By Nana O 
High-grade glioma, an aggressive and often devastating form of brain cancer affecting both children and adults, presents a formidable challenge to the medical community. Its insidious nature stems from several critical factors: the critical and difficult-to-access locations of these tumors within the brain, a high propensity for recurrence even after aggressive treatment, and the significant hurdle posed by the blood-brain barrier, which severely limits the efficacy of many conventional drug therapies. In the face of these pervasive obstacles, researchers from leading institutions have joined forces, forging a collaborative path toward uncovering a novel therapeutic strategy that offers a glimmer of hope for patients battling this relentless disease.
A Collaborative Breakthrough: Targeting the PDGFRA Pathway
A groundbreaking study, recently published in the prestigious journal Cancer Cell, details the significant findings of this multidisciplinary team, comprising researchers from the University of Michigan, the Dana Farber Cancer Institute, and the Medical University of Vienna. Their collective efforts have illuminated a potential new avenue for treating high-grade gliomas by focusing on specific genetic alterations within tumor cells. The study highlights the remarkable response of high-grade glioma tumor cells harboring DNA alterations in the PDGFRA gene to the drug avapritinib. This pharmaceutical agent is already established in the medical armamentarium, having received United States Food and Drug Administration (FDA) approval for treating specific forms of gastrointestinal stromal tumors (GIST) with a PDGFRA exon 18 mutation, as well as advanced, indolent, and systemic mastocytosis.
Dr. Carl Koschmann, a key figure in this research and the ChadTough Defeat DIPG Research Professor and clinical scientific director of the Chad Carr Pediatric Brain Tumor Center at C.S. Mott Children’s Hospital, expressed palpable excitement about the findings. "We were excited to see that avapritinib essentially shut off PDGFRA signaling in mouse brain tumors," Dr. Koschmann stated, underscoring the drug’s potent inhibitory effect on a crucial signaling pathway implicated in tumor growth.
The Scientific Rationale: Targeting a Common Genetic Aberration
The pursuit of effective treatments for high-grade gliomas has historically been hampered by a lack of targeted therapies. Beyond the established approaches of surgery and radiation, particularly effective pharmacological interventions remain scarce, especially when tumors recur. Recognizing this critical unmet need, Dr. Koschmann and his collaborators strategically focused their attention on the PDGFRA gene. This gene is frequently identified as one of the most commonly mutated genes in various cancers, including high-grade gliomas, making it a compelling target for the development of novel drug therapies.
"We’d been doing screens with a lot of commercially available drugs that inhibit PDGFRA," Dr. Koschmann explained, detailing the extensive preclinical work that preceded this significant breakthrough. "We found avapritinib to be the strongest and most focused inhibitor that targets PDGFRA alterations." This rigorous screening process identified avapritinib as the leading candidate due to its superior potency and specificity in inhibiting the aberrant activity of the PDGFRA gene.
Overcoming the Blood-Brain Barrier: A Crucial Hurdle Cleared
A significant challenge in developing brain cancer therapies is the inherent difficulty for drugs to penetrate the blood-brain barrier (BBB). This highly selective physiological barrier protects the brain from pathogens and toxins circulating in the bloodstream, but it also acts as a formidable impediment to the delivery of therapeutic agents to brain tumors. The research team, working in conjunction with colleagues from the laboratories of Dr. Mariella Filbin at the Dana Farber Cancer Institute and Dr. Johannes Gojo at the Medical University of Vienna, who were independently investigating the efficacy of PDGFRA inhibitors, were particularly enthused by avapritinib’s ability to cross this critical barrier.
Kallen Schwark, a U-M M.D./Ph.D. student and one of the study’s lead authors, elaborated on the significance of this finding. "When we gave mice the drug and showed that it reached the brain, we knew we were onto something," Schwark remarked, emphasizing the pivotal moment when the drug’s brain penetrance was confirmed. This discovery was a crucial step, validating the potential of avapritinib not just as a molecular inhibitor, but as a drug capable of reaching its intended target within the brain.
Early Clinical Translation: Patient Access and Promising Outcomes
Building upon the compelling preclinical data, the research team was able to facilitate early access to avapritinib for a select group of patients with high-grade glioma. This was achieved through an expanded access program established by Blueprint Medicines, the manufacturer of avapritinib, while a formal clinical trial was still in its nascent stages. This compassionate use initiative allowed for the treatment of the first eight patients diagnosed with high-grade glioma across multiple international institutions.
Dr. Koschmann shared the encouraging preliminary results from this cohort: "The patients tolerated the drug well and in three of the eight patients, we were able to see their tumors shrink." The observation of tumor shrinkage in a substantial portion of these early patients is a significant indicator of avapritinib’s therapeutic potential in this challenging patient population.
Paving the Way for Larger Clinical Trials and Future Therapies
The promising early clinical data, coupled with the robust preclinical findings, has served as a critical foundation for further clinical investigation. This evidence has been instrumental in the decision to include pediatric high-grade glioma as a cohort within a Phase I pediatric solid tumor trial. This trial has recently completed patient accrual, and the analysis of its results is currently underway, representing a significant step forward in evaluating avapritinib’s efficacy in a broader pediatric patient population.
Dr. Koschmann highlighted the broader implications of these findings for the field of neuro-oncology. "We have very few examples of drugs entering brain tumors like this and shutting down key oncogenic pathways. These results support a lot of ongoing efforts to build on the success of avapritinib and other brain penetrant small molecule inhibitors," he stated, underscoring the importance of this research in fostering the development of new classes of brain-penetrant drugs.
The Long Road Ahead: A Multi-faceted Approach to Treatment
Despite the encouraging progress, the researchers and the medical community acknowledge that high-grade gliomas remain a formidable adversary. These cancers are characterized by their extreme aggressiveness, with a grim prognosis of less than two years for many patients and a stark scarcity of effective treatment options. While the work on avapritinib represents a significant advancement, it is crucial to recognize that this research is still in its preliminary stages.
Dr. Koschmann emphasized the need for a comprehensive strategy, stating, "We know a single drug is not going to be enough for this disease." This sentiment reflects the complex biological nature of high-grade gliomas, which often develop resistance to single-agent therapies. The future of treating these aggressive brain tumors, therefore, lies in the development of multi-modal treatment regimens.
"The way to make true progress will be combining many different types of modalities, like combining drugs that are target pathways activated by the first drug," Dr. Koschmann elaborated. This forward-thinking approach suggests a strategic plan to build upon the success of avapritinib. The team is already exploring synergistic treatment strategies, with a promising follow-up study investigating the combination of avapritinib with MAP kinase inhibitors. "We already have a follow-up story on targeting avapritinib with MAP kinase inhibitors that we are just as excited about," he concluded, signaling continued dedication to innovating and advancing the fight against high-grade glioma. This ongoing research exemplifies the collaborative spirit and scientific rigor required to make meaningful progress against one of the most challenging cancers in medicine.
