BRAF Mutation in Malignant Astrocytoma Origin, Evolution, and Response to Therapy
Location(s): United States
Despite the investigation of numerous novel therapeutics and treatment approaches, the outcome for pediatric malignant astrocytoma (MA) patients has seen little improvement over several decades of basic, preclinical, and clinical research. Our research is expected to 1) inform regarding the cellular origin of MA;2) provide new insight about the molecular mechanisms of neoplastic transformation, especially those involving asymmetric cell division (ACD), that promote brain tumor development;3) increase our understanding of brain tumor cell subpopulations responsible for therapy resistance and tumor recurrence, and as such our studies will 4) ultimately facilitate the identification of molecular targets for improved MA treatment.
Aim 1. Using genetically engineered mouse models (GEMMs), we will determine effects of BRAFVE expression on ACD, proliferation, differentiation, and survival, and association with MA tumorigenesis in NSCs and mature astrocytes.
Aim 2. To complement the GEMMs studies in aim 1, we will suppress p16 expression and force BRAFVE expression in human NSCs and normal human astrocytes, using lentiviral shRNA knockdown and BRAFVE gene transfer, respectively. Modified NCS and NHAs as well as MA cells with BRAFVE expression will be characterized, both in vitro and in vivo, for the same characteristics as for the mouse model tumors in aim 1.
Aim 3. Investigate BRAFVE tumor cells and tumor tissues, in vitro and in vivo, respectively, for molecular changes, TIC composition, and ACD in association with response to BRAFVE targeted therapy. This research will include comparison of effects when tumors are in a responsive phase to therapy, as well as when they have acquired resistance to therapy, and will utilize both human tumor xenograft and mouse allograft models. Our project will: 1) generate new information regarding the cellular origin of BRAFVE induced MA;2) provide insight about the molecular mechanisms of neoplastic transformation resulting in brain tumor development;3) increase our understanding of brain tumor cell subpopulations that are responsible for therapy resistance and tumor recurrence, and in so doing, 4) will ultimately lead to improved treatment outcomes for MA patients.