Drug Response and Resistance in Advanced NF-1-Associated Cancers
Final rept. 1 Apr 2012-31 Mar 2015
CALIFORNIA UNIV SAN FRANCISCO
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Juvenile myelomonocytic leukemia JMML is a myeloproliferative neoplasm MPN that sometimes progresses to acute myeloid leukemia AML. The NF1 gene is frequently inactivated in NF1 patients who develop either JMML or AML. However, AML is a more aggressive malignancy that contains multiple genetic alterations that cooperate with NF1 loss. We have characterized MPN and AML in Nf1 mutant mice and have investigated mechanisms of drug responses and resistance. Our studies of MEK inhibitors in Nf1 mutant mice unexpectedly showed that cooperating mutations that are acquired in AML increase the dependence of these cells on RafMEKERK signaling. However, resistant AML clones rapidly emerged in vivo. The goal of this project is to deploy mouse models of AML to test the requirement for NF1 GTPase activating protein GAP activity in cancer maintenance and to develop a preclinical paradigm for combining conventional and targeted anti-cancer agents in vivo. Major accomplishments of this project include 1 developing a robust system for modulating gene expression in primary leukemia cells in vivo 2 constructing versatile vectors for restoring GAP activity in primary cells 3 generating data supporting the hypothesis that AML cells remain dependent on Nf1 inactivation 4 implementing protocols for treating mice with CPX-351 and 5 performing in vivo studies of drug combinations in Nf1 mutant AML.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research