Targeting mTOR pathway can improve the effectiveness of chemotherapies for pediatric brain cancer

Two experimental drug approaches targeting vulnerabilities in cancer cell metabolism may extend survival and increase the effectiveness of standard chemotherapies for a highly aggressive form of childhood brain cancer.

The findings were reported by researchers at the Johns Hopkins Kimmel Cancer Center in two published studies.

Medulloblastoma is the most common malignant brain tumor in children. A subgroup of patients with tumors, known as group 3 MYC-amplified medulloblastoma, has an overall survival rate of less than 25%.

In these patients, the cancer-promoting MYC oncogene stimulates cancer cell growth by altering the metabolism of cancer cells. Cancer cells use energy differently than normal cells, so they are potentially vulnerable to therapies targeting the abnormal metabolic pathways downstream of MYC.

In the first study, published March 22 in the Journal of Neuropathology and Experimental Neurology, pediatric oncologist and senior author Eric Raabe, MD, Ph.D., associate professor of oncology at Johns Hopkins University School of Medicine, focused on changing the metabolism drug DON (6-diazo-5-oxo-L-norleucine).

DON is a naturally occurring substance that has been studied in clinical trials of cancer in adults and children since the 1980s, but it has never been systematically tested against MYC-powered brain tumors.

While DON was safe in children in early cancer clinical trials, it is not currently available clinically.

The research team, led by Barbara Slusher, Ph.D., MAS, director of Johns Hopkins Drug Discovery and professor of neurology at Johns Hopkins University School of Medicine, modified DON to increase its ability to cross the blood-brain barrier and create a DON prodrug, JHU395. In a prodrug, the chemistry is changed so that the drug is only activated in cancer cells.

The promise of DON prodrugs is to develop a treatment that would not damage normal cells, but could be delivered preferentially in brain cancer cells. “

Eric Raabe, MD, Ph.D., study senior author and pediatric oncologist, Johns Hopkins University School of Medicine

In one series of experiments, researchers treated human high-MYC medulloblastoma cell lines with JHU395 and with DON. They found that the prodrug effectively suppressed growth and killed the cancer cells at lower concentrations compared to DON alone.

Mice with implanted human medulloblastoma tumors were then treated with JHU395. The researchers found that the treatment resulted in the selective killing of the MYC-controlled cancer cells, while sparing normal brain cells. In addition, treatment with JHU395 significantly prolonged survival. Treated mice lived almost twice as long as mice given a placebo.

“JHU395 is as effective as DON at a lower dose because it has better penetration of brain cancer cells,” says Raabe. “Coming up with a new therapy with potentially reduced side effects means we can combine drugs for better patient survival, and that’s what it’s all about.”

In a second study, published online Feb. 8 in Cancer Letters, Raabe and colleagues from three other cancer research institutions focused on the mammalian rapamycin complexes involved in cell metabolism. The protein mTOR signals cancer cells to grow, invade healthy tissue and resist therapy.

Previous research showed that, in addition to high MYC expression, aggressive pediatric medulloblastoma tumors have high mTOR expression, suggesting to researchers that mTOR inhibitors may have therapeutic value. A bioinformatics drug trial identified TAK228 (aka sapanisertib), a brain-pervasive mTORC1 / 2 kinase inhibitor as a potentially effective drug for children, Raabe says.

Researchers found that TAK228 inhibited mTORC1 / 2, suppressed tumor cell growth by up to 75%, and effectively killed MYC-driven human medulloblastoma cancer cells.

Next, the researchers focused on measuring the abnormal metabolism of MYC-powered medulloblastoma. In cancer, elevated glutathione is an agent that makes tumor cells resistant to chemotherapy. Glutathione specifically causes cells to block the effect of chemotherapy drugs containing platinum, such as cisplatin and carboplatin.

These platinum-containing drugs are some of the major components of medulloblastoma therapy. In human medulloblastoma tumors grown in mice, Raabe and colleagues found that the tumor cells contain more glutathione than normal brain cells. Using the excess glutathione may be one way these cancer cells resist chemotherapy.

The researchers found that the TAK228 mTOR inhibitor disrupted and reduced glutathione synthesis in cancer cells. When they treated mice with high MYC medulloblastoma brain tumors with a combination of TAK228 and carboplatin, the combination effectively killed tumor cells and prolonged survival more than any drug used alone.

Mice treated with combination therapy lived nearly twice as long as control mice. Of the combination-treated mice, 20% were considered very long survivors, living almost 80 days after the start of the experiment, while all control mice died of their tumor within 25 days.

“By targeting the mTOR pathway, TAK228 overcame an important mechanism of resistance that cancer cells have to traditional chemotherapy,” says Raabe. “These MYC-induced cancers make a lot of glutathione – they grow so fast they need a lot of it. TAK228 reduces the amount they can make, making them vulnerable to chemotherapy.”

“These are valuable preclinical data for future studies in children with a combination of mTOR inhibitors and traditional chemotherapy, which may ultimately change the outcomes for children who will be diagnosed with MYC-driven medulloblastoma,” he adds.

Source:

Journal reference:

Pham, K., et al. (2021) Novel glutamine antagonist JHU395 suppresses MYC-driven medulloblastoma growth and induces apoptosis. Journal of Neuropathology and Experimental Neurology. doi.org/10.1093/jnen/nlab018.

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