Dawn of a New Era for Aggressive Brain Tumors

Relapsed brain tumors have been difficult to treat, but a new approach at St. Jude offers a ray of hope.

By Corey Carmichael; Photo by Justin Veneman

The founder of St. Jude Children’s Research Hospital said it first: “No child should die in the dawn of life."  So when doctors created a new plan to save children with the most aggressive brain and spinal cord tumors, the choice was clear: The clinical trial would be called SJDAWN.

“We called it DAWN as a play on Danny Thomas’ phrase,” explains St. Jude oncologist Giles Robinson, MD, “but we also wanted to signify a new age of treatment.”

This study aims to improve cure rates for children with malignant brain tumors that fail to respond to treatment or that return after therapy. Most clinical trials for such children evaluate only one drug. SJDAWN proposes a new approach to treating these tumors. Clinicians will combine promising therapies based on tumor type and the molecular characteristics of the child’s tumor.

SJDAWN proposes a new approach to treating malignant brain tumors that fail to respond to treatment or that return after therapy. Clinicians combine promising therapies based on the tumor’s type and molecular characteristics.

 
 

Journey to St. Jude

SJDAWN is designed for patients like Chelsea McKita, whose brain tumor has returned three times in 11 years.

Chelsea still remembers that day in the seventh grade, when her parents arrived at the principal’s office to check her out of school after a CT scan startled her physicians.

“Cancer was not on my mind whatsoever,” she says. “I remember seeing my parents sitting there, but don’t remember anything after that until we were halfway to the hospital in Pittsburgh. Even then, brain surgery was not on my mind.”

Doctors found a golf-ball sized mass at the base of her brain. Chelsea had medulloblastoma, a brain tumor that starts at the base of the skull, but also tends to spread to other parts of the brain and to the spinal cord.

After surgery, chemotherapy and radiation, Chelsea was declared cancer-free in spring 2008. Unfortunately, that’s not where her cancer journey ended.

Medulloblastoma returned during her junior year of college. This time, the tumor lodged at the base of her spine and the frontal lobes of her brain. Nearly a year later, Chelsea was once again in remission.

It would not be long before the cancer came back yet again, just as she returned to college in August 2017.

“I feel like the hospital experience has been my life since I was 13,” Chelsea says.

Then her family found St. Jude.

Giles Robinson, MD, consults with patient Chelsea in an exam room

Moving discoveries into the clinic

Giles Robinson, MD (at right), consults with Chelsea McKita, who has enrolled in SJDAWN.

With knowledge comes options

“We had a biopsy done in June of 2018 at the National Institutes of Health,” says Chelsea’s mother, Heather McKita. “Before that biopsy, we had all these straws to grasp at with clinical trials, but that biopsy took all of our straws down to one – and that was St. Jude.”

The only clinical trial that could offer Chelsea hope was SJDAWN.

Robinson is the primary investigator for SJDAWN and treats brain tumor patients at St. Jude. He is optimistic about how enriched molecular analysis and genomic sequencing can provide new targets for treatment and can teach oncologists more about these tumors.

“It’s fantastic that we can look at the molecular construct of tumors and potentially dictate therapy,” Robinson says. “The more we do it and the more we understand, the more targets we’re going to find, the more potential medicine to help these patients.”

It’s fantastic that we can look at the molecular construct of tumors and potentially dictate therapy. 

Giles Robinson, MD

 
 

The one-two punch

Once a team of pathologists, led by Brent Orr, MD, PhD, analyze a patient’s tumor, they help the oncologists assign the child to one of three treatment arms tailored for that tumor type.

Each treatment plan is based on a “doublet” therapy, combining two drugs. Every child in SJDAWN receives a medication called ribociclib. This drug is a cell-cycle inhibitor, which prevents the signal (the cell cycle) that tells a cancer cell to grow and divide. If scientists can stop this process, they can stop the tumor’s progression.

Clinicians combine this cell-cycle inhibitor with a helper drug tailored to each child’s tumor type and treatment group. This type of drug combination has been tremendously successful in treating adults with breast cancer. In that case, ribociclib was combined with estrogen therapy.

In SJDAWN, one of three helper drugs is given along with ribociclib. These drugs are called gemcitabine, trametinib and sonidegib. Gemcitabine has been used to treat adults with ovarian, breast, lung and pancreatic cancer. The other two drugs have been approved by the FDA to treat adults with certain types of skin cancer.

Leading the way

In the lab, St. Jude tumor cell biologist Martine Roussel, PhD; Clinton Stewart, PharmD, of Pharmaceutical Sciences; and other scientists showed that the cell- cycle inhibitor would be a viable option when paired with the helper drugs used in SJDAWN. With ribociclib as the base, the team hopes to block the transition of the cancer cells’ growth cycle and stop the rapidly dividing cells.

“Most successful cancer treatments have used a cocktail (or mixture) of medicines because aggressive cancers tend to be resistant to single medicine therapy since the cancer cells have a lot of built-in escape routes. This doublet therapy is not that much different in theory, but the drugs are newer and hopefully more precise at killing these particular brain tumor cells,” Robinson explains.

After many years of treating children with recurrent brain tumors, Amar Gajjar, MD, chair of St. Jude Pediatric Medicine, sees this type of therapy as a positive step for treating children who otherwise might have no hope for cures.

“We’ve got a big initiative at St. Jude to use targeted combination therapies,” Gajjar says. “It’s positioning our program and our institution to lead the way in providing new therapeutic approaches.”

From Promise, Winter, 2019

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