A team of scientists at Fred Hutchinson Cancer Research Center will lead an initiative launched June 27 by the National Cancer Institute to advance the use of targeted proteomics and genomics against the most lethal gynecological malignancy, ovarian cancer.
The new Proteogenomic Translational Research Centers, or PTRCs, established by the NCI’s Office of Cancer Clinical Proteomics Research, or OCCPR, involves teams of researchers and oncologists across the U.S. and aims to integrate proteomics with genomics (“proteogenomics”) into NCI clinical trials.
“We envision that PTRCs will collaborate with NCI-sponsored clinical trials to expand/deepen our knowledge of drug response and resistance, ultimately improving our understanding of the cancer and tumor proteome,” said Dr. Henry Rodriguez, director of OCCPR.
At Fred Hutch, Dr. Amanda Paulovich is co-principal investigator of a team that will use recent technological advances in collecting and analyzing massive proteogenomic data sets to find ways to better match ovarian cancer patients with treatments that will work.
“Despite advances in chemotherapy and surgery, the overall survival of patients with ovarian cancer has not significantly changed in decades,” said Paulovich, a member of the Clinical Research Division at Fred Hutch. “This is because drug-resistant cancer cells enable tumors to keep growing.”
Some 239,000 women are diagnosed and 152,000 die around the world each year from ovarian cancer, according to the World Health Organization’s GLOBOCAN project.
About 20 percent of women with ovarian cancer are resistant to the standard of care, a platinum-based chemotherapy.
“Ovarian cancer by nature is often diagnosed at a late stage. Unfortunately, there’s no way to know ahead of time whether the initial treatment will work,” said Dr. Michael Birrer, co-principal investigator with Paulovich on the new grant. Birrer is an ovarian cancer doctor who has more than 30 years of clinical trial and translational research experience. He leads the gynecological cancer program at Massachusetts General Hospital, and later this year he will become director of the University of Alabama at Birmingham Comprehensive Cancer Center.
“If the treatment doesn’t work the patients can be left too sick to participate in a clinical trial,” Birrer said. “This project has the potential to identify biomarkers to predict these patients and to identify pathways that will provide novel therapeutic targets.”
Previous studies have tried to find a predictor of treatment response and have failed, possibly because they were looking at only the genome or were only able to look at one protein at a time, Paulovich said.
“There’s no one mechanism of resistance; we’re going to look at the entire network of proteins and genes that together have a role,” said Paulovich, who’s also a professor of medicine in the Division of Oncology at the University of Washington School of Medicine.
She and her collaborators believe that technological advances in large-scale proteogenomics that can look at many biological markers at once will be able to reveal how a particular person’s tumor resists chemotherapy.
“I am very excited about the talented team we’ve put together for this important project,” Paulovich said. Co-investigators on the team are:
- Mayo Clinic: Drs. Scott Kaufmann, John Weroha and Larry Karnitz
- Massachusetts General Hospital: Dr. Steven Skates
- Icahn School of Medicine at Mount Sinai: Drs. Pei Wang and Eric Schadt
- Harvard Medical School: Dr. Steven Gygi
- University of Washington School of Medicine: Dr. Andrew Hoofnagle
For the new five-year project, Paulovich and her collaborators will first develop large-scale proteogenomic data on ovarian tumor samples and identify which proteins are linked to chemotherapy resistance. Then Paulovich’s lab will develop targeted proteomic assays, or tests, that measure the tumor proteins of interest. The researchers will use the biological assays they’ve developed in clinical trials with ovarian cancer patients.
“The goal at the end of five years is to know if there’s a signature that we can use to determine who will respond to platinum-based chemotherapy,” Paulovich said. “It would be great if we also are able to identify new possible therapeutic targets to help overcome treatment resistance.”
In a different project announced earlier this year, her lab is developing assays for measuring proteins important for immunotherapies. These assays initially will be tested in lung cancer, but they may be applicable to many cancer types.
Since 2007, Paulovich’s lab at Fred Hutch has been a part of NCI’s Clinical Proteomic Tumor Analysis Consortium, or CPTAC, which supports proteogenomics research collaborations across the U.S.
“Proteogenomics has great potential to unleash new insights in oncology,” said Rodriguez of the NCI. “The combination of proteomic, transcriptomic and genomic data can now reproducibly identify proteins in cancer genomes that were difficult or not possible to infer by genomics alone.”
— Molly McElroy / Fred Hutch News Service
Photo by Robert Hood / Fred Hutch News Service
Pancreatic cancer specialist Dr. Sunil Hingorani was awarded a two-year, $1 million peer-reviewed research grant this week from the Pancreatic Cancer Action Network that will support his work to develop more effective, cutting-edge therapies for patients with these tumors.
“It is especially gratifying to win this award because of the sponsoring organization, the nature of the review process involving an independent panel of the leading pancreas cancer experts in the country, and the translational potential of the work,” said Hingorani, who is the Raisbeck Chair for Pancreatic Research at Fred Hutchinson Cancer Research Center. “This award is a testament to the hard work and accomplishments of the entire research team.”
In addition to being hard to detect, pancreatic cancers are also unusually resistant to all current forms of chemotherapy and radiotherapy. Recently, Hingorani and others have begun to identify previously unrecognized processes in the tumor that help to explain their unique behaviors. What the researchers have come to appreciate is that a pancreatic tumor represents a coordinated evolution of a cancer cell together with a number of other cell types and processes that are complicit in its survival. Thus, attacking these supporting processes offers new opportunities for therapies.
For example, Hingorani and his colleagues have identified extremely high pressures inside these cancers that cause the majority of blood vessels inside them to collapse; this makes it difficult to get chemotherapies into the tumor, because they are delivered via the bloodstream. The major component of the supporting matrix inside the tumors that causes these elevated pressures is hyaluronic acid. A strategy to degrade hyaluronic acid inside pancreatic cancers has led to blood vessels opening more widely and chemotherapy entering at higher and more effective concentrations.
The research team also has identified several classes of immune cells that are present from the earliest stages of pancreatic cancer development and that actually help support its growth, rather than inhibit it (by turning off the positive [effector] arm of the immune system). By attacking these cells, Hingorani and others have found that effector immunity can be awakened and actively engage in the fight against this cancer.
In the project funded by this new grant, Hingorani’s team will rigorously measure the effects of different combination strategies of agents that target tumors’ supportive matrix and those that target the cells that suppress patients’ natural immune response to the cancer. His team will then test the top regimen(s) with and without conventional chemotherapy. In the end, the best regimen to emerge from these studies will be ready for large trials in patients, which Hingorani hopes will establish a new standard of care that is more effective than the current treatment paradigm.
“The last few years have seen enormous progress in understanding the role of the microenvironment and surrounding cells that conspire with the tumor cells to create a ‘neo-organ,’” Hingorani said. “The goal of the current proposal is to investigate strategies to target some of these critical processes, how best to combine these strategies and in what order, and identify the most robust regimens to then advance into the clinic through the Precision Promise initiative.”
Precision Promise is a precision-medicine endeavor for pancreatic cancer clinical trials that was launched last fall with philanthropic funds raised by the Pancreatic Cancer Action Network. Hingorani is the principal investigator of the initiative’s Fred Hutch site, one of 12 nationwide.
The latest award, called the 2017 Pancreatic Cancer Action Network Precision Medicine Targeted Grant, is the third Hingorani has received from the organization. It is the Pancreatic Action Network’s first precision-medicine–focused grant in the 15 years of its Research Grants Program and one of 17 grants the organization made this year to 21 researchers at 12 U.S. institutions.
“Dr. Hingorani is using a powerful approach to identify ways to fight pancreatic cancer from multiple angles,” said Dr. Lynn Matrisian, chief science officer at the Pancreatic Cancer Action Network. “This kind of work is so critical to finding breakthroughs for patients and helping us to double survival by 2020.”
— Adapted from a Pancreatic Cancer Action Network release
Photo by Robert Hood / Fred Hutch News Service
Last week, more than 170 clinicians, scientists and medical trainees converged in Seattle for a two-day conference on research to counter infectious diseases that threaten the lives of patients whose immune systems are weakened by illness or treatments meant to heal them. The second annual Symposium on Infectious Diseases in the Immunocompromised Host was a deep dive into the complex technologies available to detect opportunistic infections and the growing array of strategies to prevent or treat these diseases that for decades have challenged bone marrow, blood stem cell and solid organ transplantation therapies.
“Stem cell transplantation is an incredibly complicated medical procedure, possibly ranking up there as the most complex,” said symposium organizer Dr. Michael Boeckh of Fred Hutchinson Cancer Research Center. “Knowledge of immunology, donor and host factors, infections — often the cumulative effect of multiple viruses — makes it complicated but also scientifically exciting. I think the people who attended this symposium really learned something.”
Boeckh is head of the Hutch’s Infectious Disease Sciences Program, which hosted the symposium. The group was established during the pioneering days of bone marrow transplantation. Its aim was to help blood cancer patients whose immune systems were replaced with the healthy ones of their donors, but who often succumbed to common viral infections before they could recover from the procedure.
This year’s conference drew speakers and participants from as far as Australia, Japan, Sweden and Brazil, including a contingent of Fred Hutch alums who went on to become leaders of infectious disease programs at other leading cancer centers. It was organized around five key topics of critical interest to infectious disease doctors treating patients with weakened immune systems:
- Vaccines and immunotherapies: An update on efforts to prevent infection by the viruses posing the highest risk to transplant patients; and on efforts to fight the emergence of such infections by using living immune cells that can be targeted to specific microbes.
- Fungal infections: Common fungal infections such as yeast and Aspergillus are a danger to transplant patients and are costly to treat.
- The microbiome: Communities of bacteria that inhabit the gut interact in complex ways with the immune system, and changes in the makeup of these bugs can affect transplant survival.
- Respiratory viruses: Viruses that cause croup or the common cold in healthy populations can be deadly to vulnerable patients.
- Cytomegalovirus, or CMV: It stands out among the most common and dangerous viruses for immunocompromised patients, and it continues to be the focus of vaccine and antiviral research.
Researchers at the symposium repeatedly cited a lineup of half a dozen viruses that cause the most heartache to transplant patients and their families. Many are members of the herpesvirus family, better known for a range of maladies such as cold sores, genital herpes, chickenpox and shingles. In addition to CMV, the bad actors in this family include Epstein-Barr virus (known for mononucleosis) and human herpesvirus 6. These infections may lie dormant in either the transplant recipient or the donor but can roar back while a patient is recovering from the transplant or taking immune-suppression drugs later on.
One theme that emerged was the importance of tracking multiple viral infections in patients. About 90 percent of patients acquire one viral infection in the first 100 days after blood stem cell transplant, noted Fred Hutch researcher Dr. Joshua Schiffer. About 28 percent have three infections. “The timing, when you start to see multiple viruses, is about three months after transplant,” he said. “Three or more is the danger zone.” When a fourth infection shows up, the odds of survival drop.
This has stimulated the development of drugs that target multiple viruses, as well as of immunotherapy “cocktails” of T cells that can be marshalled against them. Dr. Ann Leen, of the Baylor University Center for Cell and Gene Therapy, presented her ongoing work on this strategy. The techniques involved are similar to approaches taken to harness the body’s T cells to fight cancer.
Other presentations touched on new, more affordable drugs for treating immune-compromised patients with respiratory infections and the results, first reported in February, of a Phase 3 clinical trial of a new drug to prevent CMV infection in patients about to have blood stem cell transplants. That experimental drug, called letermovir, was linked to lower infection rates and higher survival compared to a placebo.
By design, the symposium is also an eye-opener for up-and-coming doctors and scientists. Attendee Ryan Reyes, a third-year medical student at the University of Texas at San Antonio, was drawn to cancer care in part because his mother-in-law died from complications of breast cancer. “I hadn’t heard about opportunities in infectious diseases,” he said. “But in fact it merges well with oncology.” Reyes was one of 55 trainees awarded competitive travel stipends to attend the conference.
The first symposium was launched last year in honor of the late Dr. Joel Meyers, who founded the Hutch’s Infectious Disease Sciences Program. A third Symposium on Infectious Diseases in the Immunocompromised Host is already in the works, tentatively scheduled for Seattle in June 2019.
— Sabin Russell / Fred Hutch News Service
Photo courtesy of Seattle Cancer Care Alliance
Dr. Kathleen Shannon Dorcy, a staff scientist in the Clinical Research Division at Fred Hutch and director of Clinical Nursing Research, Education and Practice at Seattle Cancer Care Alliance, the Hutch’s clinical care partner, has been named a fellow of the American Academy of Nursing. This is the first time in SCCA’s history that one of its nurses has achieved "Fellow – American Academy of Nursing," or FAAN, status, according to a June 26 SCCA statement.
“Kathleen has dedicated her career to advancing the practice standards that are critical for the delivery of excellent nursing care throughout the Seattle Cancer Care Alliance,” said Norm Hubbard, executive vice president of SCCA.
Shannon Dorcy joins the ranks of nearly 2,400 internationally recognized FAAN nursing leaders representing all 50 states, the District of Columbia and 24 countries. The American Academy of Nursing will induct its next group of 173 fellows in October during its annual policy conference in Washington, D.C.
Invitation to participate in FAAN reflects recognition of individual achievements in nursing education, management, practice and research. FAAN fellows contribute time and talent to the American Academy of Nursing to transform health policy and practice. Shannon Dorcy plans to dedicate time and energy to the reduction of health care disparities.
Shannon Dorcy attributes her selection to the Academy to mentoring and support she received from others across the continuum of her practice. “My career accomplishments have not been realized alone. My family, my colleagues and students have all contributed greatly to my professional career success,” she said.
Shannon Dorcy joined Fred Hutch in 1989 as a research nurse on the bone marrow transplant team, where she worked with Dr. Fred Appelbaum, a world expert in blood cancers. "I have had the pleasure of working closely with Kathleen and watching her excel at every level, from helping me run my clinical trials to developing her own independent research and, ultimately, leading other nurses to create their own research careers,” said Appelbaum, executive vice president and deputy director of Fred Hutch. “All of us are grateful to have Kathleen as a colleague.”
Shannon Dorcy earned a doctorate in oncology nursing from the University of Utah, obtained a master’s in nursing in community health and ethics from the University of Washington and a bachelor of science in nursing from Seattle University.
She continues to dedicate her career to the pursuit of nursing excellence; her leadership roles include membership in the Sigma Theta Tau International Nurse Faculty Leadership Academy, the Daisy Foundation Scholarship Review Board and collaborating with nurses in Guam and Uganda. Her published and presented works include more than 35 articles in journals such as the Clinical Journal of Oncology Nursing, Advances in Nursing Science and presentations at more than 80 conferences.
“Kathleen is a legend who dedicates her time and talents to influence nursing excellence with the purpose to ameliorate the suffering caused by cancer,” said Dr. Theresa M. McDonnell, chief nurse executive and vice president of Clinical Operations at SCCA. “She influences and continually reflects an unwavering commitment to delivering the most compassionate patient care while pursuing a quest to improve treatment outcomes through research. We are grateful to benefit from the example she sets every day in all of her work and interactions.”
In addition to her appointments at SCCA and Fred Hutch, Shannon Dorcy is a senior lecturer at the University of Washington School of Nursing in Tacoma, where she has taught for the past 25 years.
— Based on a Seattle Cancer Care Alliance news release