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Grant given to Texas Children's Hospital Histiocytosis Program of $25,000 in January 2015: LCH Sequencing Studies
Summary of LCH Sequencing Studies:
We have investigated all of the regions of DNA that are used to give instructions for making RNA and proteins in LCH lesions and matched blood from the same patients, with some remarkable findings. First, compared to classic pediatric “cancers”, there are an extremely small number of genetic changes in the LCH lesions. However, almost every patient has a change (or mutation) in genes that encode proteins in a pathway that regulates cell growth, proliferation and development, called the Map kinase (MAPK) pathway. Approxiately 50% of patients have a mutation in the B-RAF gene, another 25% have a mutation in a gene called MAP2K1, and other potentially significant mutations were found in other MAPK genes. In order to fully define the mutations that may give rise to LCH, we plan to perform targeted sequencing of a limited panel of candidate genes in a much larger number of LCH samples. In addition to discovering more rare mutations that may lead to LCH, these experiments will be linked to long-term clinical information to determine the impact of specific mutations on clinical outcomes. For the few cases (~25%) where no mutation is discovered by targeted sequencing, we will perform more extensive studies to look at the entire genome (whole genome sequencing) as well as RNA profile (RNASeq) to identify other potential mechanisms of pathogenesis in LCH. By the end of this study, we should be able to develop an approach to define the vast majority of mutations that cause LCH and also to interpret the clinical significance of these mutations. In the future, this information may be used to incorporate a personalized approach to therapy for patients with LCH. Specific mutations may determine intensity and duration of therapy for each patient, as well as potential to use specific targeted drugs.
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Lay Abstract:
Our laboratory is interested in taking an entirely novel approach to enhance cytotoxic function in children with defects in Natural Killer (NK) and Cytotoxic T cell (CTL) function leading to HLH. We havedeveloped and executed the first known pilot screen for small-molecule enhancers of NK and CTL function in collaboration with the NIH Molecular Libraries Small Molecule Repository Program. We identified a novel class of pharmacologic compounds in our screening assay that uses cultured human NK cells and a surrogate of NK killing. We now need to 1) validate whether enhancers of luciferase signal are true enhancers of NK cytotoxic function using patient-derived freshly isolated and cultured NK cells and 2) identify the mechanism by which the compounds are working. Our ultimate goal is identify molecular pathways that will permit new drugs to be developed for HLH. This research effort has the potential to ultimately change the outcome for children with inherited defects in cytotoxic function associated with the potentially fatal disorder, hemophagocytic lymphohistiocytosis (HLH), especially for those children and/or adults who have residual NK function. Anticipated Benefits of funding: Children with rare genetic disorders that disable NK and CTL function may develop malignancies, severe viral infections, or HLH. We predict that CTL/NK modulators will improve the function of CTL/NK in HLH and other immunodeficiencies conditions marked by impaired cytotoxic function and therefore provide an alternative or augmented therapy for these devastating conditions. We are particularly interested in the development of new drugs for children with HLH as this is our laboratory’s and hospital’s area of clinical and research expertise. The Risma laboratory has been focused on understanding perforin-dependent NK and CTL killing in children with HLH with the hopes to identify small molecule chaperones and/or correctors that would be useful to develop for clinical applications. |
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