New drug combination targets aggressive blood cancer
GRAND RAPIDS, Mich. (March 7, 2017)–A pair of drugs that may be a one-two punch needed to help combat acute myeloid leukemia (AML), an aggressive blood cancer that kills nearly three-fourths of patients within five years of diagnosis, is the focus of a new multi-center clinical trial that will enroll patients at three sites across the U.S.
The trial pairs an investigational PARP inhibitor, talazoparib, with the DNA methyltransferase (DNMT) inhibitor decitabine, which is already approved for the treatment of myelodysplastic syndrome (MDS), a disease that often precedes AML. Preclinical studies show that combining the drugs may maximize their ability to kill cancer cells.
"Long-term survival with AML is quite poor and, unfortunately, our arsenal for treating it has remained largely unchanged for decades," said Feyruz Rassool, Ph.D., an associate professor of radiation oncology at the University of Maryland School of Medicine, a researcher at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, and a member of the Van Andel Research Institute-Stand Up To Cancer (VARI-SU2C) Epigenetics Dream Team. "Combination therapies, such as talazoparib and decitabine together, allow us to attack cancer from multiple angles at the most basic level for a greater potential effect."
A paper published last fall in Cancer Cell, which describes the laboratory studies that laid the foundation for the trial, discusses how PARP and DMNT inhibitors enhanced each other when used in combination, rather than individually. Now, the new trial seeks to investigate this promising treatment approach for potential delivery into clinics and hospitals for patients who are suffering from AML.
"The trick with PARP is that it has to arrive at the site of the damage, fix it, and then go away. If it gets trapped there, it kills the cell," said Stephen Baylin, M.D., co-leader of the VARI-SU2C Epigenetics Dream Team, along with VARI's Peter Jones, Ph.D., D.Sc., co-head of Cancer Biology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and a Director's Scholar at VARI. "The same goes for molecules called DNA methyltransferases, which are important for regulating how genetic instructions are read and acted upon. We found that the DNA methyltransferase actually increases the time that PARP gets trapped at the sites of DNA damage, increasing the effectiveness of the PARP inhibitor."
AML begins as abnormal blood cells in the bone marrow and spreads throughout the circulatory system and beyond, if not diagnosed and treated quickly. Almost 20,000 people in the U.S. are diagnosed with AML every year.
"Acute myeloid leukemia is difficult to treat, especially in older patients and in patients who do not respond to initial treatment or who relapse," said Maria Baer, M.D., professor of medicine at the University of Maryland School of Medicine, director of Hematologic Malignancies and co-leader of the Experimental Therapeutics Program at the University of Maryland Greenebaum Comprehensive Cancer Center, who is leading the trial. "We hope that this new treatment regimen will help AML patients for whom effective treatments are not currently available."
The trial is now underway at the University of Maryland Greenebaum Comprehensive Cancer Center in Baltimore and will soon open at Temple University Fox Chase Cancer Center in Philadelphia and University of Southern California in Los Angeles, all affiliated with the VARI-SU2C Epigenetics Dream Team.
The DMNT inhibitor, decitabine, is already FDA-approved to treat MDS and is often used as an off-label chemotherapy for AML. The investigational PARP inhibitor, talazoparib, is being supplied by Medivation, a wholly owned subsidiary of Pfizer, Inc., and is not yet approved by the FDA.
In addition to AML, the combination therapy also has potential to treat other cancers, including those in the breasts and ovaries.
"Our work also shows promise in ovarian cancer and breast cancer–particularly triple-negative breast cancer, which is notoriously difficult to treat," Rassool said. "If this first clinical trial is successful, we hope to expand our studies to help more patients."
To date, the VARI-SU2C Epigenetics Dream Team has launched four clinical trials in different cancers, including AML, MDS and metastatic colorectal cancer. Following SU2C's revolutionary paradigm, the team unites leading investigators and industry partners from around the world to compete against cancer rather than against each other.
CLINICAL TRIAL DETAILS
Clinical trial name: Decitabine and talazoparib in untreated AML and R/R AML
ClinicalTrials.gov identifier: NCT02878785
Number of patients: 171
Clinical sites: University of Maryland Greenebaum Comprehensive Cancer Center, Fox Chase Cancer Center and University of Southern California
ABOUT THE VAN ANDEL RESEARCH INSTITUTE-STAND UP TO CANCER EPIGENETICS DREAM TEAM
The Van Andel Research Institute-Stand Up To Cancer (VARI-SU2C) Epigenetics Dream Team fosters collaboration between several of the world's most respected research and clinical organizations in an effort to translate scientific discoveries into new standards of patient care. The goal is simple–get new and more effective cancer therapies to patients faster.
The VARI-SU2C Epigenetics Dream Team was established in 2014 and builds on the foundations laid by the first iteration of the SU2C Epigenetics Dream Team, which was founded in 2009. Today's team is based at Van Andel Research Institute in Grand Rapids, Michigan, and is led by the Institute's Chief Scientific Officer Peter Jones, Ph.D., D.Sc., and Stephen Baylin, M.D., VARI Director's Scholar and co-head of Cancer Biology at Johns Hopkins University's Sidney Kimmel Comprehensive Cancer Center. The team includes leading scientists and clinicians with vast experience in translating basic science and promising therapies from the lab to the clinic.
The team is honored to be affiliated with Stand Up To Cancer, a program of the Entertainment Industry Foundation. Launched in 2008, SU2C draws on the resources of the entire entertainment industry to encourage the public to support research conducted by teams of scientists, as well as by individual investigators. To date, more than 1,200 researchers from more than 140 institutions in seven countries have collaborated across SU2C's 19 Dream Teams, six Translational Research Teams and 36 Innovative Research Grants.
Rigorous and objective scientific oversight and review is provided by SU2C's scientific partner, the American Association for Cancer Research (AACR), the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer.
ABOUT VAN ANDEL RESEARCH INSTITUTE
Van Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 360 scientists, educators and staff. Van Andel Research Institute (VARI), VAI's research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson's and other diseases and translating those findings into effective therapies. The Institute's scientists work in onsite laboratories and participate in collaborative partnerships that span the globe. Learn more about Van Andel Institute or donate by visiting http://www.vai.org. 100% To Research, Discovery & Hope®
ABOUT STAND UP TO CANCER
Stand Up To Cancer® (SU2C) raises funds to accelerate the pace of research to get new therapies to patients quickly and save lives now. SU2C, a program of the Entertainment Industry Foundation (EIF), a 501(c)(3) charitable organization, was established in 2008 by film and media leaders who utilize the industry's resources to engage the public in supporting a new, collaborative model of cancer research, and to increase awareness about cancer prevention as well as progress being made in the fight against the disease. As SU2C's scientific partner, the American Association for Cancer Research (AACR) and a Scientific Advisory Committee led by Nobel Laureate Phillip A. Sharp, PhD, conduct rigorous, competitive review processes to identify the best research proposals to recommend for funding, oversee grants administration, and provide expert review of research progress.
Current members of the SU2C Council of Founders and Advisors (CFA) include Katie Couric, Sherry Lansing, Lisa Paulsen, Rusty Robertson, Sue Schwartz, Pamela Oas Williams, Ellen Ziffren, and Kathleen Lobb. Noreen Fraser and the late Laura Ziskin are also co-founders. Sung Poblete, PhD, RN, has served as SU2C's president since 2011.
For more information on Stand Up To Cancer, visit http://www.standup2cancer.org.
Beth Hinshaw Hall