Northwestern’s SPORE has made progress in understanding the genetic basis of glioblastoma

Glioblastoma is one of the deadliest cancers known to man. While the advent of immunotherapy and other cutting-edge treatments have extended the lives of people with other types of cancer, the prognosis for glioblastoma has remained relatively constant – just 18 months.

This year and a half can be brutal: bombarding the brain with radiation in an attempt to crush the cancer until it submits, often with little success. Glioblastoma is notoriously resistant to treatment, adapting quickly and reappearing with fatal results.

SPORE is led by Matt Lesniak, MD, President of Neurological Surgery and Michael J. Marchese Professor of Neurosurgery, and C. David James, PhD, Emeritus Professor of Neurological Surgery.

It is no exaggeration to say that almost all patients with glioblastoma will unfortunately succumb to cancer. It is, in almost all cases, incurable. “

C. David James, PhD, Emeritus Professor of Neurological Surgery

The lethality of glioblastoma and the scarcity of effective treatments are what prompted Maciej Lesniak, MD, president and Michael J. Marchese professor of neurosurgery, as well as James, to apply for the Specialized Program of Research Excellence (SPORE) at the ‘National Cancer Institute. , which will be awarded to the Robert H. Lurie Comprehensive Cancer at Northwestern University. They didn’t do it alone: ​​the arrival in 2017 of renowned neuro-oncologist Roger Stupp, MD, professor of neurological surgery Paul C. Bucy and head of neuro-oncology in the department of neurology, strengthened expertise in glioblastoma. at Northwestern, and his continued leadership has been a tremendous boon to the program, said Lesniak.

Northwestern’s Brain Tumor SPORE – part of the Lurie Cancer Center – is now three years old, and the bench-to-bedside process is producing results. Under the leadership of Lesniak and James, SPORE has made progress in understanding the genetic basis of the disease and has developed potential therapies that reduce resistance to treatment and clinical trials using immunotherapies. The SPORE philosophy of collaboration and team science under one roof is alive and well.

Genetics of glioblastoma

Since the Cancer Genome Atlas (TCGA) published its 2008 landmark analysis of the genetics of glioblastoma, scientists such as Alexander Stegh, PhD, Associate Professor in the Ken Department of Neurology and Ruth Davee, Division of Neuro-Oncology, have used this roadmap to guide their research.

“The TCGA gave us this ‘periodic table’ of genes deregulated in glioblastoma,” said Stegh, who is also an associate professor of medicine in the division of hematology and oncology.

Alexander Stegh, PhD, Associate Professor in the Ken and Ruth Davee Department of Neurology, Neuro-Oncology Division, focuses on the genetic deregulation that contributes to therapeutic resistance in glioblastoma.

While some cancers have relatively easy to distinguish oncogen activations, it is increasingly understood that glioblastoma is caused by variants of many genes. This is why previous attempts at therapies targeting single genes have failed, such as those targeting alterations in the brain. EGFR gene, and why Stegh focuses on the genetic deregulation that contributes to resistance to therapy.

“Rather than going out there with the very ambitious goal of identifying multiple genes and lowering their levels of expression, we take a slightly different approach: how do we specifically down-regulate the genes that cause a resistance to therapy, as an adjuvant therapeutic approach, ”Stegh said.

Stegh has published several papers identifying important genes involved in resistance to glioblastoma treatment, but one gene, called Bcl2L12, has proven to be particularly suitable for therapeutic administration.

Combining his genetic expertise with the nanotechnology expertise of Chad Mirkin, PhD, professor of medicine in the Division of Hematology and Oncology; and the clinical trial expertise of Priya Kumthekar, MD, ’08 ’11 ’12 GME, associate professor of neurology in the division of neuro-oncology, the researchers designed a spherical nucleic acid drug that passed through the blood brain barrier and primed tumor cells for death.

The trial, published in Scientific translational medicine, was the first of its kind to show that nanotherapeutics crossed the blood-brain barrier and entered brain tumor cells in patients.

“This unique 3D design has the ability to infiltrate tumor cells to correct the genes within and make them susceptible to therapy-induced destruction,” Stegh said.

Bcl2L12 was initially identified as a treatment target by Stegh in 2007. “Going from identifying this gene during my postdoctoral work to targeting it and establishing proof of concept in patients is very rewarding. ”Stegh said. “We look forward to building on this success. “

Drill

A recurring barrier in the treatment of glioblastoma is the blood brain barrier. Efforts to develop treatments beyond simple chemotherapy are often hampered by the selective permeability of the barrier, but SPORE projects are using emerging technologies to break through. Beyond the ANS project, a group of researchers led by Lesniak used stem cell “shuttles” to deliver immunotherapy directly to the tumor site.

Neural stem cells have an affinity for the brain, often moving to areas of injury. Taking advantage of this travel model, the researchers modified neural stem cells to produce an oncolytic virus, which targets cancer cells and triggers the body’s immune response.

The phase I clinical trial, published in The Lancet Oncology, found this approach to be safe and tolerable for patients, and even showed signs that treatment may improve progression-free survival and overall survival.

“This is the first human clinical trial to test the delivery of neural stem cells of a modified oncolytic adenovirus,” Lesniak said.

Planning for the future

Roger Stupp, MD, Paul C. Bucy professor of neurological surgery, and Priya Kumthekar, MD, ’11 ’12 GME, associate professor in the department of neurology Ken and Ruth Davee, division of neuro-oncology, were the co-authors of the study published in Brain. Atique Ahmed, PhD, associate professor of neurological surgery, was the lead author.

This focus on results – or clinical trials testing therapies – is what unites all members of Brain Tumor SPORE. Kumthekar, who participates in almost all of the clinical trials that have emerged from SPORE, attributes their success to two things: planning and people.

“When we test drugs in the preclinical phase, we plan for the first clinical phase I. When we are in phase I, we plan for phases II and III,” Kumthekar said. “We are always planning the next phase with the goal of getting drugs that work for patients as quickly as possible.”

In addition, the wealth of brilliant minds within the Lurie Cancer Center made the collaboration transparent and stimulating for the participating professors. From her work with Stegh and Mirkin to preclinical work with Atique Ahmed, PhD, associate professor of neurological surgery, Brain Tumor SPORE’s biggest resource has been its staff, Kumthekar said.

A collaborative project between Kumthekar, Ahmed and Stupp found that a drug currently used to prevent organ rejection in transplant patients may also reduce resistance to chemotherapy in glioblastoma. Posted in Brain, the researchers found that this drug blocks a molecular synthesis pathway used by cancer cells treated with radiotherapy; when unable to create molecules essential for DNA synthesis, cancer cells are more likely to succumb to therapy and die.

The round-trip collaboration between Kumthekar and Ahmed – bringing together clinical trial and laboratory expertise – is one of the reasons this drug was selected by the Alliance for Clinical Trials in Oncology, which is part of the National Clinical Trials Network (NCTN). As a participating primary university site, the Lurie Cancer Center provides scientific leadership in the development and conduct of clinical research within the NCTN, and planning for the Phase I trial at Northwestern is already in full swing. A potential Phase III trial could take place at multiple Alliance Network sites in the United States, according to Kumthekar.

“The field is very interested in redirecting drugs right now, and this is helping us to accelerate the availability of drugs for patients,” Kumthekar said.

The end goal of patient care is what unites all SPORE members – from laboratory scientists to clinical trial experts – and as these therapies move through the long process of clinical trial evaluation, some scientists are hoping that better treatments are coming. the corner.

“Over the past ten to fifteen years, our body of knowledge about the molecular characteristics of glioblastoma has grown dramatically,” said James. “As we take the information generated by dozens, if not hundreds of labs, and analyze individual patients’ tumors to determine characteristics that can be targeted with specific therapies, I think we’ll start to see faster progress. in the effective treatment of this cancer. “

Lesniak, James, Stupp, Stegh, Mirkin, Kumthekar and Ahmed are members of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University and are part of the Lou and Jean Malnati Brain Tumor Institute at Lurie Cancer Center. Lesniak is director of neuro-oncology at the Lurie Cancer Center. Lesniak and James are principal investigators at Lurie Cancer Center’s Brain Tumor SPORE.

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About Hector Hedgepeth

Hector Hedgepeth

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