NCI Funds UH Rainbow Team to Study Drug Aimed at Protecting Cancer Patients from Treatment-Related Brain Effects

Innovations in Pediatrics | Summer 2023

Pediatric oncologist John Letterio, MD, has spent years witnessing and worrying about the late effects of cancer treatment on children and teens – and searching for ways to prevent them. It’s well established that treatment aimed at eradicating cancer in a young patient often has harmful effects on the developing brain and other organ systems, even with the most modern protocols. One study, for example, documented rates of hearing loss, abnormal cholesterol levels, hormonal dysfunction and abnormal lung function at more than 60 percent among adult survivors of childhood cancer, to say nothing of cancer-induced cognitive impairment.

John Letterio, MD

“We need strategies to mitigate the late effects of our lifesaving treatments,” says Dr. Letterio, who is Division Chief of Pediatric Hematology & Oncology at UH Rainbow Babies & Children’s Hospital and the Jane and Lee Seidman Chair in Pediatric Cancer Innovation.

Now, one of the key projects Dr. Letterio has worked on for decades to address this critical issue is reaching a crucial new stage. Continuing 30 years of work he pursued with his late mentor Michael Sporn, MD, Dr. Letterio and his research teams at UH Rainbow and Triterpenoid Therapeutics, Inc. have been awarded a new contract from the National Cancer Institute (NCI) to test a promising new drug candidate called 2P-Im for its ability to prevent brain-related late effects of cancer treatment – one of the few contracts to be issued by the NCI’s Small Business Innovation Research and Development Center for this purpose.

The Drug in Question

The UH Rainbow team will complete the pre-clinical testing of a drug that directly targets the brain aging process thought to be caused by chemotherapy and radiation therapy, known as senescence-associated secretory phenotype (SASP).

“There is now substantial evidence supporting the role of the pro-inflammatory, senescence-associated secretory phenotype (SASP) as a major contributor to cognitive aging and other age-related diseases and cancer-induced cognitive impairment,” Dr. Letterio says. “If you have an accumulation of activated microglia in the brain and they're increasingly senescent, they can cause a chronic inflammatory state that may be associated with aging and with neurodegenerative diseases like Alzheimer's and Parkinson's. With cancer therapy and children, much of what we see in our survivors is almost a premature aging phenotype. Importantly, studies have demonstrated the potential of senolytic agents to reduce chemotherapy-induced microglial activation, reduce expression of SASP factors and to thereby improve age-associated and therapy-related cognitive impairment.”

The molecule under study is a fifth-generation synthetic triterpenoid, a derivative of the natural triterpenoid oleanolic acid, and developed by Dr. Sporn, Dr. Letterio and others through the company Triterpenoid Therapeutics, Inc. Dr. Letterio says it’s one of the most potent synthetic triterpenoids developed to date and shows promise as a senotherapeutic – a drug that targets senescent cells. Just this year, a drug from this family, omaveloxone, was approved by the U.S. Food and Drug Administration for treatment of the rare neurodegenerative disease Friedrich's ataxia.  

“This will pave the way to the clinic for other drugs in this family,” Dr. Letterio says.

Study Details

For the study, Dr. Letterio and his team are addressing three main questions. They will determine whether oral administration of 2P-Im to laboratory animals can suppress therapy-induced production of SASP factors, whether it can limit accumulation of senescent cells, and whether it can prevent chronic microglial activation, thereby preserving cognitive function following administration of either chemotherapy or radiation therapy.

He says there’s every indication that 2P-Im will perform well.

“2P-Im is representative of a novel class of molecules that are orally bioavailable, safe, non-toxic and highly potent suppressors of the specific molecules known as the SASP that are responsible for late effects of cancer treatment,” he says. “Our prior studies have shown the ability of these drugs to be neuroprotective in models of multiple sclerosis. These studies set the stage for our current effort to show that this class of drugs can protect cancer patients from the neurotoxicity of cancer therapy. The SBIR contract that we were awarded from the National Cancer Institute was one of the highest scored applications and is supporting our studies to show this potential to prevent toxicities of cancer therapy.”

Dr. Letterio says he’s energized by the work ahead.

“I’m enthusiastic about what we’re doing,” he says. “Obviously we need to develop a good data set. But it could be that administration of the drug 2P-Im for a defined period of time before a chemotherapy dose may be enough to reduce the risk of some of the therapy-associated toxicities. That’s what we're trying to define and demonstrate right now. We have observed a positive effect on preserving cognitive function in rodents exposed to chemotherapy at a young age, so we have some very promising early data. I think six months from now we'll be in a very good position. The goal for this effort is to provide enough data to suggest that this is a valuable drug to advance to the next stage of development.”

For more information about this project, please email Peds.Innovations@UHhospitals.org.

Contribution Expert:
John Letterio, MD
Division Chief, Pediatric Hematology & Oncology
UH Rainbow Babies & Children’s Hospital
Director, Angie Fowler Adolescent and Young Adult Cancer Institute
Jane and Lee Seidman Chair in Pediatric Cancer Innovation
Professor of Pediatrics
Case Western Reserve University School of Medicine