Advances in Glioblastoma Multiforme Shift the Treatment Paradigm

Glioblastoma multiforme (GBM) is an aggressive malignant brain tumor predominantly found in adults. Even with the latest advances in cancer therapeutics, the few drugs that have been able to cross the blood-brain barrier (BBB) and reach the tumor directly face the hurdle of the BBB being disrupted in the process. With only approximately 5% of patients living 5 years after diagnosis, professionals desperately need a solution.

With advancements in the understanding of what is necessary to treat GBM, treatment approaches have begun to change. Scientists historically have focused on developing new drugs to target malignant tumors. However, drug development can span decades, and as diagnoses of this disease continue, time is not on the side of oncology professionals. To address this dilemma quickly, scientists are shifting to advance methods of local drug delivery, finding new ways to administer therapeutics effectively while circumventing the BBB. With this paradigm shift of incorporating local drug delivery technology into GBM treatment, the field of oncology is set for monumental change.

Paradigm Shift to Local Drug Administration

The primary thrust in cancer research and treatment practice has evolved to a more personalized approach to treating tumors through precision medicine and therapy. We are moving into a “genomic era,” in which scientists look at genomic patterns in each tumor to tailor drugs for optimal results.

Effective drug administration remains one of the biggest challenges, despite recent advances in cancer care. Intravenous (IV) administration is not entirely effective for GBM treatment because many drugs still cannot penetrate the BBB, which limits efficacy. Despite this, the IV delivery method is still used with drugs that can be better localized in tumors based on pharmacokinetic data. The potential of delivering much higher levels of drug directly to the tumor location with sustained release during a roughly 3-week period while maintaining minimal systemic drug exposure represents a key shift in what is possible not only in treatment of GBM but more broadly in neuro-oncology.

Investigators looking to address this delivery dilemma have come to understand that packaging a drug with a formulation that can be inserted directly at the brain tumor site allows circumvention of the BBB. Drug delivery using this packaging formulation can better encapsulate the drug and allow us to protect it from the degradation that occurs with IV administration, enabling prolonged release.

As new formulas undergo clinical investigation that would allow such prolonged release, the possibility for improved overall survival and clinical outcomes for patients with GBM becomes more real. These clinical trials have the potential to enable local drug delivery of chemotherapy directly at brain tumor sites at prolonged release rates, potentially reducing the tumor. Throughout 2022, these clinical trials are expected to progress, and during the next decade we can expect further development in additional investigations seeking new methods of crossing the BBB to advance treatment of GBM.

Using Methylation Signatures to Target Specific Pathways

A major recent development involves the number of new tools that allow oncology professionals to perform genomic classification of cancerous diseases, enabling identification of key mutations in genes that need to be targeted during treatment. By looking at genomic and epigenetic classifications, we can identify how the cells control gene activity. From there, we can look at the methylation profiles of genes, assessing how we can regulate cellular response to therapy. The combination of methylation profiling with probiotic signatures and genomic classifications has allowed oncology professionals to identify the Achilles’ heel of many cancers with these specific pathways, which can drive invasion and ultimately reduce the ability of tumors to duplicate or divide.

Repurposing Existing Drugs

Because the process for bringing a drug to market can take 10 years or more, scientists have been looking at the methods by which existing drugs are administered. Recent research has showed that how the drug is administered may play a greater role in efficacy than previously thought.

Now that we can uncover the genetic, epigenetic, or methylation signatures to assess pathways, we can identify existing drugs and those in phase 1 or phase 2 trials to repurpose and pair them with new local drug administration technologies for improving efficacy. As a result of these newly discovered molecular pathways based on genomic profiling and sequencing data, we can repurpose drugs that do not have a role in treating tumors and were not thought of as valuable in brain tumor treatment.

Taking it a step further, if we utilize FDA-approved drugs, we can halve the time it would take to prove a new drug’s safety and efficacy to get it into the hands of clinicians for their therapeutic toolbox. By embracing these new technologies, we have the potential to change the outcome in cancer care for GBM.

Clinical Trials Recover From Impact of COVID-19

As oncology evolves following the challenges of the COVID-19 pandemic, we have much to anticipate. Even before the pandemic, most patients in the United States did not participate in clinical trials because of daunting logistical complications. Problems remain, but there is more clarity regarding what we need to overcome to bring greater equality and access to the cancer clinical trial space for patients.

As we progress following the peak impact of COVID-19 on clinical trials, we must find a way to improve clinical trial structures so that all patients with GBM, especially those impacted by social determinants of health, can more easily receive care in the clinical trial setting. There is hope we will continue to see dedicated focus from those working in this space in years ahead, which will ideally bring more opportunities for patients with GBM to receive more affordable, advanced treatments.

About the Author

Mitchel S. Berger, MD, is the director of the University of California San Francisco Brain Tumor Center (BTC) and the principal investigator of the BTC’s SPORE Brain Tumor Program. He also serves on the PolyPid Scientific Advisory Board.