When brain cells turn cancerous, they acquire a potentially lethal vulnerability, according to new work by Dr. Patrick Paddison and colleagues at Fred Hutchinson Cancer Research Center published in today’s edition of Cell Reports. Using the CRISPR-Cas9 genome editing system to disrupt thousands of proteins in brain tumor cells taken from patient samples, the team discovered that many have lost a backup mechanism that ensures that normal neural precursor cells successfully divide. Surprisingly, these results couldn’t be predicted from profiles of the genetic and molecular changes in the tumor cells.
“There’s a push to sequence everyone’s tumor and use this to predict actionable therapies,” said Paddison, a researcher in Fred Hutch’s Human Biology and Public Health Sciences divisions. “We put precision medicine to the test and found that, by and large, we could not predict the outcome of our screen [using profile data].” Instead, they found that it was the activation of particular molecular pathways that are hallmarks of brain tumors, and not specific genetic changes, that turned two redundant genes into essential ones.
The vulnerability the team identified was a loss of redundancy: normal neural precursor cells rely on two proteins, WEE1 and PKMYT1, to back each other up so that cells properly progress through the cell cycle. The CRISPR-Cas9 screen showed that tumor cells (but not normal cells) died if either protein was rendered non-functional — a potential Achilles' heel the cells had acquired in their march toward cancer. When they forced normal cells to activate molecular pathways that are often overactive in cancer cells, they too became utterly reliant on PKMYT1.
“It tells us we really need to understand how driver mutations give rise to these vulnerabilities in the first place,” Paddison said. The researchers aim to “work backward” from tumor-specific vulnerabilities to their molecular profiles so that this information can, indeed, help doctors tailor therapy.
The project shows that genome editing is a viable strategy to employ to find such essential genes, he said. And most important for patients with glioblastoma, an aggressive form of brain cancer, the findings may open a path toward better, desperately needed new drugs.
“Glioblastoma has one of the worst survival rates of all solid tumors,” Paddison said. He and his colleagues had helped develop growing conditions for patient-derived brain tumor cell lines that allow them retain their tumor characteristics in culture, providing an ideal environment in which to screen for drug targets with real potential to make a difference in patient tumors. The team is currently confirming which of the many — possibly hundreds — of other potential drug targets identified in their screen are also essential to brain tumor survival.
Paddison and co-author Dr. Jim Olson of the Clinical Research Division are collaborating on potential therapeutics to target PKYMT1 and WEE1. In particular, they believe that a sequential approach, in which a therapy against WEE1 is followed by a second therapy against PKMYT1, could capitalize on glioblastoma cells’ weaknesses while also heading off drug resistance.
Dr. Gary Lyman, co-director of the Hutchinson Institute for Cancer Outcomes Research and a member of the Public Health Sciences and Clinical Research divisions at Fred Hutch, has been appointed executive officer to two SWOG committees. SWOG, formerly known as the Southwest Oncology Group, is a National Cancer Institute-funded network of nearly 6,000 physician researchers who design and conduct cancer clinical trials. The group’s goal is to change medical practice so it improves the lives of people with cancer. Fred Hutch houses the SWOG Statistical Center.
Lyman, a medical oncologist and health economist, will serve as executive officer of SWOG’s Symptom Control and Quality of Life and Cancer Care Delivery committees. He will work with the committee co-chairs to set strategic priorities, and facilitate study development and collaboration on NCI National Clinical Trials Network studies. He will also assist with SWOG participation in the newly formed NCI Community Oncology Research Program.
“Our goal is to figure out early which studies should move forward and which should not, given limited resources,” Lyman said, "by assessing whether research proposals are feasible, fulfill unmet clinical needs and support the scientific priorities of the group with the resources at hand."
The fifth edition of what has become recognized as the “bible” in the field of bone marrow transplantation – Thomas’ Hematopoietic Cell Transplantation: Stem Cell Transplantation – will be unveiled later this week at the 57h annual meeting of the American Society of Hematology in Orlando, Florida.
The book’s namesake, the late Dr. E. Donnall Thomas, Nobel laureate and director emeritus of the Fred Hutch Clinical Research Division, edited the first two editions of the seminal transplantation reference book in 1994 and 1999. He also contributed a chapter to the third edition, which was published in 2004.
“Don quite literally wrote the book on marrow transplantation,” said co-editor Dr. Fred Appelbaum, executive vice president and deputy director of Fred Hutch. “Don was a hero. He was, by far, the most influential person in my career, and I know that many others would say the same thing.”
Thomas won the Nobel in physiology or medicine in 1990 for his work in pioneering bone marrow transplantation. Thanks to his efforts and many innovations that have followed, some leukemias that once were a death sentence now have cure rates of up to 90 percent.