing this gene. We found that they were able to mount a robust immune response against the cancer cells.”

When different mice — mice with this gene — were implanted with human prostate tumors and given the drug that blocks this gene, it had the same effect: taking the brakes off the immune system and producing increased levels of certain types of T cells known to attack cancer. The drug also increased signaling molecules that allow the T cells to penetrate the tumor and kill cancer cells more effectively. The tumors in these (R)-9b treated mice were much smaller than those of mice in control groups.

Given the drug’s success in tumor penetration, the researchers investigated whether adding immune checkpoint inhibitors to treatment with the drug would be even more effective, taking the brakes off T cells in more than one way at the same time — but there was no such improvement.

“Surprisingly, we found that the immune checkpoint inhibitor is activating 

, the very pathway we are shutting down with this drug compound,” Mahajan said. “It’s possible immune checkpoint inhibitors don’t work well in these tumors because they are turning on 

, which suppresses the immune response. Similar to prostate cancer, the 

 pathway activation also could be employed by other cancers that do not respond to checkpoint inhibitors. However, these cancers could respond to (R)-9b, so we would like to investigate this drug in other solid tumors as well.”

Mahajan said the drug spurs multiple responses because of the nature of the gene it blocks. Many genes have several roles in the body, and 

’s roles in expression of the androgen receptor and in reigning in the immune system make it an appealing target for cancer therapy, especially against solid tumors with a hormonal growth component, such as prostate and breast cancers.

Washington University’s Office of Technology Management/Tech Transfer

 to file patents on the use of this drug in cancer treatment. His team is gathering data to apply for permission from the Food and Drug Administration to test the drug in a clinical trial for patients with prostate cancer.

A single drug compound simultaneously attacks hard-to-treat prostate cancer on several fronts, according to a new study in mice and human cells.