HemOnc Today's PharmAnalysis
HemOnc Today's PharmAnalysis
February 03, 2019
4 min read

Researchers tap genomic technology to develop personalized treatments for pediatric glioma

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Sabine Mueller, MD, PhD
Sabine Mueller

Researchers at UCSF Benioff Children’s Hospitals are using next-generation genomic technology to develop targeted therapies for high-grade pediatric glioma.

Sabine Mueller, MD, PhD, adjunct associate professor of neurology, pediatrics and neurosurgery at University of California, San Francisco, and colleagues aim to treat as many as 44 children and young adults with this disease.

The researchers plan to screen each tumor using the UCSF 500 Cancer Gene Panel, which can detect the most frequently occurring mutations. Tumors also will undergo whole-genome and whole-exome sequencing for all DNA and genes along with RNA sequencing.

Researchers then will create drug cocktails with up to four agents targeted to each tumor.

A parallel trial with similar protocols is underway and will specifically investigate this strategy for children with diffuse intrinsic pontine glioma.

Accrual for both trials will occur in the 18-hospital Pacific Pediatric Neuro-Oncology Consortium network.

HemOnc Today spoke with Mueller about this research effort, the potential implications of the results, and what needs to be confirmed in subsequent studies.

Question: Can you describe the need for more effective treatment s for patients with high-grade glioma ?

Answer: Overall, we haven’t made great strides in identifying better treatment options for pediatric brain tumors, which constitute the most cancer-related deaths among children. At the forefront is pediatric high-grade glioma, a heterogeneous group of tumors that can be divided into midline gliomas and other supratentorial or infratentorial gliomas. Outcomes for these children remain really poor. For midline gliomas, OS at 2 years is less than 10%. For other high-grade gliomas, the survival rate is 10% to 20%. Obviously, there is a strong clinical need to do something different. In this study, we were trying to go away from the one-size-fits-all approach to more personalized treatment now that we have next-generation sequencing readily available and possible from really small biopsies.

Q : Why do these patients typically experience such poor outcomes? Is it because of the malignancy or because trials have taken this one-size-fits-all approach?

A: It is multifactorial. The tumors that are classified under the umbrella of high-grade glioma are very heterogeneous, and treatment needs to be tailored to specific subtypes. Just getting the diagnosis correct remains challenging and often only after more detailed molecular characterization do we get this right. Another major obstacle within the field of neuro-oncology in general, and not just in pediatrics, is drug delivery. Specifically, the blood-brain barrier continues to be a challenge. Medications administered either by IV or orally often are not reaching the tumor in sufficient concentrations to have an impact, and doses cannot be further increased due to systemic side effects..


Q : What is the rationale to use personalized cocktails to maximize the potential benefit for t his patient population?

A: In this study, we are aiming to take as much of the tumor as possible. The children most likely will undergo biopsy in the midline, or a more substantial resection if the tumor is located supratentorially. We then will use state-of-the art molecular profiling, the most comprehensive available to us, to conduct whole-genome and whole-exome sequencing, as well as a targeted panel, and we will look at proteomics. A molecular tumor board will be convened to discuss the molecular profiling results and therapy options. We are aiming to match the therapy to what we think are the key alterations in the tumors that we can target. Hopefully, if we target these specific alterations, we’ll improve outcomes.

Clinical trials often explore single agents. Given the heterogeneity of these tumors, we strongly believe we need to look at a combination therapy approach. In our study, we will allow the use of up to four agents. If a subset of patients has an alteration for which drugs are available only as part of a trial, we reserve the right to refer them to such a trial.

Q: H ow will the heterogeneity of this patient population impact eligibility criteria and other factors of this study?

A: There are limited trial options for this patient population and, therefore, we do not anticipate major issues with accrual through a larger network. Families and patients with these diseases are very involved and dedicated, which leads to a higher enrollment rate than many other oncology trials.

Q: Could you provide a timeline for results?

A: Once all the trial sites are activated and approved by their own institutional review boards, it probably will take a few years to complete enrollment. Then it takes a while for the data to mature. Part of our process, and part of the philosophy of our consortium, will be to make genomic data available as soon as possible for other researchers in the field. We want to attract as many talented people to the field as possible to help improve outcomes. In order to do that, we are going to need to look at survival at 12, 18 and 24 months to really understand the outcomes. There is nothing we can do to speed that up.


Q: Could you talk about this issue that there is no standard of care for this patient population?

A: Right now, for children diagnosed with one of these gliomas, many centers are starting to offer some sort of molecular profiling. The therapeutic standard of care remains maximal safe resection, followed by focal radiation therapy, but how these patients are treated after completion of radiation therapy widely differs among centers. Many pediatric neuro-oncologists prefer to enroll in a clinical trial.

Q: What are the potential implications if this approach is shown to improve outcomes?

A: It is a strategy we are testing and not one specific therapy. We will definitely gain a deeper understanding of the heterogeneity of these tumors, which may allow us to start to understand who will benefit from an individualized therapy approach. – by Rob Volansky

For more information:

Sabine Mueller, MD, PhD, can be reached at UCSF, Box 0663, San Francisco, CA 94143-0663; email: sabine.mueller@ucsf.edu.

Disclosure: Mueller reports no relevant financial disclosures.