TGen Starts First-in-Patient Trial to Test the Feasibility of Molecular Profiling in Glioblastoma

The Scottsdale, Arizona, based Ben & Catherine Ivy Foundation, has awarded $10 million in grants for two groundbreaking brain cancer research projects at TGen, the Translational Genomics Research Institute. One of those projects has officially received the final regulatory approval from the University of California, San Francisco, which means patient enrollment for the trial can begin.

In the $5 million project, TGen and its partners will lead first-in-patient clinical trial studies that will test promising new drugs that might extend the survival of Glioblastoma patients. This multi-part study will take place in clinics across the country and TGen laboratories.[1]

Glioblastoma Multiforme or GBM is a disease that needs answers now, and we strongly believe those answers will be found in the genome...

Glioblastoma multiforme
Glioblastoma multiforme or GBM is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors.

"GBM is one of the top three fastest-killing cancers out there and it affects people of all ages," explained Catherine (Bracken) Ivy, founder and president of The Ben & Catherine Ivy Foundation. "It is critical that we fund research that will help patients live longer so we can study and treat brain cancer."

Clinical trial
The project begins with a pilot study of 15 patients, using whole genome sequencing to study their tumor samples to help physicians determine what drugs might be most beneficial.

Genomic data
To support molecularly informed clinical decisions, TGen labs also will examine genomic data from at least 536 past cases of glioblastoma, as well as tumor samples from new cases, developing tools that will produce more insight into how glioblastoma tumors grow and survive. TGen also will conduct a series of pioneering lab tests to measure cell-by-cell responses to various drugs.[1]

"We need answers Now"
"GBM is a disease that needs answers now, and we strongly believe those answers will be found in the genome," noted David W. Craig, PhD, TGen's Deputy Director of Bioinformatics, Director of TGen's Neurogenomics Division, and one of the projects principal investigators. "Identifying the genes that contribute to the survival of glioblastoma will provide valuable information on how to treat it, and may also lead to an improved understanding of what drives other cancers as well."

To get new treatments to patients as quickly as possible, this five-year study will include a feasibility study involving up to 30 patients, followed by Phase II clinical trials with as many as 70 patients. TGen is teaming with the Ivy Early Phase Clinical Trials Consortium that includes: University of California, San Francisco; University of California, Los Angeles; the MD Anderson Cancer Center; Memorial Sloan Kettering Cancer Center; University of Utah; and the Dana-Farber/Harvard Cancer Center.

The results of these clinical trials should not only help the patients who join them, but also provide the data needed for FDA approval and availability of new drugs that could benefit tens of thousands of brain cancer patients in the future.

Understanding treatment in context
"Working with physicians, the project will aim to understand treatment in the context of the tumor's molecular profile. We will have the opportunity to determine when combinations of drugs might be more effective than using a single drug, quickly identify which therapies don't work, and accelerate discovery of ones that might prove promising for future development," explained John Carpten, PhD, TGen's Deputy Director of Basic Science, Director of TGen's Integrated Cancer Genomics Division, and another of the project's principal investigators.

Other studies
TGen is also involved in other studies looking at AZD1775 (MK1775) a new drug that may offer a a possible treatment for glioblastoma. AZD1775 is a small molecule inhibitor of the tyrosine kinase WEE1 with potential antineoplastic sensitizing activity. The WEE1 inhibitor MK-1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x rays to kill tumor cells.[2]

One of the trials is designed to test how much of AZD1775 is present in tumor, blood, and skin after one dose of the drug. The purpose of the study is not to treat the tumor, but to see if the drug actually gets into the tumor cells. [2] Another trial  studies the side effects and best dose of WEE1 inhibitor MK-1775 when given together with radiation therapy and temozolomide in treating patients with newly diagnosed or glioblastoma multiforme that has come back. Because drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing, adding AZD1775/MK-1775 together with radiation therapy and temozolomide may work better in treating glioblastoma.

MK-1775 selectively targets and inhibits WEE1, a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDC2) to inactivate the CDC2/cyclin B complex. Researchers have shown that the inhibition of WEE1 activity prevents the phosphorylation of CDC2 and impairs the G2 DNA damage checkpoint. This may lead to apoptosis upon treatment with DNA damaging chemotherapeutic agents.

Unlike normal cells, most p53-deficient or mutated human cancers lack the G1 checkpoint as p53 is the key regulator of the G1 checkpoint and these cells rely on the G2 checkpoint for DNA repair to damaged cells. Annulment of the G2 checkpoint may therefore make p53-deficient tumor cells more vulnerable to antineoplastic agents and enhance their cytotoxic effect. [3]

In addition to helping patients as quickly as possible, research to test the feasibility of new treatments for GBM significantly expands Arizona's network of brain cancer experts.

For more information
[1] A Pilot Trial Testing the Feasibility of Molecular Profiling in Recurrent/Progressive Glioblastoma (NCT02060890) [Study Record Detail]
[2] A Phase 0 Study of AZD1775 in Recurrent GBM Patients (NCT02207010) [Study Record Detail]
[3] WEE1 Inhibitor MK-1775, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme (NCT01849146) [Study Record Detail]

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