Metabolic processes in cancer cells may unlock therapeutic potential for glioblastoma

important point

  • Glioblastoma is a lethal brain tumor with few treatment options and a poor prognosis for most patients.
  • A UCLA-led team has identified a genetic mutation that occurs in 60% of people diagnosed with glioblastoma. The mutation disrupts cancer cell metabolism.
  • This finding suggests that one possible approach to treat glioblastoma is therapeutics that target metabolic processes in patients with genetic mutations.

Targeting metabolic processes in people with specific genetic mutations could help treat glioblastoma, an aggressive brain tumor, in a study led by researchers at UCLA Johnson Comprehensive Cancer Center It has been found.

A genetic alteration, a deletion of a gene called CDKN2A, is present in about 60% of glioblastoma patients. This mutation causes changes in the distribution of lipids within cancer cells, making them more susceptible to destruction. The findings, published in Cancer Cell, may point the way toward the development of targeted therapies that specifically target that vulnerability.

“Each patient’s tumor may have a unique combination of genetic alterations,” said David Geffen, co-senior author of the study and associate professor of molecular medicine and pharmacology at the University of California, Los Angeles. David Nathanson said. “All of these tumors are different, so we need to understand how specific genetic alterations affect tumor metabolism to identify potential targets for future therapies.”

Scientists believe that disrupting cancer cell metabolism—the way cancer cells process energy and nutrients to survive, grow, and invade healthy cells—is a new and effective treatment. I think it could be one of the keys.

Nathanson, who is also a member of the Johnson Cancer Center, said the development of new treatments for glioblastoma is essential. Glioblastoma is a rapidly growing, fatal brain tumor that currently has few treatment options. A person diagnosed with a brain tumor has a life expectancy of only 12-15 months, and only about 5% of people diagnosed with glioblastoma are alive five years after his diagnosis. Both President Joe Biden’s son Bo and Senator John McCain died of the disease.

Looking for possible patterns in how cancer cells process fat, which could indicate that cancer cells may be vulnerable to drugs, the researchers analyzed data from 84 glioblastoma tumors, 42 human cell lines, and 30 glioblastoma mouse models. They found several abnormalities in CDKN2A, a gene that is mutated in the majority of glioblastoma patients.

They found that this gene rewired lipid metabolism to work differently than cells without the genetic modification. Also, if the CDKN2A gene is defective, the way cancer cells process fat makes them more susceptible to cell death, or ferroptosis.

The researchers then used drugs to target this process and found that glioblastoma cells with mutations in CDKN2A were highly susceptible to cell death, whereas glioblastoma cells without mutations It was found not to respond to drugs.

“We found that CDKN2A may be a key regulator of cancer cell metabolism, despite its deletion in other types of cancer. has not been shown before,” Nathanson said. “Importantly, we found that CDKN2A deletion rewires lipid metabolism not only in our model but also in glioblastoma patient tumors. It shows that it may be a therapeutic target for patients with blastoma.”

Although there are no existing drugs that can penetrate the brain to target the process the UCLA scientists studied, Nathanson said the study provides a strong rationale for developing drugs.

Steven Bensinger, Shelley and Donald Morrison’s professor of immunology and co-senior author of the study, said another important aspect of the study was that diet and other lifestyle factors He said it could shed new light on how it affects cancer progression and how patients respond to cancer. treatment.

“Our data show that CDKN2A-deficient cancer cells alter the type of lipids they use to build their cell membranes, and that this difference can be used to kill tumors,” Bensinger said. rice field. “This raises the intriguing possibility that prescribing a special diet with the ‘wrong’ lipids may make it more responsive to treatment or reduce tumor growth.”

The database of 156 glioblastoma samples analyzed by the researchers is now available to researchers worldwide. The research team also expanded the number of samples in the database to more than 500, allowing scientists to identify further relationships between cancer-fighting genes and specific types of lipids used in brain cancer. I hope it helps.

Another co-senior author of the study is Scott Dixon of Stanford University. Co-authors are UCLA PhD candidates Jenna Minami and Nicholas Bailey, and Daniel Morrow, who will complete his PhD at UCLA in 2021. Other co-authors are Elizabeth Fernandez, Jennifer Salinas, Christopher Tse, Henan Zhu, Baolong Su and Leah Prawat. , Anthony Jones, Alessandro Sanmarco, Dr. Linda Liau, Thomas Graeber, Kevin Williams, and Dr. Timothy Krausey, all of UCLA.

This study was funded in part by grants from the National Institutes of Health and the Department of Defense.

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