October 07, 2019
Moon Shot rises to challenge of glioblastoma
BY Clayton Boldt, Ph.D.
Glioblastoma (GBM) is not among the most commonly diagnosed cancers in the U.S., but it can certainly be among the most devastating. Of the roughly 15,000 patients diagnosed annually, only 5-10% will survive five years.
The Glioblastoma Moon Shot® is working to change those odds and save the lives of patients with a coordinated, multidisciplinary team of researchers and physicians committed to findings new vulnerabilities, testing new therapies and implementing better treatment approaches in the clinic.
The effort is part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Frederick Lang, M.D., chair of Neurosurgery, is one of the co-leaders of the Moon Shot® team. Together with Amy Heimberger, M.D., professor of Neurosurgery, and John de Groot, M.D., chair ad interim of Neuro-Oncology, Lang directs the Moon Shot toward impactful discoveries and new therapies. He spoke with Cancer Frontline about the work of the Moon Shot.
Q: What’s the current outlook for patients diagnosed with glioblastoma?
A: The prognosis for patients with glioblastoma is poor and the survival is not long, but more problematic is the fact that the outlook has not changed a great deal in the past 30 years. If you look at data from 1980, the median survival was roughly 12 months. Today, the median survival is only 15 months with our current standard of care – surgery, then concurrent radiation and chemotherapy (temozolomide), followed by adjuvant temozolomide.
However, there is hope because we now know there are subsets of patients with specific molecular markers, like MGMT methylation, who live well over two years on average. Nevertheless, the chance of making it to five years remains low. Additionally, although we have made major advances in more accurately classifying brain tumors based on molecular markers, like IDH1/2 mutation, it has been discouraging that many of the newer targeted therapies and immunotherapies, which have been very effective in other cancers, are proving to be ineffective in glioblastoma.
So, this is why we need a Moon Shot. Indeed, if there is any cancer that requires a Moon Shot effort, it is glioblastoma.
Q: How have you, as a team, organized the Glioblastoma Moon Shot?
A: Our Moon Shot has brought together a critical mass of investigators, including those who have traditionally been studying the disease as well researchers that typically have not worked in the brain tumor space. This allows our team to synergize in our thinking around the problem. We need lots of smart people helping to understand this very difficult cancer.
With this in mind, we recently reorganized our Moon Shot from a strategic point of view. Whereas before we were focused primarily on therapeutic goals, we now understand that we need significantly more early-stage discovery research.
In the past, we have relied too often on drugs developed for other cancers with the hope that they will work in GBM. Unfortunately, this approach has not been fruitful. We really need approaches developed specifically for GBM. Our early-stage research will shed light on glioblastoma’s weaknesses so we can develop new therapies. We have the expertise, we have the infrastructure, and I think we’re heading in the right direction.
Q: What are the primary focus areas of the Moon Shot?
A: We’ve organized ourselves into three flagships – Discover, Develop and Deploy. These flagships all work to complement and inform one another.
Within the Discover flagship, we are trying to identify new vulnerabilities in GBM that can lead us to new treatments. In one of our biggest projects we are partnering with an international group called the GLASS Consortium to understand the changes in brain tumors over time at the genetic level. We are sequencing large numbers of patient samples taken at different treatment points to understand how tumors evolve over time and respond to therapies. We hope this will give us insight into what is making GBMs so resistant to therapy.
We are also working to establish a topographic immune atlas to better understand the microenvironment of the tumor, including the immune cells that populate glioblastomas, to see how the immune system plays a role in tumor development and treatment response. Finally, we are identifying biomarkers from liquid biopsies - blood and spinal fluid samples - that could be used to help us identify tumors more easily and monitor their growth and response during brain tumor treatment.
For our Develop flagship, we are focused on projects that have proven compelling in the preclinical setting and need the added resources of the Moon Shot to complete translational and regulatory studies so that we can begin testing in the clinic. We’ve brought several new people to the team for these projects, and we’re exploring several exciting immunotherapy-based approaches.
Finally, the Deploy flagship is focused on implementing and executing transformational clinical trials designed to bring important new options to our patients. We’re conducting window-of-opportunity trials to understand the effect of the treatment on the tumor. We have been pioneers in these types of clinical trials, and we are currently testing several approaches with this trial design.
Q: What project are you most excited about at the moment?
A: We have a number of compelling trials that are in progress or will soon be launched. We are testing a T-cell strategy attacking cytomegalovirus (CMV) antigens which are highly expressed in GBM, and we hope to soon test natural killer cells engineered to attack glioblastomas.
Recently we began a Phase I clinical trial investigating mesenchymal stem cells (MSCs) as delivery vehicles for an oncolytic virus, called Delta-24-RGD, which was developed through a collaboration between one of our neuro-oncologists, Juan Fueyo, and David Curiel at the University of Alabama Birmingham. This trial is particularly unique because the MSCs are delivered into the arteries that supply the tumor using endovascular approaches originally developed for strokes and brain aneurysms. We are pioneering a new field called endovascular neurosurgical oncology.
The approach takes advantage of the fact that GBMs are highly vascularized and supplied by many blood vessels. We can deliver therapies specifically through the arteries that supply the tumor and not those that supply the rest of the brain. Because of new technologies and methods, we can thread a catheter into the tumor-specific vessels and infuse agents directly into that tumor. We are using this approach to deliver MSCs loaded with Delta-24-RGD. We enrolled our first patient on this trial in April, and we’ve recently treated our third participant.
Q: How is your work enabled by the Moon Shots Program and its infrastructure?
A: The Moon Shots Program been critical to create opportunities for out-of-the-box thinking and for funding highly innovative projects that we probably wouldn't have been able to support in the past. We have been able to secure NIH funding and our group holds a SPORE in Brain Cancer, but the Moon Shots Program gives us a chance to explore less conventional strategies and to do large scale analyses requiring multidisciplinary teams of experts. The platforms especially give us access to technologies that would not otherwise be available to our group.
We really appreciate the support and infrastructure provided by the platforms. We’re continually working to better utilize their expertise and we believe the platforms are an invaluable resource to all of the Moon Shots teams here at MD Anderson. Overall, the Moon Shot has been tremendous in revolutionizing our capacity to bring important new treatments to our patients with GBM.