A defining hallmark of glioblastoma cells is their ability to alter cell metabolism to evade cell death and escape most available therapies. We have yet to fully understand the fundamental mechanisms of how brain cancer cells regulate these metabolic pathways to fuel unrestricted cell growth. Our understanding of cancer metabolism has largely focused on the utilization of glucose. However, emerging evidence from both our lab and others is uncovering mannose metabolism as an overlooked regulator of metabolic reprogramming essential to driving cancer cell survival and proliferation. Our work aims to uncover new roles for mannose metabolism in glioblastoma cell growth, and ways to manipulate these pathways in order to improve efficacy of radiation therapy and treatment outcomes for children with glioblastoma.
Targeting the glioma immune environment by creating tertiary lymphoid organs (TLOs)- Dr. Hideho OkadA
The absence of lymphatic organs and professional antigen presenting cells are thought to be two major causes for insufficient immune responses in the brain. Although TLOs have not been reported in brain cancers, in patients with autoimmune disorders of the brain, ectopic formation of TLOs in the brain has been reported. Based on our previous studies showing that intra-tumoral injection of type-1 DCs enhances T-cell homing and functions in gliomas13,16-18 and induces TLO-like structures in mouse sarcoma and colorectal cancer,4 we will develop novel and feasible methods of TLO induction in mouse glioma models using type-1 DCs as the vehicle for delivery of TLO-inducing factors.
James K. Chen, Ph.D.
Professor and Chair, Department of Chemical and Systems Biology, Stanford University School of Medicine
Our work focuses on the molecular mechanisms that promote the onset and progression omedulloblastoma and the pharmacological inhibition of these processes. We recently identified ARHGAP36 as an oncogene that is highly expressed in certain types of medulloblastoma and may contribute to tumor recurrence. With the support of the Rachel Molly Markoff Foundation, we are now investigating how ARHGAP36 promotes tumorigenesis, including which regions within ARHGAP36 are essential for its function and which proteins interact with ARHGAP36 to activate oncogenic pathways. We are also pursuing the development of small molecules that bind directly to ARHGAP36 and block its activity. Our studies will provide new insights into the biochemical mechanisms that drive medulloblastoma and advance efforts toward effective therapies for this pediatric brain cancer.
We funded four research proposals in 2016. All the proposals come from outstanding institutions involving laboratories and investigators who are renowned for their work in brain tumors and immunology. The proposals look at very different mechanisms and approaches yet use some similar technologies that will allow future collaborations among he laboratories and investigators.
The proposal from New York University, made by Drs. Snuderl and Possemato, focuses on finding novel targets against pediatric brain tumors. They combine their respective labs and use various approaches, including looking at the interactions between the genes, epigenes and the cell metabolism, to find these novel targets.
The second proposal comes from Dana Farber Cancer Institute and was made by Dr. Kieran as a continuation of his work from last year and will focus on hunting for genes that are “turned on” that confer resistance to standard therapies in a rare pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). By finding these genes, Dr. Kieran can then focus on ways to target these genes and reinstate sensitivity to standard anti-cancer therapy.
The third proposal that was funded comes from the laboratories of Drs. Bernstein, Batchelor and Suva at the Massachusetts General Hospital, who are directing their research on cancer stem cells that confer resistance to treatment. Their research efforts are focused on the Notch pathway and will use a multipronged approach to understand if inhibiting this pathway can kills the cancer stem cells.
The final proposal comes from Dana Farber Cancer Institute by Dr. David Reardon and will be the continuation of the work funded last year by Art in Giving and The Rachel Molly Markoff Foundation. His work will be extending the initial work that evaluated inhibition of brain tumors using therapies directed at the immune system and will now focus on better understanding the critical factors that drive response to these agents as well as mechanisms of resistance.
Written by Debasish Roychowdhury, MD.
Clinical Director, Center for Neuro-Oncology
Associate Professor of Medicine, Harvard Medical School
Funding provided by the Rachel Molly Markoff Foundation will support my laboratory efforts aimed at utilizing the immune system to eradicate brain cancers. Our work focuses on high-grade gliomas, an incurable primary brain tumor that affects both pediatric and adult patients. Glioblastoma and diffuse intrinsic pontine glioma are two deadly variants of high-grade glioma that respond transiently at best to currently available therapies. Innovative treatment strategies are desperately needed to improve outcome for patients with these tumors.
Our research efforts focus on optimizing combinatorial treatments that utilize the immune system (the natural defense system of the body) to recognize brain cancers as foreign and attack them. Many tumors including brain cancers have evolved highly sophisticated mechanisms to shield or cloak themselves from attack by the immune system. Our therapeutic approaches aim to overcome these protective, self-preservating mechanisms exploited by tumors. If successful, our interventions offer the promise of not only killing existing tumors, but also then preventing their future relapse based on the memory capability of immune sensitization. Dramatic and durable tumor responses have been seen in other challenging solid tumors utilizing these approaches. Although significant challenges exist in developing these treatments for brain cancer patients, our research efforts, supported by the Rachel Molly Markoff Foundation, are working to overcome these challenges and help realize the truly exciting potential offered by these novel therapeutic strategies.
Director, Pediatric Neuro-Oncology Center
Associate Professor of Pediatrics, Harvard Medical School
Significance of proposed research to brain cancer patients: Current brain cancer therapy induces apoptotic (dying) tumor cells and cell debris. We have determined that conventional chemotherapy can contribute to tumor progression as the debris of killed cancer cells stimulates tumor growth. In medulloblastoma, radiation and cisplatin based chemotherapy may therefore be a double-edged sword: the more effective they are at killing tumor cells, the more tumor stimulating factors are released. There is a natural process that stops this from happening, using a series of molecules called ‘resolvins’. We have identified these molecules are normally expressed in the brain and turned off by the tumor. In this research proposal, we will activate the natural debris-clearing process using resolvins, a natural product of the tissue that normally serves to end the inflammatory process to evaluate whether they can prevent the tumor-stimulating effect of dead cancer cells caused by current cancer therapies for brain tumor patients. These proposed studies would open an entirely new domain of brain tumor research. We expect that resolvins will exhibit minimal toxicity as they are already found in all tissues, including the brain and spinal fluid. The overall patient impact is potentially far reaching because recurrence or progression of medulloblastoma is rarely curable. Resolvins may allow us to reduce the toxic effects of current chemotherapy or radiation treatment regimens in medulloblastoma and have the potential for use in the treatment of other brain tumors such as malignant gliomas and diffuse intrinsic pontine gliomas. This pre-clinical characterization of resolvins is potentially paradigm-shifting and will guide us in determining the optimal way to use resolvins in treating human brain cancer.
James K. Chen, PhD
Dr. Chen is studying the development of next-generation chemotherapies, specifically novel Hedgehog pathway antagonists, as potential medulloblastoma therapeutics. Conventional treatments of medulloblastomas in children are associated with high rates of recurrence, metastasis, and permanent disability. Selective pathway antagonists resulting from these studies will further future investigations of the Hedgehog pathway and the development of new therapies for this deadly cancer. Here is a letter from Dr. Chen (PDF) giving thanks for the Foundation’s funding that is much needed for cancer research.
Todd Golub, MD
One priority of the Broad Institute is to compile a complete molecular description of cancers. A systematic analysis of these alterations across all tumor types will enable a deeper understanding of cancer and it promises to revolutionize how cancers are classified, diagnosed, and treated. Specially, the Foundation grant will enable the lab accelerate its ability to profile the activity of cancer causing proteins and tyrosine kinase in tumor cells and to extend the profiling to new and other types of proteins.
Adrienne C. Scheck, PhD
Barrow Neurological Institute
Dr. Scheck’s lab her current research is to identify novel genes involved in this resistance through the use of a variety of molecular biology techniques, and to identify molecular markers for the diagnosis and prognosis of gliomas and meningiomas.
Charles Eberhart, MD, PhD
Johns Hopkins University
Dr. Eberhart‘s laboratory was focused on understanding the molecular basis of medulloblastomas.
Myrna R. Rosenfeld, MD, PhD
University of Pennsylvania
Dr. Rosenfeld’s research was on “Novel Approaches to Angiogenesis Inhibition in Experimental Glioma.”
Allen E. Bale, MD
Yale University School of Medicine
Dr. Bale’s research was on “The Hedgehog Pathway in Medullablastoma.”
Daniel W. Fults, MD
University of Utah School of Medicine
Dr. Fults’ project was “Somatic Cell Gene Transfer to Model Medullablastoma.”
James Waschek, PhD
University of California Los Angeles
Dr. Waschek is utilizing genetically engineered mice to study the role of STAT3 in medulloblastoma immune evasion. Model systems are created to mimic the molecular, cellular and biological characteristics of human tumors in order to better understand the tumor biology and test therapies.
Robert Wechsler-Reya, PhD
Dr. Wechsler-Reya works on pediatric brain tumors to gain a better understanding of how these tumors develop, with the ultimate goal of discovering more effective therapies against these cancers.