Article Category: In the Media

Medical School faculty named to National Academy of Inventors

Noted innovators Samuel Achilefu, PhD, David Holtzman, MD, and Eric Leuthardt, MD – faculty members at Washington University School of Medicine in St. Louis – have been named fellows of the National Academy of Inventors (NAI). The 2017 class of NAI fellows was announced Tuesday.

They are recognized as fellows for demonstrating innovation in creating and facilitating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society.

The newest class of fellows – 155 scientists from universities and governmental and nonprofit institutions – will be honored April 5 at a ceremony in Boston.

Other NAI fellows at Washington University include Chancellor Mark S. Wrighton; Holden Thorp, provost and executive vice chancellor for academic affairs; and Jennifer K. Lodge, PhD, vice chancellor for research.

Samuel Achilefu

Achilefu, the Michel M. Ter-Pogossian Professor of Radiology, is being recognized for his innovative approach to integrating engineering, biology and medicine. He is known for pioneering the development of strategies for molecular imaging and treatment of human diseases using novel molecular probes and light-sensitive drugs. Also a professor of biochemistry and molecular biophysics, and of biomedical engineering, he discovered a new molecular entity that can be used to deliver drugs to many types of tumors.

Achilefu also led a team that developed a wearable, goggle-based imaging system for guiding surgical removal of cancer in real time. Cancer cells are notoriously difficult to see, even under high-powered magnification. Achilefu’s eyewear is designed to make it easier for surgeons to distinguish malignant cells from healthy cells, helping to ensure that no stray tumor cells are left behind during surgery to remove a cancerous tumor. The glasses could reduce the need for additional surgical procedures and the subsequent stress on patients, as well as time and expense.

After receiving a PhD in chemistry at the University of Nancy, France, and postdoctoral training in blood oxygen transport mechanisms, Achilefu came to St. Louis in 1993 to join the nascent Discovery Research Department at Mallinckrodt Medical Inc. In 2001, he joined Mallinckrodt Institute of Radiology at Washington University, where he now heads the Optical Radiology Laboratory. A Siteman Cancer Center researcher, he is also director of the university’s Molecular Imaging Center and a co-director of the Center for Multiple Myeloma Nanotherapy.

He is the recipient of numerous awards, including the prestigious St. Louis Award, given to St. Louis-area residents whose achievements reflect positively on the community. He also has been issued more than 50 U.S. patents.

David M. Holtzman

Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, is being honored for distinguished contributions to understanding the pathogenesis of Alzheimer’s disease and for developing diagnostics and treatments for the disease.

His research has focused on how levels of the Alzheimer’s proteins amyloid beta and tau in the brain and spinal fluid are linked to risk for and progression of the disease. He helped develop a technique known as stable isotope-linked kinetics (SILK) for monitoring production and clearance of amyloid beta in the brain and spinal fluid. The technique involves giving people a slightly altered form of one of the amino acids the body uses to make proteins. Through monitoring the presence of proteins with the altered amino acid, scientists can track how quickly the proteins are produced and cleared from the brain. The technique also can be adapted to study other diseases and biological processes.

His laboratory also developed antibodies against amyloid beta and tau that are currently in clinical trials in people with very early stages of Alzheimer’s disease. Holtzman co-founded a company called C2N Diagnostics in 2007 with Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology, to develop biomarkers for neurodegenerative diseases.

Holtzman earned his bachelor’s and medical degrees from Northwestern University. He completed an internship, residency and postdoctoral fellowship at the University of California, San Francisco, where he was an assistant professor of neurology from 1991-94 before joining the Washington University faculty.

Past honors include the MetLife Foundation award for research on Alzheimer’s disease, the Potamkin Prize for Alzheimer’s research from the American Academy of Neurology, the 2014 Chancellor’s Award for Innovation and Entrepreneurship at Washington University, and election to the National Academy of Medicine of the National Academy of Sciences. He also is a fellow of the American Association for the Advancement of Science.

Eric Leuthardt

Leuthardt, a professor of neurosurgery, of neuroscience, of biomedical engineering, and of mechanical engineering and applied science, is an expert in brain mapping and in devices that link the brain with computers. He studies how the brain encodes information so researchers can develop electronic devices controlled by the mind. Such brain-computer interfaces could allow patients to use their thoughts to communicate, move artificial or paralyzed limbs, or perform other neurological functions.

As director of Washington University’s Center for Innovation in Neuroscience and Technology, he gathers neurosurgeons, engineers, mathematicians, physicists and computer scientists to collaborate and develop new technologies to improve neurosurgery. He has helped develop techniques to identify the location of brain functions such as language and motor function to minimize the chance that surgery will impair crucial abilities.

With more than 500 issued patents and six startup companies for medical devices and brain-computer interface technologies, Leuthardt is a prolific inventor. He was named a Top Young Innovator by the Massachusetts Institute of Technology’s magazine Technology Review in 2004, and won the Academy Award of the American Academy of Neurological Surgery that same year. He also received the Innovation Award from the Academy of Science in St. Louis and was honored with the Chancellor’s Award for Innovation and Entrepreneurship at Washington University.

A native of Cincinnati, Leuthardt earned his bachelor’s degree in biology and theology at Saint Louis University and his medical degree from the University of Pennsylvania School of Medicine before returning to St. Louis to do his residency in neurological surgery at Barnes-Jewish Hospital and the School of Medicine. He joined the School of Medicine faculty in 2006.

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.]

New gene-altering treatment offered for blood cancers

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis is one of the first centers nationwide to offer a new immunotherapy that targets certain blood cancers. Newly approved by the Food and Drug Administration (FDA) for types of advanced non-Hodgkin lymphoma in adults, the CAR-T cell therapy harnesses a patient’s own immune system to fight cancer.

Washington University doctors and researchers were involved in clinical trials that led to the FDA approval of the new CAR-T cell therapy, called Yescarta, and are working to develop other immunotherapies that attack cancer.

“This is the beginning of a new era of cancer therapy,” said Washington University oncologist Armin Ghobadi, MD, an assistant professor of medicine at the School of Medicine who treats patients at Siteman. “With CAR-T cell therapy, we can take patients’ own cells and turn them into a powerful weapon to attack cancer. It’s a highly personalized, innovative therapy and one we hope also will prove to be effective against many different types of cancer.”

At the heart of the new therapy are the immune system’s T cells, which typically fight off disease. In cancer patients, T cells lose the ability to recognize and attack cancer cells. CAR-T cell therapy involves extracting a patient’s own T cells and genetically altering – or supercharging – those cells to home in on cancer cells and destroy them.

The first cancers to be treated with CAR-T cell therapy include advanced lymphomas in adults and acute lymphoblastic leukemia (ALL) in children. CAR-T cell therapy for pediatric ALL was approved by the FDA at the end of August and is available through Siteman Kids at St. Louis Children’s Hospital. These cancers are characterized by the production of too many B cells, a type of white blood cell that is also a part of the immune system.

Currently, CAR-T therapy for adults with non-Hodgkin lymphoma is available only to patients whose cancer has not responded to standard treatments — including chemotherapy and bone marrow transplantation. Kite Pharma, a Gilead company, developed the new treatment.

Clinical trials of CAR-T therapy have shown what doctors have called remarkable remission rates among children with ALL and adults with lymphomas and multiple myeloma. In patients whose disease has not responded to standard therapies or has relapsed, CAR-T therapy has achieved from 40 to 80 percent remission rates. Some patients have remained in remission for several years.

“The availability of this new treatment offers a novel and very effective option for patients whose choices were once limited to joining a clinical trial of an investigational drug or entering hospice care,” Ghobadi said.


These modified T cells have been dubbed CAR-T cells, which stands for chimeric antigen receptor T cells.
A patient’s T cells are isolated from the blood and modified in a way that lets the T cells specifically home in on the type of cell affected by the cancer. These modified T cells have been dubbed CAR-T cells, which stands for chimeric antigen receptor T cells. Once a CAR-T cell finds its target, it behaves as any T cell should — triggering a chain of reactions that destroys the target cell. HUY MACH



If cancerous cells find ways to fly under the radar of immune surveillance, the new therapy renders these cancers visible again.

“The immune system can’t always see cancer cells as threats — the T cells are sometimes blind to them,” said John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine in Oncology and director of the Division of Oncology at the School of Medicine and deputy director of Siteman Cancer Center. “By modifying these T cells, we tell them what to look for. Now they can go right to the leukemia or lymphoma and eliminate the cancerous cells.”

Over decades, an extensive body of research gradually has revealed the details of what many types of cancers look like on the cell surface. And in this new therapy, that information is, in a sense, programmed into the T cell. A patient’s T cells are isolated from the blood and modified in a way that lets the T cells specifically home in on the type of cell affected by the cancer. These modified T cells have been dubbed CAR-T cells, which stands for chimeric antigen receptor T cells.

Once a CAR-T cell finds its target, it behaves as any T cell should — triggering a chain of reactions that destroys the target cell. CAR-T cells often are referred to as a living drug because they expand their numbers dramatically once in the bloodstream. And like other T cells, they remember what their targets look like, sometimes long after the offending cells have been eradicated. While long-term data is still being gathered, there is evidence that some CAR-T cells may maintain their active surveillance and ramp up again in response to cancer recurrence. The fact that CAR-T cells can be given different programming, locking them on to different cell surface features, suggests the strategy could be expanded to other cancers.

But because the therapy induces a heightened immune response, there can be a range of side effects, from fever and shortness of breath to kidney failure and seizures. Many of the side effects are manageable, but some are severe and a few can be life-threatening, which is why the first centers selected to administer the new therapy are those with extensive expertise in treating blood cancers. That expertise includes long histories of success in bone marrow transplantation and management of the sometimes severe side effects of that similarly intensive, but standard, therapy for many blood cancers.

“The toxicities of bone marrow transplantation and CAR-T cells are completely different, but we are well-equipped to manage both,” DiPersio said. “We have approved therapies we can give to counter one of the primary side effects of CAR-T cells called cytokine release syndrome, which causes symptoms like low blood pressure, high fevers, chills, swelling and kidney failure. Some patients who receive CAR-T therapies also can experience life-threatening neurologic toxicities that we are still working to understand.”

Washington University doctors at Siteman also are evaluating CAR-T cell therapy in a clinical trial for leukemia and soon will begin a trial in patients with multiple myeloma, another type of blood cancer, and ovarian cancer. Clinical trials currently available for sarcoma, a cancer of bones and connective tissue; lung cancer; and melanoma, a skin cancer, involve therapies very similar to CAR-T cell therapy.

For more information about CAR-T cell therapy, patients should visit siteman.wustl.edu or call toll free 800-600-3606.

Siteman Cancer Center opens expanded St. Charles County facility

Siteman Cancer Center will open its newly expanded and renovated outpatient facility at Barnes-Jewish St. Peters Hospital in St. Charles County on May 1.

The expansion nearly doubles the facility’s size, to 37,000 square feet. With the larger capacity, additional physicians will be available to see patients in newly added exam and treatment rooms.

The facility offers access to the same advanced treatments, including more than 500 clinical trials, available at Siteman’s other satellite locations in the region and on the Washington University Medical Campus at Barnes-Jewish Hospital.

“Recognized among the best cancer centers in the country by U.S. News & World Report, Siteman Cancer Center offers highly advanced care,” said Timothy J. Eberlein, MD, Siteman’s director and the Spencer T. and Ann W. Olin Distinguished Professor at Washington University School of Medicine in St. Louis. “Our patients deserve the best, and with additional Washington University physicians and new facilities, we can continue providing exceptional care closer to where patients live.”

The multidisciplinary, coordinated care provided by Washington University radiation oncologists, medical oncologists and surgeons at Siteman-St. Peters helps to ensure that patients can see as many as three physicians in one visit. This team approach also means a patient’s treatment plan can be determined in one visit with a team of nationally recognized cancer specialists.

Located near Mexico and Jungermann roads on the campus of Barnes-Jewish St. Peters Hospital, the newly expanded facility provides:

  • Five medical oncologists to serve patients, up from three.
  • An increase in medical oncology exam rooms to 16, from eight.
  • An increase in chemotherapy infusion chairs to 32, from 11.
  • 28 chemotherapy infusion bays and four private infusion rooms.
  • An increase in radiation oncology rooms to seven, from four.
  • Two state-of-the-art linear accelerators with a wide range of treatment capabilities, including stereotactic body radiation therapy and stereotactic radiosurgery, which deliver precisely targeted radiation to tumors in the body or brain.
  • More space for Washington University surgeons to consult with patients.

“At Siteman-St. Peters, we offer our patients nationally recognized care in a community hospital setting,” said John DiPersio, MD, PhD, Siteman’s deputy director and the Virginia E. and Sam J. Golman Professor of Medicine at the School of Medicine. “With access to hundreds of clinical trials, advanced technology and world-class care, patients don’t have to choose between the two.”

With the unique needs of cancer patients in mind, planners at Washington University and Barnes-Jewish St. Peters Hospital defined several guiding principles for the facility’s design and expansion, striving to provide an atmosphere that promotes trust, instills calm, conveys respect, ensures quality and offers inspiration.

“Patients don’t need to choose between world-class care and the comfort and convenience of a community hospital setting,” said Chris Watts, president of Barnes-Jewish St. Peters Hospital. “With this new and expanded facility, residents of St. Charles County and the region can have both.”

Ravi Vij, MD, is medical oncology director and Lannis Hall, MD, is director of radiation oncology at the St. Peters facility. Kelly Tschannen is nurse manager and Diane Foglesong is radiation oncology manager.

CORE10 Architecture and Christner Inc. were the external and interior architects, respectively, for the $13.1 million project. Pillar Design Group Inc. and Glasper Professional Services Inc. were the structural and civil engineers, respectively. William Tao & Associates handled mechanical, electric, plumbing and fire engineering. Kadean Construction Co. managed construction. Barnes-Jewish St. Peters Hospital, part of BJC HealthCare, contributed $10.6 million to the expansion, with the School of Medicine providing the additional funds.

The facility’s address is 150 Entrance Way, St. Peters, MO 63376 (map). For more information about the new location, visit its website.

Siteman’s other locations are:

  • Washington University Medical Center in St. Louis, where Barnes-Jewish Hospital’s Parkview Tower now under construction will include private, inpatient rooms for Siteman patients.
  • Barnes-Jewish West County Hospital in Creve Coeur.
  • Siteman Cancer Center-South County, near Interstate 55 and Butler Hill Road.

To schedule an appointment at any Siteman facility, call 314-747-7222 or 800-600-3606 toll-free from 8 a.m. to 4:30 p.m. weekdays, or visit siteman.wustl.edu.

Siteman Investment Program awards $2.2 million in cancer research grants

Research on breast cancer and the effects of chemotherapy are among the seven projects that will benefit from $2.2 million in new grants announced by Siteman Cancer Center through its Siteman Investment Program. The goal of the grants is to support and accelerate the pace of innovation in cancer research.

The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge and Illumination gala, through the Cancer Frontier Fund at the Foundation for Barnes-Jewish Hospital; the Fashion Footwear Association of New York; the National Cancer Institute; and the Barnard Trust.

The research projects are described below.

Title: Siteman Cancer Center Breast Cancer SPORE

Principal investigator:William Gillanders, MD, a professor of surgery at Washington University School of Medicine and a research member of Siteman Cancer Center

Amount:$400,000 over one year

Goal: To create a Specialized Program of Research Excellence (SPORE) focused on tumor immunology, oncologic imaging, surgical oncology and breast cancer prevention that will enable researchers to quickly translate basic science discoveries to clinical uses for patients with breast cancer

Description: Breast cancer is a mixed and diverse disease that will require a combination of prevention, diagnostic and treatment approaches to decrease mortality. This project brings together a multidisciplinary team of investigators leveraging institutional strengths in basic and translational research. The objective is to obtain NCI funding for a Breast Specialized Program of Research Excellence (SPORE) that will enable rapid clinical translation of basic science discoveries with the goal of impacting patient care. Siteman Investment Program funds will provide critical continuing support for the development of a Breast Cancer SPORE at Siteman Cancer Center with a focus on tumor immunology, oncologic imaging, surgical oncology, and breast cancer prevention.

Title: RNA as a target of alkylation chemotherapy in cancer

Principal investigators:Nima Mosammaparast, MD, PhD, an assistant professor of pathology and immunology at the School of Medicine and a research member of Siteman Cancer Center, and Hani Zaher, PhD, an assistant professor of biology at Washington University School of Arts and Sciences

Amount:$400,000 over two years

Goal: To better understand the importance of chemotherapy-induced RNA damage of cells which will impact our understanding of how tumors respond to chemotherapy and ultimately may lead to new targets for chemosensitization

Description: Alkylating agents, a highly reactive group of molecules, are frequently used in cancer chemotherapeutics. These drugs are thought to work primarily by damaging the genome, which consists of DNA. However, another key molecule in the cell that is targeted by these drugs is RNA. Yet, we do not understand whether RNA damage by alkylating agents is important for tumor responses to these drugs. At a chemical level, RNA is very similar to DNA and changes to its structure often affect its function during protein synthesis. Therefore, we propose that RNA damage contributes to cell death upon exposure to alkylating agents. Our studies will focus on understanding how cells deal with RNA damaged with alkylating agents, and how this may affect tumor responses to these commonly used drugs. This work represents a major paradigm shift in our understanding of how tumor cells respond to chemotherapy, and may provide new ways of treating multiple types of cancer.

Title: Optimizing decision making about breast reconstruction after mastectomy: A patient-centered approach

Principal investigators: Siteman Cancer Center research members Terence Myckatyn, MD, a professor of surgery at the School of Medicine, and Mary Politi, PhD, an associate professor of surgery at the School of Medicine

Amount:$400,000 over two years

Goal: To develop a clinical decision support tool that will enable physicians and patients to make high-quality breast reconstruction decisions, ultimately improving cancer survivorship for women with breast cancer

Description: Deciding whether or not to have breast reconstruction after mastectomy, when to have reconstruction, and which type of reconstruction to have is very challenging for patients with breast cancer. Currently, this choice is limited by inadequate information and deficits in knowledge about treatment options. In this proposal, we aim to develop and evaluate a novel clinical decision support tool that integrates patients’ unique clinical characteristics with their preferences to enable clinicians and patients to make high-quality breast reconstruction decisions. This research will promote personalized cancer care for patients with breast cancer. Ultimately, this proposal has the potential to improve knowledge of treatment risks, harms and benefits; enable patients across racial groups to get the treatments they prefer; and improve outcomes patients find important, thereby improving cancer survivorship for women with breast cancer.

Title: Evaluating cognitive function and functional connectivity in breast cancer survivors who received chemotherapy

Principal investigators:Jay Piccirillo, MD, a professor of otolaryngology at the School of Medicine and a research member of Siteman Cancer Center; Lindsay Peterson, MD, an assistant professor of medicine at the School of Medicine; Alex Wong, PhD, an assistant professor of occupational therapy at the School of Medicine; and Bradley Schlaggar, MD, PhD, a professor of neurology at the School of Medicine

Amount:$400,000 over two years

Goal: To better understand the basis of chemotherapy-related cognitive impairment (CRCI) in breast cancer patients, to ultimately improve the survivorship experience

Description: Chemotherapy has been linked to cognitive impairments among breast cancer patients, especially related to planning, learning and attention. The neurological basis of this phenomenon, termed chemotherapy-related cognitive impairment (CRCI), is unknown, and the impact in patients over an extended period of time is lacking. The study aims to establish the groundwork to allow the assessment of the structural brain reasons that CRCI occurs and to evaluate why some patients develop CRCI and others do not. All newly diagnosed eligible breast cancer patients scheduled to undergo chemotherapy at Siteman Cancer Center will be enrolled in order to establish the Clinical Database for Cognitive Assessment. These patients will complete several cognitive function measures pre- and post-chemotherapy. A subset of these patients will complete special MRI functional imaging pre-and post-chemotherapy. Ultimately, the results of this project will support the exploration of the reasons why CRCI occurs and identify ways to improve the survivorship experience for breast cancer patients.

Title: A genetic model of perineural invasion

Principal investigator:James Skeath, PhD, a professor of genetics at the School of Medicine and a research member of Siteman Cancer Center

Amount:$200,000 over two years

Goal: To discover the molecular causes of cancer metastasis along nerves (perineural invasion) and better understand the molecular basis of this aggressive yet poorly understood form of metastasis

Description: Metastatic spread of tumors is often the key event that leads to cancer-related mortality. Although the blood and lymph systems represent the most common routes for tumor metastasis, nerves identify a key under-appreciated path for cancer spread. Perineural invasion is the process by which tumor cells migrate along nerves to invade distant tissues. First identified in the 1800s, perineural invasion is common in many cancers and a marker of poor outcome. Despite its clinical significance, the causes of perineural invasion remain unknown. We have developed one of the first in vivo model systems of perineural invasion. Here, we will exploit this system to uncover the molecular causes of perineural invasion. Given the lack of knowledge about perineural invasion, our research holds the potential to break open the field and catalyze advances in our understanding of this poorly understood form of cancer metastasis.

Title: Fatty liver promotes hepatic breast cancer metastasis

Principal investigator:Steven Teitelbaum, MD, the Messing Professor of Pathology and Immunology at the School of Medicine and a research member of Siteman Cancer Center

Amount:$200,000 over two years

Goal: To better understand the mechanisms by which fatty liver disease, a reversible and preventable disease, promotes breast cancer metastasis to the liver

Description: The United States is experiencing an epidemic of obesity which is often associated with fatty liver disease, estimated to be present in 20 percent to 30 percent of Americans. Surprisingly, nothing is known about the influence of fatty liver disease on liver metastasis. We find that whereas normal mice are resistant to liver metastasis of breast cancer, those with fatty liver are predisposed. This observation is important as fatty liver disease is reversible. We propose to determine why fatty liver predisposes to liver metastasis and if reducing liver fat prevents cancer spread. If our data extends to humans, it would have significant public health implications.

Title: Nonsense-mediated mRNA decay in DNA damage response

Principal investigator:Zhongsheng You, PhD, an associate professor of cell biology and physiology at the School of Medicine and a research member of Siteman Cancer Center

Amount:$200,000 over two years

Goal: To better understand the effects that DNA damage generated by radiation and chemotherapy has on the healthy cells surrounding the tumor, in order to develop new therapeutic strategies that will ultimately lessen side effects and cancer relapses.

Description: The mainstays of cancer treatment have been radiation and chemotherapy that generate DNA damage. However, the efficacy of DNA-damaging therapies is hampered by serious side effects and frequent cancer relapse. A major cause of cancer relapse is the alterations in gene expression that occur after treatment in the cells in the environment surrounding a tumor. Thus, it is imperative to understand the molecular mechanisms for the gene expression changes induced by DNA damage. The goal of this pre-R01 application is to explore the role of an RNA degradation pathway called nonsense-mediated mRNA decay in the reprogramming of gene expression in response to DNA damage. This project is expected to generate key experimental results that will enable development of new therapeutic strategies targeting harmful changes in the tumor environment.

Siteman Cancer Center benefits from QVC Presents “FFANY Shoes on Sale”

QVC and FFANY present a contribution of $300,000 as a result of charitable multiplatform event

For more than 20 years, QVC Presents “FFANY Shoes on Sale” has combined great shopping with an even better cause. Last October during the annual charitable shoe sale, more than 80,000 pairs of shoes were purchased at half the manufacturer’s suggested retail price,* generating awareness and funds for breast cancer research and education.   

The Fashion Footwear Association of New York (FFANY), the Fashion Footwear Charitable Foundation (FFCF) and QVC selected the Alvin J. Siteman Cancer Center as one of the nine beneficiaries of the 2015 event. QVC and representatives of FFANY presented a check in the amount of $300,000 to Timothy Eberlein, MD, director of the Alvin J. Siteman Cancer Center, and Karen Kharasch, Siteman’s executive director of research and business administration, both of whom accepted the donation on behalf of the organization. 

“Our breast cancer program and our patients from across the United States have benefited greatly from the more than $3.8 million that QVC Presents “FFANY Shoes on Sale” has generated for the Alvin J. Siteman Cancer Center since 2005,” Dr. Eberlein said. “We are extremely grateful for their generosity and that of the footwear industry and QVC’s customers, who help our researchers continue their groundbreaking work.”

Since its inception, QVC Presents “FFANY Shoes on Sale” has sold over 1.8 million pairs of shoes and generated more than $50 million to benefit leading breast cancer research and education institutions. Designated as the event’s “Special Pink Benefactors,” Nine West Group, Caleres, Camuto Group and Marc Fisher Footwear each donated shoes worth more than $500,000. Their contributions included brands such as Nine West, Anne Klein, Easy Spirit, Via Spiga, Franco Sarto, Naturalizer, Vince Camuto, BCBGMAXAZRIA, Jessica Simpson, Guess, Tommy Hilfiger and Ivanka Trump. 

*The manufacturer’s suggested retail price is based on supplier’s representation of value. No sales may have been made at this price. 

About QVC

QVC, Inc., a wholly owned subsidiary of Liberty Interactive Corporation (NASDAQ: QVCA, QVCB), is the world’s leading video and ecommerce retailer. QVC is committed to providing its customers with thousands of the most innovative and contemporary beauty, fashion, jewelry and home products. Its programming is distributed to approximately 360 million homes worldwide through operations in the U.S., Japan, Germany, United Kingdom, Italy, France and a joint venture in China. Based in West Chester, Pa. and founded in 1986, QVC has evolved from a TV shopping company to a leading ecommerce and mobile commerce retailer. The company’s website, QVC.com, is ranked among the top general merchant Internet sites. QVC, Q, and the Q Ribbon Logo are registered service marks of ER Marks, Inc.

About the Fashion Footwear Charitable Foundation 

The Fashion Footwear Charitable Foundation was created to support ongoing research and education programs in the fight against breast cancer and is supported by members of the Fashion Footwear Association of New York (FFANY). Donated footwear is sold on live television through QVC during the Fashion Footwear Charitable Foundation’s annual charity benefit, QVC Presents “FFANY Shoes on Sale.” Funds are distributed to leading breast cancer research and education institutions across the United States, including beneficiaries for the 2015 event: The Abramson Cancer Center of the University of Pennsylvania, The Breast Cancer Research Foundation, The Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, The Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, The University of Michigan Comprehensive Cancer Center’s Breast Oncology Program, The University of Pittsburgh Cancer Institute, The Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, The Margie and Robert E. Petersen Breast Cancer Research Program at the John Wayne Cancer Institute at Providence Saint John’s Health Center. The Fashion Footwear Charitable Foundation makes its home at 274 Madison Avenue, Suite 1701, New York, NY 10016, www.FFANY.org. 

About Siteman Cancer Center 

Siteman Cancer Center, ranked among the top cancer treatment centers by U.S. News & World Report, also is one of only a few cancer centers in the country to receive the highest rating of the National Cancer Institute (NCI) – exceptional. Comprising the cancer research, prevention and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, Siteman is Missouri’s only NCI-designated Comprehensive Cancer Center and the state’s only member of the National Comprehensive Cancer Network.

Potential drug target identified for deadly brain cancer

Glioblastoma is the most common and deadly form of brain cancer in adults, with an average survival time of only 15 months after diagnosis. New research at Washington University School of Medicine in St. Louis provides clues to why some patients with glioblastoma fare worse and identifies a drug target that potentially could improve survival.

The research shows that glioblastoma patients with a protein called oncostatin M receptor on their tumors face a particularly poor prognosis. Further, the findings suggest that treatments that target the receptor have the potential to halt progression of the especially aggressive tumor.

The research is available online in Nature Neuroscience.

“None of the treatments developed for glioblastoma over the past decades has been effective,” said senior co-corresponding author Azad Bonni, MD, PhD, the Edison Professor of Neuroscience and head of the Department of Neuroscience at Washington University. “We wanted to go back to the basic science and understand how these tumors arise so that we can identify new targets for potential therapy.”

Tumors arise when cells accumulate mutations that allow them to escape normal constraints and start multiplying uncontrollably. The typical tumor cell carries mutations in multiple genes, and the effect of mutating one gene can depend on which other genes also are mutated in the cell.

For example, earlier work by Bonni and colleagues at Harvard Medical School had shown that a protein called STAT3 protects against tumor formation, unless a mutated form of another protein, epidermal growth factor receptor (EGFR), is present. In such cases, STAT3 switches from protecting against tumor growth to actively promoting tumors.

More than half of glioblastoma tumors contain mutations in the gene for EGFR or the sections of DNA that control how much EGFR is produced. Researchers reasoned that since mutated EGFR promotes tumor formation, inhibiting it should shrink tumors. Drugs that target EGFR, however, have had little effect on the survival of glioblastoma patients.

“It looked like we were missing something in the EGFR-STAT3 pathway,” Bonni said. “If inhibiting EGFR didn’t work, maybe it was because we needed to hit something else, too.”

Using brain tumor stem cells derived from human tumors, Arezu Jahani-Asl, PhD – lead author of the study and an assistant professor at McGill University – and colleagues looked for other genes in the pathway. They found that the oncostatin M receptor, a protein associated with cell proliferation, was produced in cells that carried both STAT3 and the mutated form of EGFR. Furthermore, the receptor paired up with the mutated EGFR to trigger the production of even more of the receptor in a positive feedback loop.

“Oncostatin M receptor started looking like an important target because it amplifies the EGFR pathway, which we already know is important in glioblastoma,” Bonni said. “But before going further, we asked, ‘Is this really relevant to human patients?’”

Two publicly available databases collect information about the molecules expressed on tumors from individual patients and how long those patients survived. In both datasets, the researchers found that the more oncostatin M receptor on the tumor, the sooner the patient died.

The researchers then removed the receptor gene from human brain tumor stem cells and injected the modified cells into mice. The cells lacking the receptor formed tumors a fraction of the size of those formed by the same human brain tumor stem cell line with the receptor, indicating that the protein plays a key role in tumor formation, growth or both.

“Being able to stop tumor formation entirely was a dramatic and shocking result,” said senior co-corresponding author Michael Rudnicki, PhD, a professor at the University of Ottawa. “It means that this protein is a key piece of the puzzle and could be a possible target for future treatments.”

Scientists now are looking for drugs that can inhibit the receptor or block its interaction with EGFR. Such drugs potentially could lengthen survival times for glioblastoma patients.

“It really gets down to personalized medicine,” Bonni said. “People whose tumors don’t express the receptor wouldn’t see an effect. But for people who overexpress the receptor, blocking it might really help.”

Treating prostate cancer with precision

The treatment, called focal needle ablation, makes use of a needle that can freeze (cryoablation) or use heat (radiofrequency ablation) to destroy cancer cells.

In the past, when a biopsy—the standard diagnostic procedure for the past 20 years—detected a small amount of prostate cancer, it wasn’t known whether the cancer was small or whether the biopsy had grazed the side of a large tumor. Erring on the side of caution, urologic surgeons would make a large incision in the abdomen to remove the entire prostate. As treatment options advanced, the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine was among the first centers in the United States to perform laparoscopic, nerve-sparing radical prostatectomy for most patients with prostate cancer. During the past decade, treatment of small cancers has taken another step forward, with urologists using needle ablations to freeze and kill cancerous areas in the prostate.

“We’ve come to recognize that radical prostatectomy or radiation to treat the entire prostate can be overtreatment. And overtreatment results in too many side effects and unnecessary costs,” says Gerald Andriole Jr., MD, chief of the Division of Urologic Surgery. “If we can tailor the treatment to the man’s individual cancer, he will benefit, and the treatment will be more efficient.”

Cryoablation: The “male lumpectomy”

Washington University urologic surgeons at Barnes-Jewish Hospitalfirst used cryoablation as an investigational treatment and now use it in about 10 percent of prostate cancer cases. They also use cryoablation for focal treatment of kidney and liver cancer.

For prostate cancers, the treatment process begins with a biopsy and ultrasound to determine the size and location of the cancer. Optimally, magnetic resonance imaging (MRI) is used to confirm the cancer’s location and determine that it truly is localized.

During a cryoablation procedure, the urologic surgeon, using ultrasound guidance, inserts one or two cryoneedles below the scrotum and into the prostate. The needles freeze small pear-shaped areas that include the cancerous parts of the gland. The treatment is performed as an outpatient procedure, and most patients are well enough to return to work the next day.

“In the last few years, our targeting has improved as imaging technology has advanced,” says urologic surgeon Sam Bhayani, MD. “We work closely with radiologists at Washington University’s Mallinckrodt Institute of Radiology,  who use advanced 3 Tesla MRI and ultrasound technology.”

The procedure is known as male lumpectomy because it preserves a major part of the prostate, just as a lumpectomy to treat breast cancer preserves most of the breast tissue. Urologic surgeons take great care to avoid the rectum and the nerves needed for erections, which are located just outside the prostate. “You need very detailed, continuous monitoring when you are performing cryoablation,” says Andriole.

Vascular-targeted photodynamic therapy

Washington University urologists have completed a clinical trial to evaluate what may be the next advancement in focal ablation: vascular-targeted photodynamic therapy (VTP).

In VTP, an intravenously injected drug adheres to the capillaries that provide blood supply to tumors. These capillaries, which help the cancer grow, differ from blood vessels associated with healthy tissues. Laser energy released from a fiber placed next to the cancer-supplying capillaries blocks the blood vessels, which interrupts blood flow to the cancer and kills tumor tissue.

“Cancers have a growth pattern that’s a lot like a tree,” says Andriole. “There’s a good deal of normal prostate tissue in between the tentacles and branches of the cancer. When you perform cryoablation, you’re making a pear-shaped ice ball that kills everything inside the ball—cancerous and normal tissue. There are likely more side effects with cryoblation than with VPT, in which you’re more selectively killing the cancer.”

The Food and Drug Administration will review data from the VTP clinical trial at Washington University and elsewhere. If the therapy is approved, it will be offered at Siteman Cancer Center.

Identifying aggressive cancers

To determine the best treatment options, Washington University urologists are investigating new ways to determine which prostate cancers are slow-growing and which are more aggressive.

Pathologists have traditionally relied on Gleason scoring to measure cancer aggressiveness. Looking under a microscope at multiple biopsy specimens taken from different areas of a patient’s prostate, they categorize tumor patterns on a scale of 1 to 5, with 5 being the most aggressive. The two top scores are added, with a final range of 2 to 10.

But Gleason scores aren’t always accurate, so Andriole and a team of scientists at The Elizabeth H. and James S. McDonnell III Genome Institute at Washington University are looking at the genetic makeup of prostate cancers.

“When we remove a cancerous prostate, there are, on average, at least five separate cancers in it,” Andriole says. “Are the genes that these different cancers express the same or different? If they are different, how can we use those differences to more precisely characterize the aggressiveness of a man’s cancer?”

Siteman Cancer Center unveils new, state-of-the-art mammography van

Mobile mammography services continue to move forward in the St. Louis region with unveiling of Siteman Cancer Center’s new mammography van.

Equipped with high-resolution 3-D digital technology, the van provides the same advanced imaging that patients receive at Siteman’s four St. Louis area mammography clinics. Washington University radiologists who specialize in breast imaging read all Siteman mammograms, whether the exam takes place in the van or at a clinic.

“Mammography is known to reduce a woman’s risk of dying from breast cancer by an estimated 30-40 percent or more,” said Catherine Appleton, MD, chief of breast imaging at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. “But it matters where you receive your mammogram. Our team of physicians specializes in comprehensive breast imaging, and our van delivers that lifesaving expertise to women throughout the region.”

The 40-foot van is the fourth in three decades for Siteman Cancer Center.

In 2015, the mammography van served nearly 4,000 women at more than 100 sites:

  • 1,287 women at 35 office parks and other corporate locations;
  • 1,239 women at 40 community locations, including Schnucks and Shop ‘n Save grocery stores and YMCAs; and
  • 1,369 medically underserved women through our outreach program at 30 additional sites throughout the area.

“Siteman Cancer Center celebrates a long history of providing world-class care to our patients, and that certainly includes women who come to us for their mammograms,” said Timothy J. Eberlein, MD, Siteman’s director. “Mammography is the best test for identifying breast cancer before it can be felt – when the cancer is more likely to be curable.”

3-D imaging, also called tomosynthesis, uses X-rays to create multiple images. Then a computer digitally recreates the breast, allowing the radiologist to page through the scans on a computer screen like pages in a book or on an iPad or Kindle.

“This technology allows us to essentially see through the breast, one millimeter at a time,” Appleton said. “This has been shown both to reduce false alarms and to help reveal more breast cancers.”

Each exam takes about 20 minutes, and the exam fee is billed to the patient, her insurance company or Medicare. Results are reported to the patient and her physician within seven to 10 days.

The National Comprehensive Cancer Network (NCCN), an alliance of 26 of the nation’s leading cancer centers, recommends yearly mammograms for women age 40 and older with an average risk of developing the disease.

The Siteman Cancer Center van is certified by the U.S. Food and Drug Administration and is sponsored in partnership with Washington University’s Mallinckrodt Institute of Radiology, whose board-certified radiologists review all digital mammography images.

To make an appointment, call 1-800-600-3606 toll-free. Women should bring their insurance card to the appointment. For those without insurance, assistance is available. Call 314-454-8466 for more information.

For more information about mammography van dates and locations, visit http://sitemanmammogram.wustl.edu.

Washington University leads national effort to improve radiation therapy for U.S. veterans

Washington University School of Medicine in St. Louis has been selected to lead national efforts to improve and standardize radiation therapy for veterans with cancer.

The goal is to ensure that veterans across the U.S. receive the same high-quality radiation therapy at any of the 40 Veterans Health Administration (VHA) radiation oncology centers nationwide. Working with the American Society for Radiation Oncology, Washington University radiation oncologists — members of Siteman Cancer Center — are developing a system to provide continuous feedback on the progress, quality and safety of each veteran’s cancer therapy.

The VHA, an arm of the U.S. Department of Veterans Affairs, is the country’s largest integrated health-care system, serving more than 8 million veterans each year.

“We are pleased to be taking a lead role in managing this program,” said Jeff M. Michalski, MD, the Carlos Perez Distinguished Professor of Radiation Oncology and a member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “We have significant experience working with the National Cancer Institute to provide platforms for assessing quality and standards of care for patients, and we are excited to work with the American Society for Radiation Oncology to bring that experience to bear on behalf of our nation’s veterans.”

Along with surgery and chemotherapy, radiotherapy is a major treatment method for a variety of cancer types. About 60 percent of all cancer patients receive some form of radiation therapy.

The new program is called the Radiation Oncology Practice Assessment Program. In the first year, radiation oncologists will set up the infrastructure required to evaluate quality of care for veterans undergoing treatment for lung and prostate cancers. To provide detailed evaluations for individual patients, the program will rely on new information technologies that will draw on the VHA’s electronic medical record system as well as treatment management systems that control and track how radiation is delivered to each patient.

Much of the software that will enable this new reporting system was developed by Radialogica, a St. Louis-based health-care information technology company co-founded by Washington University faculty.

The new program will provide VHA radiation oncologists with detailed analyses of their patients’ treatments, compared with national standards. The feedback also will include traditional measures of cancer therapy outcomes, including patient survival and tumor recurrence. The aim is to provide oncologists with complete and consistent snapshots of each patient’s therapy and response to the treatment on a continuous basis.

Once the new program is fully in place, VHA radiation oncologists will receive continuously updated electronic reviews of each patient’s cancer evaluation, treatment and outcome.

The new automated system goes well beyond the current periodic review process, according to the developers. Instead of analyzing physician performance, the new system focuses on the patient, allowing doctors to see how changes in clinical practice, radiation planning, delivery technology and radiation dose prescription impact the success of a patient’s therapy.

“We are pleased to be working with leading organizations on this innovative program, the first of its kind nationwide,” said Maureen McCarthy, MD, Veterans Affairs acting assistant deputy undersecretary for health and patient-care services. “Our veterans deserve nothing less.”