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TGen-Barrow study shows drug penetration of glioblastoma

Innovative ‘Phase 0’ clinical trial successful in reaching deadly brain tumors

PHOENIX, Ariz. — May 24, 2018 — In a first-of-its-kind clinical trial, a drug called AZD1775 was shown to penetrate deadly glioblastoma brain cancer cells, according to a study conducted at Barrow Neurological Institute and initiated by the Translational Genomics Research Institute (TGen).

Glioblastoma catapulted into the public spotlight in recent months after Arizona’s U.S. Sen. John McCain was diagnosed with this aggressive cancer, which has a median survival time of just 12-16 months.

The study of 20 patients at Barrow was published today in the scientific journal Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR).

This so-called “Phase 0” clinical trial showed that AZD1775 could penetrate the blood-brain-barrier that protects the brain from toxins but also blocks most anti-cancer drugs.

“This Phase 0 approach for malignant brain tumors is a game changer in cancer research and our program is the first of its kind in the world,” said Dr. Nader Sanai, M.D., the study’s lead author, a brain tumor surgeon at Barrow Neurological Institute who also directs Barrow’s Brain Tumor Research Center, and co-Director of the Brain Tumor Early-Phase Clinical Trials Unit at TGen. “This study confirms the utility of Phase 0 trials as part of an accelerated paradigm for drug development in glioma patients.”

Unlike other clinical trials, which in successive phases assess a drug’s safety, dosage, side effects, and effectiveness, Phase 0 clinical trials simply check to see if a drug can get to its target and in what concentration.

This study’s findings set the stage for additional clinical trials, in which AZD1775 could be paired with temozolomide (TMZ), the primary chemotherapy given to glioblastoma patients.

“The hope is that these drugs — AZD1775 and TMZ — could work in tandem to exploit a particular genetic vulnerability discovered by TGen in certain glioblastoma tumors,” said Dr. Michael Berens, Ph.D., a TGen Deputy Director, a co-Director of TGen’s Early-Phase Clinical Trials Unit, and one of the study’s authors.

TGen research showed that disruption of a particular cell-cycle function known as the G2 checkpoint — which otherwise repairs DNA — can leave glioblastoma cells vulnerable to DNA-damaging agents such as TMZ and radiation therapy.

“Cancer cells divide unceasingly, instead of eventually dying as they should. Controlled cell death is crucial for normal human development and good health. A drug that could help arrest cells from continuing to divide out of control could be a benefit to patients with cancer, including brain cancer,” said Dr. Harshil Dhruv, Ph.D., TGen Assistant Professor, and one of the study’s authors.

This study was almost sidetracked by a competing study that appeared to show in laboratory models that AZD1775 could not cross the blood-brain barrier, a layer of ultra-small capillaries that protects the brain from most toxins and hormonal surges.

“We decided, ‘Let’s find out if it’s true in humans.’ It looks like AZD1775 gets across the blood-brain barrier,” said Dr. Berens, who also is Director of TGen’s Cancer and Cell Biology Division and TGen’s Glioma Research Lab.

Dr. Patricia LoRusso, D.O., Associate Director of Experimental Therapeutics at Yale Cancer Center, said the results of the AZD1775 test shows that the often time-consuming drug-testing process — which can take a decade or more for FDA approval — can be accelerated by using Phase 0 clinical trials.

“Phase 0 clinical trials could become a significant part of a true paradigm shift in cancer drug development, which will be necessary to reach the ultimate goal of attaining significant increases in patient benefit and survival,” said Dr. LoRusso, the study’s senior author.

Each of the study’s 20 patients had previously received the current FDA-approved standard of care, including surgery to remove their brain tumors, followed by radiation treatment and TMZ. Each patient’s cancer had returned. Each was then given varying doses of AZD1775 at various times just prior to subsequent operations to remove tumors that had grown back.

Despite recent advances in understanding glioblastoma, survival statistics have not significantly improved over the past three decades. This year, nearly 17,000 Americans will die of brain and other nervous system cancers.

Glioblastoma multiforme, or GBM, is the most common primary tumor of the brain and central nervous system. One of the first treatments for glioblastoma is surgical removal of the tumor. However, because of the aggressive way glioblastomas invade surrounding brain tissue, it is impossible to surgically remove all parts of the tumors. The cancer eventually returns and spreads, inevitably killing the patient.

“This new study brings hope to the thousands of glioblastoma patients around the world who are counting on us to find better treatments, and eventually a cure, for this devastating disease,” said Catherine (Bracken) Ivy, President and Founder of The Ben & Catherine Ivy Foundation, which provided significant funding for this study.

The American Society of Clinical Oncology (ASCO) and the U.S. Public Health Service also helped fund this study, Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients.

Also contributing to this study was the Barbara Ann Karmanos Cancer Institute at Wayne State University.

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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 $82 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.

About Barrow Neurological Institute
Barrow Neurological Institute at Dignity Health St. Joseph's Hospital and Medical Center is an internationally renowned medical center that offers care for people from throughout the world with brain and spine diseases, disorders and injuries. More brain surgeries are performed at Barrow than any hospital in the United States and the Institute trains more neurosurgeons than anywhere in the world. Barrow is also the busiest operative brain tumor center in the United States. St. Joseph's is consistently voted among the top hospitals in the United States for neurology and neurosurgery. For more information about Barrow, visit barrowneuro.org.

About TGen
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 FacebookLinkedIn and Twitter @TGen.

Media Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]


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