For Families Battling Brain Cancer, New Treatment Brings Hope

In the beginning of 2024, Modifi Biosciences was once again struggling to find investors and on the verge of running out of money.

Yale School of Medicine (YSM) researchers launched the spinout company in 2021 to develop a novel drug for glioblastomas, a highly aggressive and deadly form of brain cancer. Co-founder Ranjit Bindra, MD, PhD, Harvey and Kate Cushing Professor of Therapeutic Radiology, has been treating brain tumors in both adults and children for over a decade, and he can count on his fingers the number of patients he has seen with glioblastomas who are still alive today.

Clinicians primarily treat glioblastomas with a chemotherapy known as temozolomide, but the cancer inevitably mutates and becomes resistant.

Outside of the clinic, Bindra’s research focuses on bringing new brain tumor therapeutics from bench to bedside. And in 2020, he and his colleagues made a breakthrough—a new compound called KL-50 that could specifically target drug-resistant brain tumors while sparing healthy surrounding cells.

The appetite for investing in new glioblastoma treatments, however, was low. Other research teams had tried and failed to develop improved therapeutics since temozolomide was approved by the U.S. Food and Drug Administration (FDA) in 1999. And because glioblastoma is a rare cancer, investors were concerned about profitability.

“There’s probably 15,000 cases a year in the U.S. of glioblastomas, but not the 200,000 cases a year of other cancers that we treat,” says Bindra, a member of Yale Cancer Center.

The Modifi Biosciences team often felt pressure from investors to pivot their focus to a less financially risky cancer. Instead, Bindra hung up pictures around the lab of glioblastoma patients whose lives could possibly be saved with a drug like KL-50. Among them included a young girl who was diagnosed with a deadly and incurable glioblastoma at only 9 years old.

But in an unlikely move, in fall 2024, Merck & Co. decided to acquire Modifi Biosciences in a $1.3 billion deal. While a pharmaceutical giant like Merck would not be typically interested in a drug still in its early stages of development like KL-50, its unique mechanism and potential to also treat other kinds of cancers had caught the company’s attention. In its hands, if all runs smoothly, Bindra says KL-50 could become available to patients as early as next year.

A father himself, Bindra’s pediatric patients were his inspiration to stand behind KL-50 even when the obstacles seemed insurmountable. “One of the reasons I treat kids, as devastating as it is to watch each one fight their battle, is that they have such resilience and strength,” he says. “To be 9 years old and be so brave right up until the end—it shows you the power of the human spirit.”

One of those inspirations was Avery Lafferty, a soccer-playing, science-loving fourth grader who died from glioblastoma in 2024. But during her life, and even after, her story and spirit helped push the researchers to develop a new drug and staunchly advocate for it when no one wanted to fund it.

Avery Lafferty exuded confidence when she glided across the soccer field.

She was a natural athlete, her father Paul says. “We’d drop her off at the soccer field—because we were always running late for something—and then go park the car,” he recalls. “By the time we’d get back, Avery would have already scored several goals.”

But in the weeks leading up to Christmas of 2021, Avery started getting headaches. Doctors were puzzled. One thought she might have spinal meningitis, but she wasn’t having fevers. Not eager to put the young girl through a lumbar puncture, the doctor instructed her parents to continue monitoring her and bring her to the emergency room at any sign of a fever or worsening headaches.

December 18 started out as a good day. The family was spending the weekend skiing in Vermont, and Avery’s headaches seemed to be at bay. She told her mother, Lisa, over a cup of hot cocoa that she had “one of the best ski days ever.”

But that evening, the headaches returned. Paul gave her some Tylenol to help ease the pain, and she went to sleep. At midnight, Avery woke her parents up to tell them her headache had returned. Outside, a snowstorm had begun brewing. They tried giving her a little more Tylenol. Hours passed, but the headache still persisted. Although she didn’t have a fever, Paul and Lisa feared that something was wrong.

At 2 a.m., the family decided to pack the car and attempt the drive through blizzard conditions back to Connecticut. They made it as far as the emergency room in Brattleboro. “It was snowing pretty bad, and her head was just pounding too much,” Paul says.

Because COVID restrictions were still in place, Paul was initially the only one allowed to come in with Avery. After some unsuccessful attempts to ease her headache, Avery then underwent a CT scan. The doctors invited Lisa and Avery’s older sister Lexi to come in.

“This is when I knew something had gone wrong because all of a sudden, they were waiving the COVID policy,” Paul says.

At 4 a.m., the family learned that the scan found a mass on Avery’s brain, and they found themselves in an ambulance to Yale New Haven Hospital (YNHH). By 6 a.m., they met Michael DiLuna, MD, professor of neurosurgery at YSM and chief of pediatric neurosurgery at YNHH, who biopsied the mass and performed a surgery to drain entrapped cerebrospinal fluid.

Avery’s medical team worked rapidly to get her home in time for Christmas Eve. “We didn’t know what we were facing yet, so there was a lot of hope,” Paul says. “We had a very nice Christmas with the four of us at home.”

For about half of glioblastomas, the cancer cells don’t express a DNA repair gene called MGMT. Temozolomide—the standard of care for glioblastoma—works by depositing a methyl group onto the DNA of cells, specifically on guanine, one of DNA’s four base molecules. Healthy cells that still have their MGMT gene intact will simply pluck the methyl group back off.

In the DNA of cancerous cells, however, the guanine is damaged by the methyl group. Typically, during DNA replication, guanine pairs with the base cytosine. However, when the cancerous cell tries to replicate its DNA, the addition of the methyl group causes a DNA mismatch—it pairs the methylated guanine with the incorrect base thymine.

This triggers a pathway called mismatch repair (MMR), a process through which the cell proofreads the DNA and corrects mismatches. “As the methyl group persists, this MMR pathway cycles over and over again and realizes it can’t resolve this issue, so it triggers cell death,” Bindra explains.

As a result, temozolomide is highly effective in treating patients with MGMT-deficient glioblastomas. However, in many of these patients, the tumor will recur and become resistant for reasons that were long unknown to oncologists. Over the last several decades, however, research has shown that the cancerous cells can mutate so that they lose the MMR pathway.

“So now the tumor cells make mismatches, and the cell doesn’t care,” Bindra says.

There are no available therapies for treating this mutation. But Bindra wondered if there was a way to modify the structure of the temozolomide molecule to alter the way the drug kills cells. He sought out synthetic chemist Seth Herzon, PhD, Milton Harris ’29 Ph.D. Professor of Chemistry in Yale's Faculty of Arts and Sciences.

“Bindra came to me and said we needed a temozolomide analog that can overcome this resistance mechanism,” Herzon says. “So that is what we set out to do.”

Bindra and Herzon laid out a plan—Herzon’s laboratory would create molecules from scratch based on temozolomide, and Bindra’s laboratory would in turn test these molecules in models of glioblastomas. But first, they needed a trainee who could take on this project.

Kingson Lin’s mother and father had only just immigrated to the United States from the rural fishing providence of Fujian, China when he was born in New York City. As the new parents found their footing, they sent Lin back to China to be raised by his grandparents. He spent his early childhood hearing stories of America from his parents until he reunited with them in Queens at 5 years old. From there, his family moved to the suburbs of Philadelphia, where he spent the rest of his childhood.

Despite attending a large, underfunded high school that offered limited guidance for higher education, Lin became the first in his family to go to college after getting accepted into the University of Pennsylvania. At first, he struggled to find direction.

“I didn’t know what I wanted to do,” he says. “I knew I was good at science, but I didn’t feel that I had a passion for anything at that time.”

But then, he discovered chemistry. “Most people hated organic chemistry, but some weird part of my brain experienced the opposite effect where I thought, ‘Oh, this is really cool. I want to learn more of this,’” he says. “I loved making molecules and being able to create something from the simplest building blocks.”

When writing grants and scientific papers, Lin often justified the significance of his work by pointing to its potential pharmaceutical implications. But many of the compounds he worked with ended up back in the fridge, never to be tested.

“And I grew really curious—what does it take to make a drug instead of just making a random combination of A plus B?” he recalls.

After graduating from the University of Pennsylvania, Lin went on to join Bindra’s laboratory as an MD-PhD student at YSM. “When I first met [Bindra], I noticed he was a really energetic person,” Lin says. “He was teaching, he ran a lab, he was involved in biotech. And I thought that this was someone that I wanted to be like professionally.”

Spending time in Bindra’s laboratory fostered his growing interest in brain cancer. Along the way, Lin also completed a rotation with Herzon. The duo immediately recognized Lin’s potential. “He is one of the most talented MD-PhD students we have ever worked with,” says Bindra.

Lin’s dual interests in cancer research and building molecules, they realized, made him the perfect candidate to bring a new molecule that targeted drug-resistant brain tumors to life.

Avery had been having excruciating headaches the night before her school called her parents. She had vomited in class and needed to be taken to the emergency room.

It was April, and she had already been through a lot within the first few months of 2022. She had been diagnosed with a thalamic glioblastoma, and DiLuna had referred the family to Mark Souweidane, MD, at Weill Cornell Medicine, who conducted a near-total resection of the tumor in January. While the family knew that the cancer would grow back, the surgery gifted them more precious time with Avery.

“For at least the first year of Avery’s cancer, there wasn’t a tumor growing—just a cavity where it had been,” says Paul.

Back at home, Avery received radiation therapy under the supervision of Bindra, who did his best to ensure she kept as much of her hair as possible. She was also about to enroll in a clinical trial at the Children’s Hospital of Philadelphia testing the efficacy of a promising combination of potential drugs.

As she underwent treatment, one event Avery was especially looking forward to was her first CT Blast Cancer Walk. These walks, held by the charity, The Cure Starts Now, help raise money for pediatric brain cancer research. She was excited to attend with her soccer friends, who had all registered to show their support.

But now, the night before the walk, she and her family were at the hospital. Scar tissue formation had caused fluid build-up in the brain, and she needed another shunt to drain it.

After some discussion with DiLuna, the family decided that the surgery could wait for a few days. Avery attended the walk on Saturday with her friends and family at her side and underwent the shunt procedure the following Monday.

Lin’s goal was to develop a compound like temozolomide that targeted MGMT-deficient tumor cells but would not be susceptible to resistance.

First, he dove into the scientific literature to see what had already been tried. Then, using the backbone of the temozolomide molecule, he explored how tinkering with the part of the structure associated with depositing the methyl group and damaging the cellular DNA impacted the molecules’ mechanisms.

Lin spent months making analog after analog. But the hard part, he says, was differentiating the promising molecules from the duds. So, the team brought in a postdoctoral researcher, Susan Gueble, MD, PhD, who is now an assistant professor of therapeutic radiology at YSM. Using her background in cellular biology, Gueble propagated cell cultures that mirrored cancerous cells lacking MGMT and MMR.

“I started running different assays looking at what the molecules were doing within cells in terms of DNA damage and activation of different DNA repair pathways,” Gueble says.

With these cell lines, the team could quickly screen for the molecules capable of killing the resistant cells. This ultimately led them to discovering KL-50, which the team named after Lin.

Temozolomide works by depositing a methyl group—a carbon atom bonded to three hydrogen atoms—onto cellular DNA. KL-50, on the other hand, contains a fluoroethyl group, or a molecule composed of two carbons, four hydrogens, and a fluorine.

Through their experiments, Lin and Gueble discovered that this compound worked in a surprising way. Carbon-fluorine bonds are usually known by chemists to be non-reactive.

“Fluorocarbons are called forever compounds because they’re famous for being very inert and staying around forever,” says Lin, who graduated from YSM in 2024. Teflon, for example, the brand name for a type of polymer made up of carbon and fluorine, is commonly used in cookware because its low reactivity makes the material non-stick.

But in Gueble’s cell culture experiments, the team discovered that KL-50 was crosslinking the cellular DNA. In other words, it bonded to both strands of the cellular DNA—rather than just a single strand like the methyl group—zipping it shut.

“This makes it really hard for the cell to unravel the DNA and copy it, because the cross-link stitches the DNA together,” says Lin. Because the cells cannot replicate their DNA, they cannot divide and they ultimately die.

Drugs that form crosslinks are not unique, but most existing ones cannot differentiate between healthy and non-healthy cells. However, the researchers found that KL-50 worked in a novel way so that it only targeted MGMT-deficient cancer cells.

Because of the low reactivity of fluorine, when KL-50 deposits fluoroethyl groups onto the cells, the crosslinks are slow to form. “That fluoroethyl group just sits there for about a day or so, and then it forms a crosslink,” says Lin.

This delay gives healthy cells with MGMT the chance to remove the fluoroethyl group from their DNA. As a result, only the cancerous cells experience the crosslinking and die.

“This was a really transformational discovery,” says Bindra. “No one had ever thought that you could make a molecule like this.”

Avery, her sister Lexi, and Paul stood outside the new Elm City Bioscience Center in September of 2022.

While her surgeries and radiation therapy had been taxing to the fifth grader, she was getting back to doing the things she loved. She was excelling in school, especially in math and science. Although her brain surgery had thrown off her balance and coordination, she was determined to keep doing her best on the soccer field.

“All of those things that used to come naturally didn’t come as naturally anymore, but her work ethic quadrupled,” says Paul. She began practicing soccer every day to keep up with her peers. “I would come home from work, and she’d immediately want to practice together, or I’d find her already doing her workouts in the playroom.”

Now, the family was at the ribbon-cutting for the new headquarters of Modifi Biosciences, a startup co-founded by Bindra, Herzon, and Lin. They had just published a paper in Science demonstrating the mechanism of their novel compound. Through their newfound company, they hoped to turn KL-50 into a novel glioblastoma drug that could treat tumors like Avery’s. But they knew they would face a challenging market.

At first, the scientists had to turn to their friends and family for funding, as well as some local Connecticut groups that Bindra had connections with. Through their help, the team raised their first million dollars.

“We went and told them—this is very exciting science,” Lin says. “We have really high standards for what we believe is good quality work, and we wouldn’t ask our loved ones for money if we didn’t think it was going to succeed.”

This initial funding enabled them to hire a bare bones team to gather the data needed to sway investors. Meanwhile, neither Bindra nor Herzon took salaries for their roles in the company. Gradually, KL-50 began receiving interest from cancer research foundations and some local small venture capital firms. The growing funding helped support the team in moving into their own space.

At the ribbon-cutting, many Modifi Biosciences employees and investors had the opportunity to meet Avery and her family for the first time. “She looked great and was in really good spirits,” Bindra says. “Our staff was so amazed—rarely do they get to see the patients that they are trying to develop novel drugs for.”

Over the next few years, the startup would face what sometimes seemed like insurmountable hurdles. But Avery quickly became the battle cry for the company.

“We went and visited their offices, and they had one of Avery’s pictures from one of our cancer walks blown up in a poster in their boardroom,” says Paul. He also noticed that Bindra kept a framed selfie he took with the family at his desk. “It showed how much they cared about us.”

With patients like Avery in mind, the team held their ground. “We were adamant that whoever invested in this would honor our choice to continue developing KL-50 as a brain cancer drug,” says Lin.

On June 8, 2024, Avery and Lexi carried the opening torch at the soccer match for Gotham FC and Angel City Football Club—two of Avery’s favorite teams.

Her tumor was growing again. The Lafferty family was working with their medical teams to ease her symptoms. At one of her appointments at Yale, Paul told Bindra that he had reached out to some of Avery’s favorite teams, and that they were going to send her a signed scarf and ball. “And Bindra went, ‘Just a signed ball?‘” Paul says. “Then he put together a whole day for her.”

Surrounded by her friends and family, Avery met her favorite players and cheered on both teams as Gotham secured a victory. The match was supposed to be the perfect way to celebrate her upcoming 12^th birthday. But towards the end of the game, she seized on the field.

“We started out the day with having this wonderful event and then ending it spending the weekend in the hospital at Yale,” Paul says.

At the hospital, the family faced the possibility that it might be time to say goodbye. The next day, they began creating Avery’s Little Army, a grassroots organization with a mission to raise funds for and advance pediatric cancer research.

Modifi Biosciences was at a critical decision point regarding their strategic funding plan when Merck approached them, and they had a very narrow window of time in which to decide on the fate of the company at the time.

It turned out that the senior oncology leader at Merck was Bindra’s benchmate over a decade ago when they were post-doctoral researchers at Memorial Sloan Kettering Cancer Center. The duo reconnected as Bindra pitched KL-50 over dinner one night in Boston.

By that time, the team had realized that KL-50 might have potential beyond treating brain tumors. Through their research, they learned that as many as 10% to 30% of all cancers are associated with a lack of MGMT. Furthermore, doctors have used temozolomide to treat a range of cancers, which evolve similarly to glioblastomas and become resistant.

“We were learning in real time that temozolomide didn’t work in all sorts of tumors like colon cancer and lung cancer because they acquired mismatch repair mutations,” says Bindra.

“Having generated that data made investors more optimistic that KL-50 is not for a small brain tumor market,” Lin adds. “Now, we were looking at a broader market of all cancers that don’t have MGMT.”

But Merck did not just want to be an investor. They wanted to buy Modifi Biosciences. Brain cancer drugs were not new to the pharmaceutical company—it had been involved in the development of temozolomide several decades prior. And given its expertise and strong infrastructure for drug development and running large clinical trials, the Modifi Biosciences team was optimistic that Merck was well equipped to help bring KL-50 to patients in need.

“And so, we made the decision at the eleventh hour to go with Merck because KL-50 was our baby,” says Bindra. “And we thought that they would take care of our baby in the best possible way.”

Merck officially acquired Modifi Biosciences on October 15, 2024. Bindra and Herzon are continuing to collaborate as consultants. Now, the pharmaceutical company is running investigational new drug experiments, studies required by the FDA to demonstrate the drug’s safety before researchers can begin a Phase I clinical trial.

“If everything goes according to plan, it’s projected that next year it could be in patients,” says Bindra.

“KL-50 is now in Merck’s capable and competent hands,” says Lin. At an American Society of Clinical Oncology meeting in June 2025 in Chicago, discussions had already begun about how to set up the Phase I clinical trial. “We’re very confident that we’re going to get there, and we want to make sure that we design the trial in the best way possible to continue moving the drug forward.”

One month after seizing on the field, Avery passed away at home surrounded by her family.

Following the soccer match, doctors had given her a high dose of dexamethasone, a strong anti-inflammatory medication that allowed the family to bring their daughter home from the hospital. “It snapped her out of it and brought her back,” says Paul. “It bought us a month and a day to make a lot of memories and give us all a chance to say goodbye.”

The Lafferty family made casts of their hands held together and heartbeat recordings. Avery wrote messages to her loved ones, even as the cancer spread to other parts of her brain and made it difficult to process her thoughts. “We wouldn’t trade that month for anything,” says Paul.

On July 12, 2024, Avery’s family told her that it was okay to rest and that they would see her again one day. Her legacy lives on through Avery’s Little Army, which is striving to spread awareness about pediatric cancer, fund research, and support local families with their own battles. They have raised over $250,000 for organizations including Children’s Brain Tumor Project, The Cure Starts Now, the ChadTough Defeat DIPG Foundation, and Dana-Farber Cancer Institute.

The family hopes that drugs like KL-50 could soon help pediatric patients with glioblastoma who otherwise have few options. “It’s stunning when you hear your child has a diagnosis like this and you realize there’s nothing out there,” says Lisa. “What we love about Dr. Bindra is he always seemed innovative and knew this was a massive gap that needed to be funded.”

Paul says that the passionate doctors and researchers that the family came to know through Avery’s battle give him hope that one day there will be better treatments. “The soccer player is doing everything he can to win the game—that’s how these individuals do their research,” he explains. “It’s beyond just a paycheck for them. The passion they have to try to find a cure for these diseases is impressive.”

Now, over a year after her passing, her family keeps her memory alive. “I loved Christmases and holidays with her because we’d always have a little competition to see who could get the other more gifts,” says Lexi. “Every moment with her was so much more fun and filled with joy.”

“She was also very much a trickster,” Lisa adds. “She used to hide in her hamper, and when I would go to get the clothes, she’d jump out.”

In her 12 years of life, Avery touched the lives of many people. And through Avery’s Little Army, she is continuing to help families facing pediatric cancer.

“You can’t take any moment for granted, because you never know how much time one of your family members has left,” says Lexi. “But with our foundation, we can turn a tragedy into something greater than what we were given.”