Projects

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 Andy 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.