NCI Specialized Program Of Research Excellence (SPORE)
The Developmental and HyperActive Ras Tumor (DHART) SPORE is sponsored by the National Cancer Institute, with the goal of implementing effective targeted molecular therapies for neoplasms and cancers characterized by germline and somatic NF1 mutations.
The SPORE is co-led by Kevin M. Shannon, MD (UCSF) and D. Wade Clapp, MD (Indiana University School of Medicine), and brings together researchers at the Pediatric Branch of the NCI and six academic institutions. Other UCSF investigators conducting research on the SPORE include Benjamin Braun, MD, PhD; Elliot Stieglitz, MD; Mi-Ok Kim, PhD; and Scott Kogan, MD.
The overall goal of the SPORE is to implement effective new targeted treatments for tumors characterized by mutations of the NF1 tumor suppressor gene. The collaborating researchers are pursuing this goal by conducting integrated, mechanistically based translational research. In contrast to most other SPORE efforts supported by the NCI, the DHART SPORE does not focus on a particular type of cancer. Instead, the strategy is to implement new treatments for tumors that develop in different tissues due to NF1 mutations.
This program encompasses three highly integrated projects and three cores. Across all three projects, genome-wide analysis of clinical specimens and murine cancers will elucidate molecular mechanisms of tumorigenesis in primary and second malignancies.
The DHART SPORE represents the translational research component of the Cancer Center’s Pediatric Malignancies Program, which brings together basic and clinical researchers with the shared goal of improving the outcome for children with cancer.
Overview
The focus of the DHART SPORE is on tumors that develop in patients with neurofibromatosis type 1 (NF1). NF1 is a both a disorder in which the development of multiple different tissues is abnormal and the most common inherited cancer predisposition syndrome. Persons with NF1 have a markedly increased incidence of developing specific tumors, which are frequently diagnosed in children, adolescents, and young adults. NF1 is also the founding member of a group of developmental disorders called the “Rasopathies” that also includes Noonan, Legius, Costello, and cardiofaciocutaneous syndromes. A unifying molecular feature of the Rasopathies is that they are caused by inherited mutations that aberrantly “turn on” Ras proteins or activate proteins that are regulated by Ras.
While the focus of this SPORE is on testing rational, mechanism-based treatments for tumors that develop in patients with NF1, this research has broad relevance for improving the treatment of the large number of cancers arising in patients without NF1 that carry mutations in NF1 or in RAS genes. These common cancers include glioblastoma, lung cancer, melanoma, and leukemia. In addition, molecular and epidemiologic studies within the DHART SPORE address the role of radiation and chemotherapy in causing secondary malignancies, with is a fundamental problem in the growing population of cancer survivors worldwide. Given the central importance of aberrant Ras/GAP function in human cancer and the emerging role of somatic NF1 mutations in common sporadic malignancies, achieving the goals of this SPORE will broadly advance translational cancer research and stimulate the development of “next generation” treatments.
Research Projects
- Project 1: From Neurofibroma to MPNST: Models, Biology and Translation to Clinic
- Project 2: NF1-associated Glioblastoma
- Project 3: A High Content Clinical Trial of the MEK inhibitor Trametinib in JMML
Learn more about the research projects here.
Cores
The cores provide support for the main research projects, developmental research projects, and career development investigators to facilitate and expand translational research for the SPORE research efforts. The Administrative Core provides scientific and fiscal oversight for the program as well as coordination of the development of an integrated SPORE database in which all preclinical and clinical trial data will be stored and shared by all investigators. All data, including data generated and analyzed by the following research cores will be delivered and integrated into the database.
There are two state-of-the-art research core research facilities. The Biospecimen/Pathology Core receives human and mouse samples from all three SPORE projects, and also performs pathological review of these samples. The Omics Core provides state-of-the-art support for research design consultation, performance of genomics and kinomics experiments, and integrated data analysis to DHART investigators to elucidate changes during NF1-related tumor development and in response to therapy.
Learn more about the cores here.