While steady advances have been made to better understand and treat central nervous system (CNS) cancers, the key to future progress is the ability to learn more about the molecular and cellular properties that drive tumor development and growth, and how to apply that knowledge to the creation of novel targeted therapies that destroy cancer cells while sparing nearby sensitive tissues.
With these goals in mind, the Brain Tumor Center at Memorial Sloan Kettering has many ongoing projects underway representing the various stages of research. Below are descriptions of some of our projects.
Several risk factors have been identified for gliomas. They include male gender, Caucasian race, and family history; the only known environmental factors are radiation exposure, which increases risk, and allergies, which decrease risk. Recent genome-wide-association studies (GWAS) have identified about ten genetic regions related to risk. The aims of this large international study are to identify common genetic variants related to glioma, both by replicating results of earlier studies and by conducting a new GWAS. In addition, we will identify gene-gene and gene-environment interactions that influence risk. There will be 6,000 cases and 6,000 controls recruited from 15 sites. Epidemiologist Sara Olson is the Memorial Sloan Kettering principal investigator, leading recruitment of 375 cases and 375 visitor controls (Protocol 10-073). Participants complete an interview and donate a blood sample for genetic analysis. Marc Rosenblum is a member of the Pathology team that reviews diagnoses from all sites. This study, supported by the National Cancer Institute (R01CA139020), is led by Melissa Bondy, at Baylor University.
Family history of glioma is associated with increased risk for the disease. The aim of the GLIOGENE consortium, formed in 2006, is to identify genetic regions that could account for disease in families with multiple cases of glioma. So far we have used linkage techniques to identify a region on chromosome 17 (17q12-21.32) that is associated with inherited susceptibility in some families (Shete et al., Cancer Research, 2011). Current work involves deep sequencing of this region; future work will include exome sequencing of other families and sequencing of identified genes in all enrolled families. This study, led by Melissa Bondy, at Baylor University, takes place at 15 centers in the United States, Europe, and Israel; epidemiologist Jonine Bernstein is the Memorial Sloan Kettering principal investigator (Protocol 07-137).
An important goal in neuro-oncology is accurate intraoperative visualization of malignant gliomas for image-guided resection. The laboratory of Moritz Kircher is developing novel molecular imaging nanoprobes that allow glioblastomas to be visualized both before and during surgery.
Such nanoprobes are based on multilayered gold-silica designs that contain a specific reporter detectable with Raman spectroscopy imaging. Raman imaging is an emerging optical technology that allows higher sensitivity and multiplexing capabilities than fluorescence-based optical imaging, and thus holds promise for more-accurate brain tumor delineation. The nanoprobe’s gold core also allows detection by photoacoustic imaging, a novel method that provides three-dimensional imaging with better depth penetration than optical imaging. Additional paramagnetic properties of the nanoprobe allow concomitant detection with MRI. In conjunction with a unique pharmacokinetic behavior, this allows preoperative MRI staging and intraoperative MRI/photoacoustic/Raman imaging to be performed with a single molecular imaging nanoprobe injection.
Memorial Sloan Kettering’s high-throughput screening (HTS) core facility, under the direction of Hakim Djaballah, has begun screening libraries of 250,000 compounds for effects on tumor cells. In these initial screens, several interesting compounds have been identified, including those that enhance the ability of radiation to kill cancer cells, specifically block cell proliferation, inhibit development of specific stem cells, and prevent cancer cell survival.
Radiation, which is one of the main treatments for gliomas, generates DNA damage, and our investigators are seeking ways to administer this therapy with minimal damage. Through a completed HTS screen, molecular biologist John Petrini and Hakim Djaballah identified a compound that synergizes with radiation in a nonneural tumor type. Ongoing projects include testing this compound in glioma cell lines or in glioma models, as well as performing screens looking for compounds that sensitize cells to radiation, specifically in glioma cells lines.
Molecular biologist Andrew Koff has a specific interest in the biology of the cell cycle in gliomas, and is working to understand the way that cells decide to replicate.
CNS stem cells play a role in response to injury, regeneration, and brain tumor formation. Developmental biologists Lorenz Studer and Viviane Tabar are using recent advances in stem cell biology to develop radically new therapies for degenerative disease and cancer. Mark Tomishima, who directs the human embryonic stem cell core facility, provides additional stem cell expertise.
Growth of primary brain tumors, especially gliomas, is characterized by a prominent proliferative vascular component. In response to angiogenic cytokines, chemokines and growth factors, endothelial progenitor cells are mobilized to the glioma vascular niche, subsequently differentiating and incorporating into the sprouting neo-vessels.
Neurosurgeon Philip Gutin along with Shahin Rafii, a hematologist at Weill Cornell Medical College, is studying the mobilization and recruitment of these bone marrow-derived pro-angiogenic cells — including endothelial progenitors and myelomonocytic precursors. This will expand the Brain Tumor Center’s repertoire in the diagnostic and therapeutic fronts to exploit glioma angiogenesis in the context of functional biomarkers and cell-based therapeutics.
Rapid high-field cellular magnetic resonance imaging methods (CMRI) are currently being employed to investigate the migrational patterns of magnetically-labeled myelomonocytic precursor cells to suitable preclinical brain tumor models by Michelle Bradbury. The translation of these cellular methodologies to the clinic will facilitate our understanding of tumor angiogenesis and other biological processes pertaining to tumors, as well as be utilized for therapeutic purposes. CMRI has recently been approved for use in brain tumor patients as part of an NIH phase I clinical trial.
There are some signaling pathways that are abnormally elevated in gliomas. Some of these — such as the PDGF, Ras, and Akt — have been shown in mouse modeling experiments to cause glioma formation. Human Oncology and Pathogenesis Program chairman Charles Sawyers and laboratory head of the Molecular Pharmacology and Chemistry Program Neal Rosen are focused on these pathways and developing drugs targeting these pathways in central nervous system tumors.
Investigators at Memorial Sloan Kettering have long been leaders in the development of mouse models for glioma, pre-clinical trials in glioma models, and molecular imaging of these models.
Cancer biology and genetics laboratory head Eric Holland developed the RCAS/tv-a system for glioma modeling, and has developed the testing of signal inhibitors and radiation in this mouse model. Some of the compounds tested have gone into brain tumor clinical trials, which have been based, in part, on pre-clinical trial data. The Holland laboratory has also developed bioluminescence reporter mice for use in preclinical trials.
In addition to utilizing optical imaging strategies in preclinical models, neuroradiologist Michelle Bradbury is focused on the non-invasive monitoring of central nervous system pathologies utilizing translational molecular imaging tools, such as positron emission tomography (PET).
By attaching a radioactive label to the most promising probes, PET imaging can be used to monitor and quantitate relevant tumor biology at the receptor level and in downstream signaling pathways. Using these methods, novel PET probes are currently being used to monitor treatment response to radiotherapy and small molecule pathway inhibitors in genetically engineered mouse models from the Holland laboratory. Additionally, nanoparticle probes are being formulated and tested in experimental models for future targeting of specific brain and head and neck tumors.
The immune system has been successfully harnessed to destroy cancer-bearing cells in experimental models of leukemia, lymphoma (Epstein-Barr Virus lymphoma), and prostate cancer. Immunologist Michel Sadelain is currently focused on the treatment of gliomas, specifically, on the role of cytokines in attracting T cells to these tumor types. Critical to targeting cancer cells is the ability to design and construct antigen receptors that will be used to genetically engineer T cells. The trafficking of these genetically engineered T cells in the CNS can then be observed non-invasively.