The goals of this project are to use genetic means to demonstrate that the Rho GTPase, Cdc42 constitutes a novel target in leukemia stem cells (LSCs), and to apply a lead pharmacologic inhibitor of Cdc42 to suppress deregulated Cdc42 activity in human blood stem cell malignancies. The Cdc42 signaling axis lies at the crossroads of many signaling events and the functional interaction between Cdc42 and many of its implicated effectors mediate a variety of physiological responses including actin cytoskeletal reorganization, adhesion, migration, survival, and proliferation, of blood stem/progenitor cells. Cdc42 has been suggested to mediate Ras-transformation by signaling through growth factor receptors and to transduce cytokine signals into the nucleus to impact on cell proliferation. In the preliminary results, we have built up a basic conceptual framework suggesting that Cdc42 targeting can inhibit leukemia stem cell adhesion and engraftment, promote LSC mobilization from the bone marrow, and induce LSC apoptosis, in mouse models. We have also generated and established a collection of important reagents, mouse models, and methodologies including a conditional gene targeted mouse model, a human stem/progenitor transformed acute myeloid leukemia xenograft model in """"""""humanized"""""""" mice, a lead Cdc42-activity specific inhibitor, CASIN, that is capable of specifically suppressing Cdc42 activity in blood progenitors, and Cdc42 mutant reconstitution/xenotransplantation add-back methods in defining the requirement of immediate signaling pathways regulated by Cdc42. In this proposal, we will test the hypothesis that Cdc42 is essential for the maintenance of LSCs in the BM niche and represents a novel therapeutic target for leukemia eradication. We will (1) genetically validate Cdc42 as a target in murine AML onset and progression by conditional gene targeting and mutant reconstitution approaches; (2) determine the effect and molecular mechanisms of Cdc42 knockdown on human AML progression in a humanized mouse model;and (3) apply the Cdc42-specific inhibitor, CASIN, to mobilization of human AML leukemia stem cells from xenograft mouse bone marrow and examine the combinatorial effect of CASIN together with the conventional chemotherapy agents on AML leukemia stem cell eradication. Our studies may implicate Cdc42 as a critical nodal of intracellular signal flows from multiple stimuli involved in leukemia stem cell maintenance in the bone marrow niche. The results will bear direct therapeutic value that pharmacologic targeting of Cdc42 in LSCs may allow for more effective combinatory chemotherapy in the effort to eradicate leukemia.
Cdc42 GTPase and leukemia stem cells have emerged as potential anti-cancer therapeutic targets by recent studies. The proposed work will pursue genetic and pharmacologic targeting of Cdc42 to benefit leukemia therapy by introducing a novel concept that targeting Cdc42 in leukemia stem cells could result in their mobilization from the niche and this could serve as a new means in combinatory therapy. The studies will translate the mechanistic information obtained from the decades-long biochemical, cell biological, and genetic studies of Cdc42 and leukemia into future therapy.
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|Zandvakili, Inuk; Davis, Ashley Kuenzi; Hu, Guodong et al. (2015) Loss of RhoA Exacerbates, Rather Than Dampens, Oncogenic K-Ras Induced Lung Adenoma Formation in Mice. PLoS One 10:e0127923|
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|Melendez, Jaime; Liu, Ming; Sampson, Leesa et al. (2013) Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice. Gastroenterology 145:808-19|
|Zhou, Xuan; Zheng, Yi (2013) Cell type-specific signaling function of RhoA GTPase: lessons from mouse gene targeting. J Biol Chem 288:36179-88|
|Shang, Xun; Marchioni, Fillipo; Sipes, Nisha et al. (2012) Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem Biol 19:699-710|
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