Critical Mass

by Cheryl SooHoo

Armed with a prestigious new grant,
investigators prepare to rapidly translate
scientific breakthroughs into better brain
tumor therapies.

 

 

 

 

Image by Sherbrooke Connectivity Lab/Science Source

Of the more than 23,000 people diagnosed with a brain tumor each year, some 65 percent will not be able to beat their disease. Glioblastoma (GBM) remains one of the most common and aggressive of primary malignant brain cancers. While gains have been made in treating GBM, today’s standard of care only yields a median survival rate of 15 months. Very few reach the cancer survivorship milestone of five years.

This sobering reality has driven Feinberg and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University to create a robust brain tumor research enterprise to vastly improve patient outcomes. In just a few short years, the strength of this institutional commitment has allowed Feinberg to attract leading investigators from around the world, develop the necessary research infrastructure and build momentum in the field of brain cancer.

To top it off, in August, Northwestern Medicine scientists obtained a highly competitive $11.5 million grant from the National Cancer Institute (NCI). With this large new award to the Lurie Cancer Center, Northwestern neuro-oncology investigators are now leading a Specialized Program of Research Excellence (SPORE) in brain cancer with a special emphasis on glioblastoma.

“Not only is this the first brain tumor SPORE ever awarded in the state of Illinois, but it is also the first SPORE for Northwestern that’s not shared with another institution,” says Maciej “Matt” Lesniak, MD, the Michael J. Marchese Professor, chair of Neurological Surgery and a principal investigator (PI) on the grant. “This is truly a transformative opportunity for us.”

The NCI’s SPORE funding program advances cancer research focused on specific organ sites, from breast to lung and brain to prostate. It awards institutions around the country that demonstrate they have the talent and resources to bring scientific breakthroughs to the clinical setting. Designed to promote discoveries that rapidly translate to human application of novel cancer therapies, these prestigious grants support projects — typically a total of four — currently in or poised to enter clinical trials. The NCI stipulates that these studies must touch and significantly benefit the lives of oncology patients within the five-year period of the grant.

Earlier this year when Lurie Cancer Center investigators applied for the brain tumor SPORE, two of their proposed GBM studies were already in clinical trials: one featuring a stem cell-based virotherapy that harnesses the power of the common cold virus to attack brain cancer cells, and the other a novel therapy that uses nanoparticles to suppress gene expression in tumor cells. Another study that takes an immunosuppressive approach to fighting GBM is projected to enter clinical trial status in 2019. The fourth study, aimed at overcoming a glioblastoma survival mechanism, is slated to enter human study within the funding period.

We have a critical mass of investigators in our brain tumor community who are uniquely focused on a specific brain cancer. Very few institutions in the country can match our depth and breadth of expertise.

C. David James, PhD, and Maciej “Matt” Lesniak, MD, principal investigators of the new brain tumor SPORE grant.

Although Northwestern’s application scored exceptionally well with the four initial studies proposed, C. David James, PhD, the Jean Malnati Miller Professor of Brain Tumor Research and vice chair for research in the Department of Neurological Surgery, says the school has additional outstanding projects in development and poised for near-term clinical application.

“We have a critical mass of investigators in our brain tumor community who are uniquely focused on a specific brain cancer. Very few institutions in the country can match our depth and breadth of expertise,” says James, who is also a professor of Biochemistry and Molecular Genetics. His research interests center on understanding how gene alterations cause tumors to develop and increase their aggressive biologic behavior.

James speaks from experience: Before joining Feinberg in 2014, he was a faculty member at the University of California, San Francisco, where he served as a project PI for one of the first brain tumor SPORE grants awarded by the NCI. Now, he is a co-PI of Northwestern’s SPORE.

To date, with the addition of Northwestern, only eight institutions around the country have received SPORE funding to support brain cancer research in the 26-year history of the NCI’s funding program.

Left: C. David James, PhD (middle), one of the SPORE’s principal investigators, with collaborators Craig Horbinski, MD, PhD (left), and Derek Wainwright, PhD (right). Middle: Highly atypical mitosis in a recurrent glioblastoma. (Image courtesy of Horbinski, who leads the biospecimen core for the SPORE.) Right: Neuro-oncologists Karan Dixit, MD, ’16 GME, and Priya Kumthekar, MD, ’11, ’12 GME, another investigator in the SPORE.

Moving the Needle

Despite advances in surgery, radiation and chemotherapy in the past couple of decades, less than two years is the best estimate that modern medicine can currently offer GBM patients. Says James, “That’s where the needle is now stuck.” The Northwestern projects supported by the new SPORE grant all involve innovative treatment strategies to enhance patient outcomes as quickly as possible. In the two studies currently in clinical trials and both coincidentally launched in May 2017, first-of-a-kind drug delivery vehicles offer hope for attacking deadly brain cancer.

One of the SPORE projects features the first drug to use nanoparticles or spherical nucleic acids to deliver and target gene suppression in tumor cells. Developed by Chad Mirkin, PhD, director of Northwestern’s International Institute for Nanotechnology, and Alexander Stegh, PhD, associate professor of Neurology in the Division of Neuro-oncology, the novel glioblastoma drug has been shown to cross the challenging blood-brain barrier to reach intracranial tumors in animal models. In the phase 0 clinical trial that is ongoing, the drug targets the gene BCL2L12 to promote therapy-induced apoptosis or cell death in glioblastoma. The study seeks to determine if systematically administered nanoparticles do, indeed, reach tumors cells in patients with deadly brain cancer.

A second Northwestern SPORE project involves a first-of-its-kind clinical trial employing neural stem cells that work with a common cold virus to infect and kill tumor cells. Developed by Lesniak, the drug is injected throughout the brain cavity during the time of surgery to remove the tumor. The phase I study aims to show that the novel stem cell therapy, which targets cancer cells hiding deep within the brain that are normally resistant to therapies, can be safely administered to patients newly diagnosed with GBM and ultimately improve outcomes. To date, eight individuals have participated in the clinical study and the results have been promising. Says Lesniak, “All of the patients have been doing favorably, so we are cautiously optimistic and looking ahead to a phase II study next year if all continues to go well.”

Left: A functional MRI image shows presurgical brain mapping of the critical motor and language white matter pathways around a glioblastoma tumor for a patient enrolled in the SPORE project testing a novel neural stem cell treatment. (Image courtesy of Benjamin P. Liu, MD, a co-investigator on the SPORE.) Middle: Roger Stupp, MD, and James P. Chandler, MD, co-directors of the Malnati Brain Tumor Institute. Right: A metastatic papillary carcinoma from lung. Northwestern Medicine investigators and clinicians study and treat a myriad of tumor types beyond the new SPORE.

Weakening Tumor Survival

Ironically, as patients battle to outlive their brain cancer, their tumors often find ways to survive as well. The capability of tumors cells to protect themselves frequently reduces the effectiveness of the most advanced cancer treatments.

The third project, co-led by Derek Wainwright, PhD, assistant professor of Neurological Surgery, Medicine in the Division of Hematology and Oncology, and Microbiology-Immunology, and Rimas Lukas, MD, associate professor of Neurology, uses immunotherapy to stimulate an immune system anti-tumor response against glioblastoma. The Wainwright laboratory has studied the influence of an enzyme known as ID01, which is found in many types of tumors. Overexpression of ID01 in glioblastoma is associated with decreased overall survival. Devising strategies to block the enzyme with already approved and available pharmaceutical ID01 inhibitors, the team plans to bring this novel concept to the clinical trial stage next year.

The final project focuses on a glioblastoma survival mechanism known as autophagy, a natural process that tumor cells employ for self-preservation when avoiding cell death from standard cancer therapies such as radiation and chemotherapy. Based on a novel activator of autophagy known as ATG4B, recently discovered by Professor of Neurology Shi-Yuan Cheng, PhD, this project will investigate the effects of inhibiting this enzyme while treating animal models with either radiotherapy, the chemotherapy drug temozolomide (TMZ), or a combination of radiotherapy and TMZ.

In 2017, the Lou Malnati Cancer Research Foundation made a transformative gift to the Northwestern Brain Tumor Institute, now named the Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute. James P. Chandler, MD, and Roger Stupp, MD, are co-directors of the institute, which is part of the Lurie Cancer Center with clinical operations at Northwestern Memorial Hospital. C. David James, PhD, is the scientific director, overseeing research efforts like the new brain tumor SPORE projects.

The latter combined approach for treating GBM is known across the globe as the “Stupp Protocol” — named after renowned neuro-oncologist Roger Stupp, MD, who joined Northwestern Medicine in 2017. Stupp and Leonidas Platanias, MD, PhD, director of the Lurie Cancer Center and the Jesse, Sara, Andrew, Abigail, Benjamin and Elizabeth Lurie Professor of Oncology, are co-investigators on this SPORE project, which will also investigate an associated inhibitor, NSC185058, for possible use in patients.

MORE SPORE: Prostate Cancer Research Thriving

by Will Doss

Moving from bench to bedside in just five years may sound like a daunting task, but the Lurie Cancer Center’s Prostate Cancer SPORE is on track to produce tangible benefits for patients as it enters its fourth year, according to principal investigator William Catalona, PhD, professor of Urology.

“Five years is a tight timeline to bring something from the research bench to a clinical trial,” Catalona says. “But it brings together the clinicians and basic scientists, gets them focused and the ball moving to help patients.”

Out of four current SPORE projects, two are running clinical trials and one is under review by Northwestern University’s Internal Review Board, hoping to improve androgen-receptor therapies or test new targets for advanced prostate cancer treatment. The fourth project, run by Catalona, is currently genotyping DNA samples from over 6,000 patients who are undergoing active surveillance, looking for patterns in genetic variants that can cause active surveillance to fail.

Key to these efforts has been the recruitment of expert clinical trialists, urological oncologists and basic scientists.

“We’ve strengthened our clinical trial portfolio, especially in designing and administering trials based on science that’s come out of Northwestern,” Catalona says.

In addition, several pilot projects led by Prostate Cancer SPORE scientists have sprouted into fully fledged investigations, spurring additional investment into Northwestern Medicine science, including four Challenge Awards from the Prostate Cancer Foundation.

“The reason these SPOREs are successful is because the institution has recruited the scientists, clinicians and pathologists,” Catalona says. “I think by the time our five years is up, we can possibly have several new treatments for prostate cancer that didn’t exist before our SPORE.”