Biopharma makes progress against a childhood killer: pediatric glioma

Modifi Bio Co-founders Dr Kingson Lin, Kevin Rakin, Dr Seth Herzon and Dr Ranjit Bindra/courtesy Modifi Bio

September is Childhood Cancer Awareness Month, which highlights the need for new developments in pediatric oncology. For American children, the leading cause of death by disease is cancer. Pediatric gliomas, the most common type of brain tumor in children, are a critical area of ​​focus for oncology research.

A Yale School of Medicine The team recently published a study describing their development of selective DNA crosslinking for tumors agent which targets drug-resistant glioma tumors.

Dr. Ranjit Bindra, MD, Ph.D., co-lead author of the study and the Harvey and Kate Cushing Professor of Therapeutic Radiology at Yale Medicine, said BioSpace there are a number of complexities when it comes to treating pediatric gliomas.

Pediatric brain tumors are unique

First, research on brain tumors in children tends to mirror what has worked in the past for adults, but this approach has many flaws.

“Pediatric brain tumors have very unique tumor mutations and molecular genetics that are distinct from adult tumors, so what works in adults generally won’t work in children,” Bindra explained.

Second, he highlighted the dire unmet need across the board for rare childhood cancers. Although cancers such as medulloblastoma or ependymoma are diagnosed less frequently than others, the malignant outcomes are devastating to families and entire communities.

During her residency at Memorial Sloan Kettering Cancer Center, Bindra witnessed “absolute devastation” from families with children who were diagnosed with rare tumors. “You see a lot of people in absolute shock. They think about their summer plans for a four-year-old at school, and suddenly they have an incurable brain tumor.

The limited patient population makes it difficult for researchers in the field of pediatric oncology to secure funding or grants. Fortunately, companies like CureSearch for childhood cancer help drive innovation. The organization helped fund the DNA repair agent research study.

Bindra explained the genetic mutations that occur in childhood cancers – and all cancers – with a motor analogy. Normal cells become cancerous when “a cancerous cell takes its foot off the brake and presses the accelerator pedal. That’s what we call two genomic hits.

In precision oncology, these characteristics can be targeted. If the cell is accelerating too fast, a drug can be developed to slow it down. But the smart cancer cells are quickly able to find a way around these drugs, causing resistance over time.

The DNA repair approach

“DNA repair is the process of repairing errors in the cancer genome,” Bindra noted. Over the past 10 to 15 years, research has shed light on how cancer cells disrupt the DNA repair process as they grow.

“The same function that allowed the cancer cell to form is also an Achilles’ heel, as it thrives in a situation where it inactivates key parts of the DNA repair system,” he said. for follow-up.

The newly developed molecules exploit this Achilles heel, inactivating a DNA repair pathway to selectively kill cancer cells. “We’re going after what actually created the cancer cell by further destabilizing the genome to the point of no return,” Bindra said.

At a higher level, the study shows that “instead of targeting proteins indirectly, you can actually modify DNA directly.”

Based on the new finding, Bindra, Seth Herzon, Ph.D. (study co-lead author), Kingson Lin, Ph.D., (study author), and Kevin Rakin (HighCape Capital partner) have co-founded Edit Bio. The new company plans to introduce the molecule into the clinic by 2024.

“Modifi Bio is now rapidly testing these molecules and trying to find the right one that will work in patients,” Bindra said.

Tovorafenib leads to an ORR of 64% in phase II

Another company working to develop treatments for childhood cancer is Day One Biography. Dr. Samuel Blackman, MD, Ph.D., co-founder and chief medical officer, said BioSpace the company name was inspired by what pediatric oncologists call the Day One Talk.

“It’s the conversation you have with the family when the child is diagnosed with cancer,” said Blackman, who completed his fellowship at the Dana-Farber Cancer Institute. “This is where you walk through the diagnosis, treatment plan, side effects, alternatives and what it’s going to be like for the family.”

The discussion usually takes several hours and involves many tissues. Blackman said he wants his company to make new drugs to offer at the Day One Talk rather than decades-old chemotherapy options.

Dr. Samuel Blackman_Day One BiographyOne such drug is tovorafenib (DAY101), an investigational pan-RAF kinase type II inhibitor. The drug is being developed to treat pediatric low-grade glioma (pLGG). First data from the phase II FIREFLY-1 trial showed that tovorafenib resulted in an overall response rate of 64%.

The FIREFLY-2 Phase III evaluation of tovorafenib will open later this year, with a full FIREFLY-1 dataset expected in early 2023.

Ultra-low radio frequency energy

A unique approach to pediatric glioma treatment comes from EMulate Therapeutics, a clinical-stage therapeutic device company. EMulate’s proprietary platform uses ultra-low radio frequency energy (ulRFE®) to record and replay a molecule’s digital fingerprint.

Business home use Haelo system is being investigated as a potential treatment for diffuse midline glioma (DMG).

Chris E. Rivera, CEO, said BioSpace, “we have developed a WAV file that emulates in our technologies”, hence the name EMulate Therapeutics. The system works to “emulate the mechanism of a number of different drugs and chemicals by developing or passing the digital electronic signals out of the molecules”.

EMulate has received Humanitarian Device Exemption from the FDA to treat GMD. To date, fourteen pediatric patients with DMG and diffuse intrinsic pontine glioma (DIPG) have been treated with the Hælo System under a compassionate use protocol. All but one of the patients were under 18 years old.

VRW Haelo_EMulate TherapeuticsThe device was worn on the back of the head to be close to the tumor, and a WAV file mimicking the chemotherapy drug paclitaxel was played through a reel.

Twelve of the 14 patients survived for at least a year. The company hopes to replicate these results in an upcoming phase III study. “We believe this will have a significant clinical impact for these patients, physicians and their families.”

With a median survival for DMG of less than one year on average, Rivera considers the treatment a “high and high unmet need.”

He said many people’s initial reaction to the company’s technology involves disbelief.

“When you’re on the cutting edge of something different, it can be hard to keep an open mind,” he said. “The challenges not only of brain cancer, but also of childhood brain cancer, are daunting. I think we have to keep an open mind and look at all the potential avenues and aspects to treat these patients. »