Maintenance of the genome: mechanism of cancer, opportunity for treatment
Along with his leadership of the Yale Pediatric Hematology and Oncology Program, Dr. Gary Kupfer also is a laboratory investigator who studies how cells normally maintain genome integrity as well as how defects in such a system can lead to cancer. While many of these studies involve basic biology, new findings in his laboratory have demonstrated to connections to adult cancer as well, such as breast cancer. In addition, the basic studies in the Kupfer laboratory have lead to the potential for clinical applications, as the Kupfer laboratory is working on a new way to treat resistant cancers. The Kupfer laboratory is currently involved in work engineering a viral protein to be used in concert with standard therapy to make chemotherapy more effective.
The Kupfer lab works on the relationship of genomic instability and the propensity towards development of cancer. Specifically, we focus on the genetic syndrome Fanconi anemia (FA). Interestingly, children with FA are born with congenital anomalies and develop aplastic anemia and an assortment of leukemias and other cancers. FA serves as a paradigm where the disciplines of development, genetics, and molecular oncology come together. Like other cancer susceptibility syndromes, such as ataxia telangiectasia and xeroderma pigmentosum, FA patients exhibit a unique hypersensitivity to DNA crosslinking agents, which is the key to the biology of FA. Unlike the other syndromes, exceedingly little is known about FA. Eleven complementation groups have been elucidated, with all exhibiting similar phenotypic characteristics, suggesting an interrelationship of proteins in a complex or in a linear pathway. To date, 13 genes have been cloned, but the encoded proteins bear no resemblance to each other or to any other known proteins. We have focused on the relationship of the FA proteins to regulation of the cell cycle, signal transduction response to DNA damage, and formation of specific protein complexes of DNA repair.
Based on our interest on marrow failure and genomic instability, we have also started working on 3 related projects. First, we have begun to purify the protein complexes containing gene products that are defective in 2 additional bone marrow failure syndromes, Diamond-Blackfan anemia (DBA) and congenital dyserythropoietic anemia (CDA). As in FA, the proteins (RPS19 for DBA, codanin for CDA) have no known function, and additional genes accounting for additional genetic complementation groups remain to be cloned and identified.
Second, we are investigating ways to use our knowledge of genomic instability for improving cancer therapeutics. We have been working on tax1, a viral oncogene encoded by HTLVI, a cousin of the HIV retrovirus. Interestingly, tax1 chemosensitizes p53 mutant cells in culture. This observation is especially important, as p53 mutations are found in a majority of all human cancers and are the leading cause of resistance to chemotherapy. Our goal is adapt the tax1 effect on cells with p53 mutations in order to make cancer therapy more effective in resistant tumors.
Finally, we have also started a more clinical project, using mass spectroscopy technology we have used to find FA binding proteins. We have adapted the mass spec to analyze sera from patients with pediatric malignancies in order to identify unique protein markers of disease. These markers could then be used for diagnosis, prognosis, staging, and tracking of minimum residual disease in patients. In addition, our goal is to identify interesting proteins for further analysis in our laboratory.
Massaro Laboratory: The biology of platelets and leukemia
Dr. Stephanie Massaro is a young faculty member who devotes her time to the study of acute megakaryoblastic leukemia (AMKL) is a rare form of leukemia that affects megakaryocytes, which are platelet-making blood cells. The disease most commonly strikes very young children. Approximately 30% of pediatric patients diagnosed with AMKL are infants who have a specific genetic abnormality that involves two genes, RBM15 and MKL1. These genes may play important roles in normal blood cell development. However, when they are incorrectly linked together, they may contribute to leukemia development by altering Notch signaling, a normal cell signaling pathway responsible for cellular growth and maturation. This aberrant Notch signal may cause a failure of the tumor suppressor protein Rb and result in uncontrolled growth of immature megakaryocytes. This abnormality is associated with an extremely poor outcome, with an average survival time of only eight months from diagnosis despite aggressive medical therapy.
This project combines clinical interest in malignant hematology and basic scientific approach to understanding the pathogenesis of AMKL. Dr. Massaro’s commitment to this project is strengthened by my interactions with the patients she follows clinically. This information may lead to superior childhood leukemia outcomes by improving diagnostic strategies and developing new immuno- and chemotherapeutic agents.