New pathway identified as a target for precision medicine against a common brain tumor

November 2, 2017

St. Jude Children's Research Hospital scientists have discovered a promising target for precision medicines to block a mechanism that drives several cancers, including about 30 percent of cases of the brain tumor called medulloblastoma. The findings appear online today in the scientific journal Developmental Cell.

Medulloblastoma develops in the cerebellum at the back of the brain and occurs in about 400 children and adolescents annually in the U.S. That makes it the most common malignant pediatric brain tumor. Medulloblastoma is less common in adults. In about 30 percent of patients, the signaling pathway called Sonic Hedgehog is inappropriately switched on and drives cell proliferation. The pathway is normally active in the brain during fetal development.

St. Jude researchers have shown that just as manufacturers rely on suppliers to keep assembly lines running, the Sonic Hedgehog pathway depends on another pathway, the mTORC1 pathway, to function.

Investigators reported that inhibiting mTORC1 disrupted the Sonic Hedgehog signaling pathway and significantly extended the lives of mice with the medulloblastoma that is driven by Sonic Hedgehog signaling. Researchers used an investigational drug to inhibit mTORC1. The drug, INK128, is in clinical trials for treatment of another brain tumor, glioblastoma, and other solid tumors.

"The role of mTORC1 in the Hedgehog pathway was unexpected and highlights the mTORC1 pathway as a potentially important molecular target for developing much needed precision medicines for patients with the Sonic Hedgehog medulloblastoma subtype," said corresponding author Young-Goo Han, Ph.D., an assistant member of the St. Jude Department of Developmental Neurobiology. "The results also raise hopes for combination targeted therapies to improve outcomes and ease treatment side effects."

Current treatment of medulloblastoma involves surgery, radiation and chemotherapy and fails to cure 20 to 30 percent of patients. Therapy also often has debilitating life-long consequences for survivors. An investigational drug that blocks Smoothened, a key protein in the Hedgehog signaling pathway, has shown promise for treatment of medulloblastoma. But not all medulloblastoma patients with the Sonic Hedgehog subtype respond to the inhibitor, and those who do eventually become resistant to the drug.

mTORC1 is an enzyme complex that anchors one branch of the MTOR pathway. Like the Sonic Hedgehog pathway, the MTOR pathway helps regulate cell growth and proliferation. Mutations in the MTOR pathway have also been linked to cancer, but the pathway's role in Hedgehog signaling has been unclear.

Using genetic, biochemical and pharmacological tools, Han and his colleagues showed that mTORC1 is part of a previously unrecognized step in the Hedgehog signaling pathway. Loss or inhibition of mTORC1 suppressed Hedgehog signaling in the brains of mice and inhibited medulloblastoma growth even in mice resistant to a Sonic Hedgehog inhibitor in clinical use for treatment of medulloblastoma and basal cell cancer.

Researchers demonstrated that the Hedgehog pathway depended on mTORC1 to free up cellular machinery to synthesize proteins including the Smoothened protein, a key component of the Hedgehog pathway. Protein synthesis is suppressed by a protein called 4EBP1. mTORC1 tagged (phosphorylated) 4EBP1 with a molecule of phosphate. That released the suppression and promoted synthesis of Smoothened, which plays a pivotal role in the unchecked signaling that is a hallmark of SHH medulloblastoma. But the importance of Smoothened protein synthesis or mTORC1's role in the process had not previously been recognized.

Researchers checked human medulloblastoma tumor samples and found elevated levels of phosphorylated 4EBP1 protein in two medulloblastoma subtypes—SHH and as well as the WNT medulloblastoma subtype. Those and other results suggest that mTORC1 may influence tumor development in other, still unknown ways.

Researchers showed that INK128 inhibited phosphorylation of 4EBP1 via mTORC1 in medulloblastoma, which results of this study suggest should block synthesis of Smoothened. Levels of Smoothened declined in mice treated with INK128. So did levels of another protein, GLI1, whose production is tied to Sonic Hedgehog signaling.

mTORC1 inhibition with INK128 even extended the lives of mice resistant to the that targets Smoothened. "These two targeted therapies act synergistically using different mechanisms to inhibit the Sonic Hedgehog ," Han said. "That suggests combination therapy offers a promising strategy for cancers like that are driven by abnormal Sonic Hedgehog signaling."

Explore further: Researchers identify a key controller of biological machinery in cell's 'antenna'

Related Stories

Researchers identify a key controller of biological machinery in cell's 'antenna'

June 6, 2017
St. Jude Children's Research Hospital molecular biologists have identified an enzyme that activates and "supercharges" cellular machinery that controls how cells become specialized cells in the body.

Targeted therapy shows effectiveness against a subtype of the brain tumor medulloblastoma

July 29, 2015
A targeted therapy already used to treat advanced skin cancer is also effective against the most common subtype of the brain tumor medulloblastoma in adults and should be considered for treatment of newly diagnosed patients, ...

Promising drug target identified in medulloblastoma

March 26, 2015
Scientists at Dana-Farber/Boston Children's Cancer and Blood Disorders Center have identified a protein critical to both the normal development of the brain and, in many cases, the development of medulloblastoma, a fast-growing ...

Blocking a protein in a critical signaling pathway could offer a new way to combat tumors

August 10, 2016
Cancer drugs that block a cell-signaling pathway called Hedgehog have shown promise in recent years in treating patients with skin cancer, leukemia and other types of tumors. But the available treatments mostly target the ...

Scientists create animal model for pediatric brain tumor

April 13, 2016
Sanford Research scientists are published in Nature Cell Biology for their work developing a model to explore therapies for a pediatric brain tumor known as choroid plexus carcinoma.

Sonic Hedgehog protein causes DNA damage and the development child brain tumors

October 14, 2014
Scientists at the IRCM and the University of Montreal discovered a mechanism that promotes the progression of medulloblastoma, the most common brain tumour found in children. The team, led by Frédéric Charron, PhD, found ...

Recommended for you

Researchers unravel novel mechanism by which tumors grow resistant to radiotherapy

November 23, 2017
A Ludwig Cancer Research study has uncovered a key mechanism by which tumors develop resistance to radiation therapy and shown how such resistance might be overcome with drugs that are currently under development. The discovery ...

African Americans face highest risk for multiple myeloma yet underrepresented in research

November 23, 2017
Though African-American men are three times more likely to be diagnosed with multiple myeloma, a type of blood cancer, most scientific research on the disease has been based on people of European descent, according to a study ...

One-size treatment for blood cancer probably doesn't fit all, researchers say

November 22, 2017
Though African-American men are three times more likely to be diagnosed with a blood cancer called multiple myeloma, most scientific research on the disease has been based on people of European descent, according to a study ...

Encouraging oxygen's assault on iron may offer new way to kill lung cancer cells

November 22, 2017
Blocking the action of a key protein frees oxygen to damage iron-dependent proteins in lung and breast cancer cells, slowing their growth and making them easier to kill. This is the implication of a study led by researchers ...

One in four U.S. seniors with cancer has had it before

November 22, 2017
(HealthDay)—For a quarter of American seniors, a cancer diagnosis signals the return of an old foe, new research shows.

Combination immunotherapy targets cancer resistance

November 22, 2017
Cancer immunotherapy drugs have had notable but limited success because in many cases, tumors develop resistance to treatment. But researchers at Yale and Stanford have identified an experimental antibody that overcomes this ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.