Researchers at UC San Francisco are leading a five-year, $10 million research project dedicated to pediatric cancer, funded by the first grant of its kind to focus on a molecular pathway that underlies many cancers rather than on a cancer in a particular organ or tissue in the body.
The grant's design captures a growing understanding, spurred by genome sequencing, that cancers may be better diagnosed and treated if defined by genetic defects in particular molecular pathways, rather than by the tissues in which they originate.
The new grant was awarded under the Specialized Programs of Research Excellence (SPORE) program of the National Cancer Institute (NCI), part of the National Institutes of Health. SPORE grants, launched by the NCI in 1992, are among the most competitive and prestigious awards for cancer research.
"This new grant reflects researchers' increasing realization that seemingly diverse cancers can be grouped together by common defects in molecular pathways. Moreover, the award is testament to UCSF's great strengths in understanding and treating childhood cancer," said Alan Ashworth, PhD, FRS, president of the UCSF Helen Diller Family Comprehensive Cancer Center and senior vice president for cancer services at UCSF Health.
Known as the DHART (Developmental and HyperActive Ras Tumor) SPORE, the grant caps more than 20 years of joint research by co-principal investigators Kevin M. Shannon, MD, of UCSF, and D. Wade Clapp, MD, of Indiana University School of Medicine (IUSM), and their colleagues on neurofibromatosis type 1 (NF1), a common inherited condition in which multiple different tissues develop abnormally. Patients with NF1 have a higher risk of developing a range of cancers, including certain forms of leukemia, which are usually diagnosed in childhood, adolescence, or young adulthood.
SPORE grants have traditionally funded research at a single institution, but the new DHART SPORE represents a collaborative effort of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) and the Indiana University Melvin and Bren Simon Cancer Center. For the new initiative, Shannon and Clapp, chair and Richard L. Schreiner Professor in the Department of Pediatrics at IUSM, have recruited a team of leading NF1 researchers from UCSF, IUSM, University of Texas Southwestern Medical School, the Johns Hopkins University School of Medicine, the University of Alabama School of Medicine, the National Institutes of Health, and other sites.
"This novel SPORE program will integrate data from preclinical studies in genetically engineered mouse models of NF1 with precision medicine technologies. The ultimate goal is to generate high-resolution molecular information on NF1-assocated tumors before and after patients are treated with targeted drugs," said Shannon, the Roma and Marvin Auerback Distinguished Professor of Molecular Oncology in UCSF's Department of Pediatrics and a member of the HDFCCC. "Another unique aspect of this effort is a focus on understanding how radiation and chemotherapy promote the development of secondary malignant neoplasms, new cancers that emerge after treatment. This is a very serious problem in both pediatric and adult cancer survivors."
NF1 is caused by mutations in a gene of the same name, which is a "tumor suppressor": the NF1 gene normally puts the brakes on the Ras pathway, a cascade of protein interactions that drives the growth and proliferation of cells. Individuals with NF1 are born with a mutation in one copy of this gene. Tumors develop after a second mutation occurs in the remaining copy of the NF1 gene in a susceptible cell in the nervous system or bone marrow, which allows the Ras pathway to operate unchecked.
In addition to its importance in NF1 patients, the NF1 gene is of wide interest in cancer research because NF1 mutations also arise in many non-inherited adult cancers, including lung cancer, brain cancer, and melanoma. Moreover, although the Ras pathway has been implicated in about a third of all cancers, the Ras protein itself has proved exceedingly difficult to target directly with drugs. Shannon said that a deeper understanding of how the NF1 protein interacts with Ras has broad implications for cancer treatment.
To study NF1 at the cellular and molecular levels, Shannon and colleagues began developing mouse models of the disease almost 20 years ago, which has helped them decipher how NF1 mutations alter the Ras pathway and to identify promising treatment approaches. The DHART SPORE will support the continuation of this basic and preclinical research.
In addition, UCSF's Mignon Loh, MD, professor of pediatrics, will launch clinical trials at UCSF Benioff Children's Hospital and a consortium of collaborating institutions to assess the effectiveness of trametinib (Mekinist)—a drug that precisely targets and blocks the action of one component of the Ras pathway—in the treatment of an aggressive pediatric cancer called juvenile myelomonocytic leukemia (JMML). Shannon and Loh discovered mutations in NF1 and other genes that control Ras activity in patients with JMML, and trametinib has been shown to be highly effective in mouse models of the disease.
Already approved by the Food and Drug Administration, trametinib is now a standard therapy for patients with certain forms of melanoma.
Another DHART SPORE project, led by Smita Bhatia, MD, MPH, director of the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham School of Medicine, and Jean Nakamura, MD, associate professor of radiation oncology at UCSF, will do basic research on secondary malignant neoplasms (SMNs). Bhatia and Nakamura will explore why and how radiation therapy in children with cancer sometimes causes these new cancers, which emerge later in life and affect between 90,000 and 100,000 patients per year.
As co-directors of a new DHART SPORE Biospecimen/Pathology Core at UCSF, Scott C. Kogan, MD, professor of laboratory medicine, and Andrew Horvai, MD, PhD, professor of pathology, will oversee storage of the data needed for the selection and analysis of specimens, and will serve a critical role in facilitating science-driven clinical trials based on concepts of precision medicine.
"Over the course of many years, we have developed a lot of understanding of how the NF1 protein regulates Ras through bench-to-bedside translational research," Shannon said. "Now, with the DHART SPORE, we plan to leverage all this knowledge to help children, adolescents, and adults with NF1-associated cancers, by working with pharmaceutical companies to target and shut down the proteins that Ras activates."
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