Genomics: Insight

Hypothesis: Genomic data has transformed the diagnostic classification and treatment of childhood malignant glioma. 

Introduction

Consider two hypothetical scenarios, one decade apart. In 2014, a newborn is diagnosed with an aggressive brain tumor, high-grade glioma. Treatment typically requires surgery, chemotherapy, and radiation, but options are limited because of this patient’s young age. Despite the medical team’s best efforts, this child succumbs to her disease in only months. Fast forward to 2024, and the landscape of pediatric oncology has been transformed. Another child, also diagnosed with high-grade glioma, undergoes sophisticated genetic testing of her tumor, which identifies a chromosome translocation leading to a hyperactive signaling protein that can respond to a precise targeted therapy. Over the months that follow, this child receives a targeted treatment and the tumor shrinks significantly, offering a hope that was once unimaginable.

The contrast between these two scenarios highlights the remarkable impact genomics has had on the treatment of pediatric malignant gliomas, particularly for infants. This review will briefly discuss the advances in genomics that have reshaped the therapeutic landscape for these aggressive tumors.

Understanding pediatric malignant glioma

Brain tumors are the most common solid tumor in children and the leading cause of pediatric cancer death^{1, 2}. While low-grade glioma can often be cured with surgery alone, malignant (or high-grade) glioma represents a unique challenge in pediatric oncology. These aggressive, infiltrative tumors have historically been approached with a one-size-fits-all approach of radiation and chemotherapy. Unfortunately, these tumors were often resistant to such therapies and had a dismal prognosis, with only 10-20% of children surviving 5 years from diagnosis^3-5.

The role of genomics 

In recent decades, the rise of genomics has transformed our understanding of cancer biology. Genomic analysis of cancer has the power to identify mutations, chromosome translocations, and other changes that are at the core of malignant transformation. Systematic studies evaluating the genomes of specific cancers have uncovered the genetic “drivers” of those diseases, paving the way for treatments that specifically target these mutated drivers. Similarly, the incorporation of next-generation sequencing (NGS) into clinical practice has enabled rapid analysis of mutations in the tumors of individual patients, making individualized targeted therapies possible.

In the case of pediatric gliomas, genomics has dramatically changed the paradigm of both diagnosis and treatment. In the 2021 reissue of the World Health Organization Classification of Tumors of the Central Nervous System, pediatric gliomas are classified not just by their appearance under the pathologist’s microscope, but also by the specific genetic changes that define them⁶.

A paradigm shift toward targeted therapies

Here I discuss three specific examples of malignant pediatric gliomas where understanding the genomics of the tumor has transformed the treatment approach.

Infant-type hemispheric glioma

Malignant gliomas in infants are often large, vascular tumors that occur in the first year of life with common symptoms ranging from seizures to lethargy. A common sign of increased intracranial pressure at this age is bulging fontanelles and an increasing head circumference. While these tumors were previously considered to be the same as gliomas arising in older children, genomic analyses have led to their re-classification as a distinct tumor type. As a result, the 2021 WHO CNS tumor classification created a new entity: Infant-type hemispheric glioma⁶. DNA sequencing of these tumors showed that these gliomas are often caused by chromosome fusions involving receptor tyrosine kinase (RTK) genes, such as NTRK1/2/3, ROS1, ALK, and MET, which are involved in growth factor signaling⁷. These fusion genes create over-active RTK signaling driving uncontrolled cell growth. The identification of fusion genes in these gliomas has allowed doctors to use specific drugs which precisely shut off the overactive RTK. Since this discovery, dramatic responses have been reported using the ALK inhibitor lorlatinib and NTRK inhibitors such as larotrectinib^8-10.

Prior to genomic research identifying targetable fusion genes in infant glioma, these tumors were treated similarly to all other high-grade pediatric gliomas. 5-year survival has been reported between 28-50% in large case series, but all survivors had significant neuro-cognitive impairment^{11, 12}. These tumors tended to respond better to surgery, chemotherapy, and radiation than high-grade tumors of older patients, suggesting distinct biology for infant tumors, which is now understood at a genetic level¹³. Since the identification of targetable RTK fusion genes in infant glioma, favorable responses to targeted inhibitors have been reported in individual patients. Because of the rarity of these fusion genes and the young age of many of these patients, the development of larger clinical trials is challenging⁸. One multi-institution trial is now underway, NCT06333899, evaluating lorlatinib for newly-diagnosed high-grade glioma with ROS and ALK fusion¹⁴.

BRAF V600E mutation

Another dramatic example of genomic knowledge changing therapy comes from glioma with a specific mutation, BRAF V600E¹⁵. Cancer genome sequencing studies unexpectedly showed that 6-7% of CNS tumors have a specific activating mutation in the BRAF gene, encoding a

V600E amino acid substitution. The remarkable thing about this mutation is that it is very common in melanoma, and specific drugs for this mutation had already been developed. From the melanoma experience, researchers knew that the BRAF mutation activates the mitogen-activated protein kinase (MAPK) pathway, which drives cell growth. To shut off the pathway, BRAF inhibition must be combined with inhibition of downstream mitogen-activated extracellular signal-regulated kinase (MEK). Repurposing these melanoma drugs for pediatric brain tumors with the BRAF V600E mutation has led to dramatic responses in highly aggressive tumors, for instance the complete clinical regression of glioblastoma in one patient and stabilization of high-grade glioma growth in others^{16, 17}.

A large trial of BRAF and MEK inhibitors (dabrafenib and trametinib) for BRAF V600E mutated pediatric low-grade glioma has been completed and showed significantly improved responses, longer progression-free survival, and a better safety profile than standard first-line chemotherapy¹⁸. A trial in adults included both low-grade and high-grade glioma with V600E mutation, and reported an encouraging objective response rate (complete and partial responses)¹⁹. Less data exists for pediatric high-grade glioma, but because of favorable responses in smaller case series, clinical trials of upfront targeted therapy for high-grade glioma are now being considered²⁰.

Mismatch-repair deficiency

Another class of pediatric glioma whose treatment has been changed by genomic data is gliomas with mismatch-repair deficiency (MMRD). These cancers are formed because of defects in the ability of cells to “proof-read” or repair errors in their DNA sequence, causing them to build up mutations over the course of cell division¹⁵. Some patients have MMRD of all the cells in their bodies due to inherited mutations. In others without such inherited mutations, MMRD may arise within the tumor itself. High-grade gliomas with MMRD were historically very difficult to treat by chemotherapy and radiation. Genomic analysis showed that the impact of MMRD in these tumors is hyper-mutation – a dramatically increased mutation rate. This led to the clinical realization that these tumors have many new antigens that can be effectively targeted by the immune system, leading to application of immunotherapies to manage these cancers^{21, 22}. The use of immune checkpoint inhibitors (PD-1 and CTLA4 antagonists) has now transformed the management of malignant gliomas with mismatch-repair defects.

Looking toward the future

The journey from the loss of a child with infant glioma to the hope for a cure for another within a decade demonstrates the transformative impact of genomics on medicine. Genomic data has allowed clinicians to make more precise diagnoses and to uncover personalized treatments aimed at the molecular vulnerabilities of each tumor type. This has changed the landscape of the fight against pediatric malignant glioma from one of despair to one of hope. With continued research and integration of genomic data into clinical practice, we can look forward to more innovation for the benefit of patients in the decades to come.

This has changed the landscape of the fight against pediatric malignant glioma from one of despair to one of hope.

References

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