- Posted Tuesday October 17, 2017
Use of arsenic trioxide could extend survival of some glioblastoma patients
PHOENIX, Ariz. - Oct. 17, 2017 - From Sherlock Holmes to Agatha Christie, arsenic is often the poison of choice in popular whodunits. But in ultra-low dosage, and in the right form, this naturally occurring chemical element can be a potent force against cancer.
Arsenic trioxide for years has been used to fend off a rare subtype of blood cancer known as acute promyelocytic leukemia (APL). Now, in a study led by Northwestern University Feinberg School of Medicine and the Translational Genomics Research Institute (TGen), this anti-cancer agent is being considered for use against glioblastoma multiforme (GBM), the most common and aggressive type of deadly brain tumors. The study was published today in Molecular Cancer Research, a journal of the American Association for Cancer Research (AACR).
"Our findings show that, for some patients, arsenic trioxide could be a powerful therapy that could extend the lives of certain glioblastoma patients by as much as three to four times the median expectation," said Dr. Harshil Dhruv, an Assistant Professor in TGen's Cancer and Cell Biology Division and one of the study's authors.
Median survival of glioblastoma patients is only 15 months, and survival statistics have improved only minimally over the past three decades. An estimated 17,000 Americans will die this year of brain and other nervous system cancers.
The origin of this new study had all the serendipitous turns of a good mystery novel.
TGen had recently identified arsenic trioxide among a library of 650 compounds that could potentially be used against different subtypes of glioblastoma. While Dr. Dhruv was presenting these findings at a scientific conference, he met Dr. Jonathan Bell, who at the time was a graduate student in the Medical Scientist Training Program (MSTP) at Northwestern University. He described his work, showing resistance of a specific subtype of GBM against arsenic trioxide. In two clinical studies they examined, the therapeutic effects of arsenic trioxide were initially dismissed. But as Drs. Dhruv and Bell drilled down into the studies, they discovered that a specific subtype of GBM cells were more responsive to the arsenic trioxide treatment.
Northwestern was involved in one of the clinical trials, which tested the efficacy of arsenic trioxide in combination with temozolomide (TMZ) and radiation in treatment of GBM. Researchers at Northwestern were able to share biospecimens from their clinical trial with TGen.
"We were then able to identify these particular patients as having the same genomic signatures as those we had tentatively identified in our computer and laboratory screenings of potential therapies," Dr. Dhruv said.
The next step will be to validate the findings published in Molecular Cancer Research by initiating a new clinical trial specifically designed to match arsenic trioxide with glioblastoma patients that have a specific genomic signature, according to Dr. Michael Berens, a TGen Deputy Director and Professor in TGen's Cancer and Cell Biology Division, and one of the study's authors. These patients also would receive TMZ, which is the current standard-of-care drug given to GBM patients.
"This is an amazing convergence of complimentary thinking," Dr. Berens said. "We tripped over a clinical partner who said, 'Oh, we've already done the (preliminary) clinical trial.' "
"We sought to identify compounds that specifically disrupt the growth of different GBM molecular subtypes," said Dr. Leonidas Platanias, Director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern's Feinberg School of Medicine, and the study's senior author.
Researchers reassessed the earlier clinical trials and zeroed in on mesenchymal (MES) and proneural (PN) glioma subtypes, whose genomic signatures differ according to distinct underlying misbehaving genes.
"Arsenic trioxide was found to be the most potent compound in non-MES GBM cells. We found that PN GBM patients responded better to ATO (arsenic trioxide) than any other subtypes as demonstrated by longer overall and progression-free survival," said Dr. Bell, the study's lead author.
Researchers identified two additional advantages of using arsenic trioxide.
First, it is a small molecule able to penetrate the network of ultra-small capillaries - the blood-brain barrier - that surrounds the brain and spinal fluid and protects the central nervous system from most toxins and spikes in hormones. It is this barrier that prevents most other anti-cancer drugs from attacking brain tumors.
Second, its costs are minimal, since its source material, arsenic, is abundant in nature.
"Rather than treat all patients, we want to design a prospective clinical trial that we can enrich for those patients whose genomic signatures indicate they would be the best candidates for success," Dr. Dhruv said. "This would be a biomarker-driven, precision-medicine clinical trial for glioblastoma - a way to match the right drug to the right patient."
Also contributing to this study were: Prairie View A&M University, the Jesse Brown Veterans Administration Medical Center, the Ann & Robert H. Lurie Children's Hospital of Chicago, and the University of Alabama.
Funding for this study - Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy is Regulated by MNK1 and mRNA Translation - was provided by grants from the National Institutes of Health (CA121192, 41 CA77816, and CA155566, U01CA168397), the Department of Veterans Affairs (I01CX000916), and The Ben & Catherine Ivy Foundation.
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About The Ben & Catherine Ivy Foundation
The Ben & Catherine Ivy Foundation, based in Scottsdale, Ariz., was formed in 2005, when Ben Ivy lost his battle with glioblastoma multiforme (GBM). Since then, the Foundation has contributed more than $70 million to research in gliomas within the United States and Canada, with the goal of better diagnostics and treatments that offer long-term survival and a high quality of life for patients with brain tumors. The Ben & Catherine Ivy Foundation is the largest privately funded foundation of its kind in the United States. For more information, visit www.ivyfoundation.org.
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with neurological disorders, cancer, diabetes, and infectious diseases, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. TGen is affiliated with City of Hope, a world-renowned independent research and cancer and diabetes treatment center: www.cityofhope.org. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. For more information, visit: www.tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.
TGen Senior Science Writer
About Northwestern University Feinberg School of Medicine
Northwestern University Feinberg School of Medicine is a top 20 medical school where nationally recognized scientists collaborate with skilled clinicians to improve human health. More than 3,400 faculty members teach, practice medicine, and conduct research at the medical school, which is a central component of Northwestern Medicine, a premier academic health system.
Founded in 1876, Prairie View A&M University is the second oldest public institution of higher learning in the state of Texas. With an established reputation for producing engineers, nurses and educators, PVAMU offers baccalaureate degrees in 50 academic majors, 37 Master's degrees and four doctoral degree programs through nine colleges and schools. A member of the Texas A&M University System, the University is dedicated to fulfilling its land-grant mission of achieving excellence in teaching, research and service.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 37,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 108 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 21,900 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit www.AACR.org.