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From the CEO’s Desk: Glioblastoma – Grappling With A Cancer That Breaks All The Rules

A version of this op-ed first appeared this morning on the news site, STAT ( STAT is a national publication focused on stories about health, medicine, and scientific discovery.

Reports out of recent prestigious conferences and from major studies in the field, paint an optimistic picture of cancer care in America. A sampling of encouraging headlines include: “Cancer survival rates at all-time high,” “Cancer mortality rates continue to drop,” and, “Cancer death rates continue to decrease in the United States.”

Driving much of the progress and related enthusiasm are emerging advances in three vital areas of cancer research and treatment: prevention and early detection, immunotherapy, and precision medicine approaches that match patients to targeted therapies.

Nearly every form of site- or tissue-specific cancer is benefitting – in at least some of its subtypes – from one or more of these developments. Yet, to their credit, many experts are careful to caution that challenges remain.

“Common cancers, including pancreatic, brain, and lung, remain stubbornly difficult to treat…Aggressive cancers such as these are difficult to diagnose early and lack adequate treatment options,” read the American Society for Clinical Oncology’s 2017 “State of Cancer Care in America” report. These cancers present a counter-narrative to the idea that we’re well on our way toward eradicating cancer as we know it.

Brain cancer, in particular, offers an intriguing look into intractable cancers. Paradoxically, its most common – and most lethal – form, glioblastoma (GBM), is actually one of the most molecularly and genetically characterized of all tumors, having been selected as The Cancer Genome Atlas’ (TCGA) pilot project a decade ago.

Data from the TCGA’s glioblastoma studies, and subsequent research enabled by it, created a veritable treasure trove of biological information on these tumors which has led to an accumulation of targets for potential new therapies. Yet, hundreds of studies testing many of the latest and greatest cancer drugs and treatment modalities have not produced durable results or improved overall survival for people with glioblastoma. This includes recent setbacks with checkpoint inhibitors, vaccine-based immunotherapies, and targeted therapies, all of which have been making significant differences in certain cancers of the breast, colon, lung, kidney, bladder, liver, head-and-neck, blood and skin.

Compounding these struggles is the lack of applicability of prevention, early detection and screening methods for brain cancer, though it’s now estimated that nearly 50 percent of all cancers could be prevented, and many more caught early through improving screening and public health efforts. Further, while many cancers typically become terminal only after they’ve metastasized to distant body sites, GBM offers only a five-percent five-year survival rate, despite virtually never moving outside the central nervous system.

So what to do about a cancer that defies all the norms? Additional resources are always welcome, of course, but, perhaps even more essential is a recalibration of how we approach complex and aggressive malignancies.

We must recommitment to rigorous, yet “basic,” biological research. What we’ve learned from the many failed trials in glioblastoma, is that we face a highly complex and adaptable foe, adept at evading treatments of all classes. We need to understand why previously tested drugs didn’t work in aggressive cancers like GBM, as well try to anticipate – prior to initial treatment – how that cancer will work to avoid or escape therapy.

One strategy we’re pioneering with a group of top researchers is the Defeat GBM Research Collaborative (Defeat GBM). Defeat GBM takes a meticulous, ‘whole-cloth’ course to identify therapeutic targets along with their potential mechanisms of resistance, as well as the corresponding biological markers that can predict treatment if a treatment is likely to work in a given patient or not. Additionally, thousands of potential new drugs, and drug combinations, are screened through a set of laboratory models that better replicate the human tumor environment than previous models. Agents are then prioritized based on their ability to effectively elicit an anti-tumor response and/or help overcome resistance.

An end-to-end discovery thru preclinical research effort, such as this, is necessary to move the field beyond the more simplistic tactic of matching a “repurposed” drug to a single targetable mutation in an individual patient in the clinic.

At the same time, industry must abandon its reluctance to develop drugs specifically for brain and other recalcitrant cancers, despite various perceived barriers. With some exception, large pharmaceutical companies with significant talent and resources have been reluctant to pursue brain cancer-specific drug development. However, we know from decades of disappointments that repurposed drugs do not offer ideal candidates for GBM treatments, as most weren’t designed to cross the blood-brain-barrier, the tight cellular network within the brain’s capillaries that protect the organ from toxins and chemicals. Yet, without that ability even ostensibly promising drugs can either fail to reach the tumor at all, or hit their target with inadequate doses.

For example, both non-small cell lung cancer (NSCLC) and GBM often harbor important mutations to the so-called “EGFR” gene. Yet, drugs developed for this target – three in fact – are available for NSCLC patients, but the same treatments have failed to demonstrate sufficient benefit in GBM patients. Beyond blood-brain-barrier issues, this target has different variants in GBM and thus unique molecular characteristics and consequences which need to be accounted for in the future.

The lesson here is that hard-to-treat cancers like GBM likely require their own wardrobes, so to speak, not “hand-me-down” drugs that were originally made for other cancers.

Ultimately, the oncology ecosystem – including research institutions, funders, government programs, and industry – must embrace the daunting challenge presented by a cancer like GBM. It may be tempting for some to believe we’ve found the “special sauce” with the advances which are currently contributing most to the field’s recent successes. But future progress, particularly in the area of recalcitrant cancers, may well rely on different interventions and different innovations than the ones we celebrate today.

From the perspective of brain cancer, we believe that a thoughtful and “systems” based approach, which addresses tumor heterogeneity, anticipates resistance, and fully-incorporate biomarkers, is required in the quest to develop new treatment strategies for the thousands of cancer patients not benefiting from today’s cancer medicines. This is the approach we are taking with Defeat GBM.

These principles will also likely need to be paired with tactics for jumpstarting orphan drug development; improving our R&D systems and processes, in accordance with the Cancer Moonshot’s recommendations; as well as continued support for multidisciplinary research and technological advances in areas like liquid biopsy and medical imaging.

More ubiquitous progress across the cancer landscape will depend significantly on future ingenuities in both the strategies and products we use to confront these diseases. When a cancer like glioblastoma breaks all the prevailing rules, the remedy is to seek evermore unique models and tactics that focus on what makes it distinctive and an outlier. Only by fully extricating ourselves from a one-size-fits-all mentality will truly novel treatments – not just the ones that have worked elsewhere – emerge to afford individuals with intractable cancer the same hope that a growing number of cancer patients have today.

NBTS wrote this opinion article as a way to provide the community with thought leadership and advocate to the research and drug development field (and those that provide a bulk of its funding) to continue to focus on difficult-to-treat cancers, such as brain tumors, and embrace the challenges they present. Specifically, we urge the field to continue its pursuit of innovative approaches that truly move cancer care toward a truly precision-based approach toward treatment strategies. In doing so, we believe it is possible that advances unlocked from research on a highly-complex and aggressive tumor like GBM will, in turn, potentially provide significant benefit to many other tumors and cancer types.

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