Emmanuelle di Tomaso, PhD
Assistant Professor of Radiation Oncology
Harvard Medical School
Edwin L. Steele Laboratory for Tumor Biology
As part of the Edwin L. Steele Laboratory for Tumor Biology, the Di Tomaso Lab studies the vascular physiology of neurofibromatosis type 2 tumors. NF2 is an autosomal dominant genetic disorder caused by mutations in the NF2 gene, and is characterized by the predisposition to develop multiple tumors, including schwannomas, meningiomas and spinal cord gliomas. Bilateral vestibular schwannomas are the hallmark of NF2, and these tumors invariably develop in patients with the disorder. Schwannomas and meningiomas are benign tumors of the nervous system that comprise 30% and 9% of all brain tumors, respectively. Although non-cancerous, these tumors cause significant morbidity including headache, hearing loss, vision loss, seizures and chronic pain. Tumor growth is often irregular with periods of growth followed by periods of quiescence. The traditional approach to treating these tumors has been surgical, but this option is not appropriate in all cases, especially for patients with multiple tumors, with tumors in the skull base or with significant medical co-morbidities. More recently, radiation therapy has been used to achieve local control in smaller tumors. Unfortunately, irradiation does not significantly decrease tumor size or reverse symptoms associated with schwannomas and meningiomas. In addition, chemotherapies for treatment of diffuse schwannomas and meningiomas are desperately needed and would have an enormous impact for these patients.
Although very well studied in the field of cancer, angiogenesis has been neglected in the field of benign tumors. However it is a vital step for any tumor to progress. The goal of my research is to use state of the art technology to address fundamental mechanistic questions regarding these tumors in a preclinical setting. The potential of using antiangiogenic treatment includes not only stabilization and or potential regression of an otherwise inoperable tumor, but also a contribution to the preservation of the acoustic nerve and or the cochlea. The use of anti-angiogenesis could therefore improve the clinical outcome by variables other than tumor growth alone.
We have developed a novel in vivo model in which schwannoma growth can be visualized within the brain of Nude mice to depths of 700 microns using multiphoton laser scanning microscopy. This technique is used to image the entire tumor volume and measure anatomical, molecular, cellular, and physiological parameters in vivo with three-dimensional resolution and greatly improved depth penetration. An invasive tumor front and individual migrating cells are easily and consistently identified, providing a reliable tool for studying potential changes in phenotypes. This approach allows us to determine the roles of various growth factors in the mechanisms of invasion and permeability-two aspects of physiology with unique characteristics in brain tumors. This project should illuminate the mechanism of the angiogenic switch in schwannomas and further the development of improved clinical treatments for these patients. We have also developed a highly innovative animal model with a tumor growing orthotopically on the nerve allowing for clinical assessment of the nerve impairment or recovery via gait analysis.
Our ultimate goal to develop a program of translational research integrating a preclinical program understanding of the mechanism of angiogenesis in this tumors with a strong clinical component seeking to establish the guide lines for a judiciously designed clinical trials.To this end my group has established a strong collaboration with the director of the Neurofibroamtosis clinic at Massachusetts General Hospital, one of the main centers in the country, providing a unique integration of 'bench and bedside."
Another important part of my research is focused on understanding angiogenesis and progression through antiangiogenic treatment of glioblastomas multiforme. Diffusely infiltrating astrocytomas are the most frequent intracranial neoplasms and account for more than 60% of all primary brain tumors. The most frequent (50-60%) of all astrocytic tumors, they are composed of poorly differentiated neoplastic astrocytes with areas of vascular proliferation and necrosis. The average survival time of glioblastoma patients is approximately 18 months after symptom onset, and is fewer than three months in about 50% of cases. Our laboratory is committed to expanding our understanding of these pathways on preclinical as well as clinical levels through correlative studies of Phase I and Phase II clinical trials in colorectal carcinoma patients. Based on the success of initial studies in colorectal cancer, similar studies with tyrosine kinase inhibitors in patients with recurrent gliomas have been initiated. It is expected that that our preclinical studies combined with additional clinical data, will suggest ways to optimize combination treatment of gliomas.
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