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Revolutionizing GBM Drug Development Through Serial Biopsies

REVOLUTIONIZING GBM DRUG DEVELOPMENT THROUGH SERIAL BIOPSIES

The 5-year survival rate for Glioblastoma is dismal: <10% for the 13,000 GBM patients diagnosed each year in the United States. The only therapeutics for GBM approved by the FDA in the past 30 years have shown little to no survival benefit.

The 5-year survival rate for Glioblastoma is dismal: <10% for the 13,000 GBM patients diagnosed each year in the United States. The only therapeutics for GBM approved by the FDA in the past 30 years have shown little to no survival benefit.

PROJECT HIGHLIGHTS

    • Therapeutic development for glioblastoma (GBM) has been stunted following several large and expensive phase III clinical trials that failed, despite encouraging preliminary results.
    • A central challenge is the complexity of the human brain, which cannot be modeled perfectly in the laboratory.
    • The Revolutionizing GBM Drug Development Through Serial Biopsies project will demonstrate the safety and feasibility of carefully performed serial biopsies, while in parallel assessing how promising new therapies directly affect these brain tumors. The team will investigate whether samples of cerebrospinal fluid and/or blood from patients may provide surrogate markers of drug activity.
    • The objective of the project is to establish a new paradigm of therapy development for GBM by utilizing longitudinal biopsies in the same patient to determine which therapies are successfully delivered to the tumor and exert an intended effect—two major hurdles which have historically hindered therapeutic advances.
    • The extraordinary level of funding support from Break Through Cancer, highly unusual in GBM research, will be essential to overcoming many financial and logistical barriers to converting the vision of longitudinal tumor sampling into a reality.

MEET THE TEAM

AllDana-Farber Cancer InstituteMemorial Sloan Kettering Cancer CenterMIT’s Koch Institute for Integrative Cancer ResearchThe University of Texas MD Anderson Cancer CenterThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

MEET THE TEAM

See Team
AllDana-Farber Cancer InstituteMemorial Sloan Kettering Cancer CenterMIT’s Koch Institute for Integrative Cancer ResearchThe University of Texas MD Anderson Cancer CenterThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

PROJECT SUMMARY

Outcomes for patients diagnosed with glioblastoma (GBM) have not significantly improved in decades. The current standard of care for GBM includes surgery, radiation and chemotherapy. Despite this treatment, GBM always recurs, usually within ten months from initial diagnosis, and remains incurable. The only therapies for GBM approved by the FDA in the past 30 years have shown only incremental survival benefit, and several recent, large, and expensive phase III clinical trials have failed to show meaningful improvements in outcome.

GBM is challenging in part because most cancer therapeutics fail to penetrate the tumor due to the protective effect of the blood-brain barrier. Therefore, clinicians are typically “flying blind” when treating GBM patients with novel chemotherapeutic, immunologic, or biologic agents. Although repeat biopsy (referred to as longitudinal sampling) has been routinely incorporated into the evaluation of promising oncology therapies for many other types of cancer, this has not been previously considered for brain tumors due to logistical and safety concerns. In addition, insurance companies do not yet cover the prohibitively high costs of repeated intracranial biopsies. Not only do these blind trials fail at stunningly high rates, but also this methodology effectively teaches us nothing about why the trial failed, leading to a futile cycle of repeated failure. Thus, without a platform for longitudinal sampling early in the clinical development of promising therapeutics for GBM, these large, costly, uninformative, and ultimately fruitless clinical trials will likely continue, providing no benefit to the hundreds of patients who are enrolled, nor to those who follow.

The breakthrough hypothesis of this project is that a novel early-stage GBM clinical trial platform providing critical information from sequential tumor biopsies, accompanied by peripheral liquid biopsies, will revolutionize our understanding of the effects of these therapies, thus transforming the approach to identifying effective therapeutic agents for GBM. This approach will fundamentally change how early GBM trials are conducted and will open this devastating disease to the kinds of breakthroughs that have transformed treatment of other cancers in the past few years.

The Break Through Cancer team will introduce a new paradigm that such longitudinal tumor sampling early in clinical trial testing should be critically considered for all therapies being developed for GBM patients. In addition, the body of knowledge created by analysis of longitudinal tumor samples over several drug and biologic agent trials will form the basis of new treatment hypotheses, and encourage pharmaceutical and biotechnology company investment in GBM.

Intracranial sampling is an invasive procedure that can now be performed with precision due to advances in neurosurgical and imaging technologies. However, its value must be irrefutably demonstrated if longitudinal sampling is to be adopted as a routine component of therapy development for GBM. As such, the initial goal of this team is to assess the safety, feasibility, and value of performing serial biopsies to determine if a therapeutic is being effectively delivered to the tumor and to obtain critical biological readouts of the effect of the drug on the tumor, with patient safety as an overriding concern. The initial trial will assess an oncolytic virus engineered to induce immune responses against GBM, which will be dosed intratumorally and on a repeated basis over time. This will provide an opportunity to safely take tumor samples each time the treatment is delivered. The team will use molecular profiling techniques such as genomic analysis, single cell RNA-sequencing, immune analyses, and sophisticated image analyses to investigate how cellular interactions and signaling in the tumor tissue are affected by the treatments.

Simultaneously, the team will also evaluate critical liquid biopsies for so-called surrogate markers of such treatment: first, using blood samples corresponding to the time of tumor interventions as well as through the course of therapy; and second, studying cerebrospinal fluid to assess for molecular changes that correspond to intertumoral sampling. If validated, these less invasive peripheral approaches to longitudinal sampling will reduce costs, improve safety further, and make this form of assessment more broadly available to physicians and patients.

Finally, this project will have an important discovery research component related to understanding how the immune response is blocked by GBM tumor cells. This will involve a series of experiments designed to identify genetic and cellular factors that are actively suppressing a more effective immune response against this disease. Another important component will assess drug effects in the laboratory using human tumor slice cultures – living pieces of human brain tumor tissue soon after they are removed from the operating room. These slice cultures can provide otherwise unknown insights into the effects of therapy on human GBM and could be scaled further to support novel therapeutic discovery in numerous ways.

MAKE A DIFFERENCE

Break Through Cancer was created in February 2021 with an extraordinary matching gift of $250,000,000. Every gift to the Foundation supports groundbreaking cancer research and helps us to meet our matching commitment.

For questions about giving please email Lisa Schwarz, Chief Philanthropy Officer at LMS@BreakThroughCancer.org

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