Xtem Pharmaceuticals Inc — Department of Health and Human Services SBIR Phase I: NCI

Description

The Bcr Abl kinaseproduced by a chromosomal translocation known as the Philadelphia chromosomeinduces CML by driving aberrant differentiation of hematopoietic stem cellsRelevant to this proposalBcr Abl is thought to promote CML by causing elevated expression of the oncoproteinc MycCML patients in the early stages of the diseaseknown as chronic phaseCPare usually responsive to tyrosine kinase inhibitorsTKIsthat target Bcr Ablin that theyear progression free survival rate isHoweverlong term remission is rarely achieved and patients usually experience relapse upon cessation of TKI treatmentThis has been interpreted as indicating that a population of leukemia initiating cellsLICsis refractory to TKI treatmentLICs are thought to possess properties similar to hematopoietic stem cells such as self renewal and quiescencerendering them resistant to therapyincluding TKI treatmentIndeed transplantation studies in mouse CML models have suggested that only this small population can initiate disease in new animalsTaken togetherthese findings suggest that CML LICs serve as a reservoir of BCR ABL possessing but TKI resistant cells that prevent remissionCML patients diagnosed with more advanced disease usually do not experience long term survivalbut insteadafter initially responding to TKIsrelapse with resistant diseaseusually resulting from kinase domain mutations of Bcr AblThis is likely the result of a larger pool of LICs in such patientsClearlynew approaches are needed to effectively treat both chronic and acute phases of CMLIt has been shown that deletion of FBWwhich encodes the substrate binding subunitthe SCFFbwubiquitin ligasein mouse CML models drives LICs out of quiescence and promotes their apoptosisas well as sensitizing them to TKIsThese effects have been shown to be the result of stabilization and resultant elevated levels of c Mycwhich is already expressed at high levels in LICsThereforewe are proposing to use mouse CML models to determine whether SCFFbwsmall molecule inhibitors have therapeutic potential in CML Chronic myelogenous leukemiaCMLis a common malignancy that usually responds to therapy that targets the Bcr Abl tyrosine kinaseHowever long term remission is usually not attained because stem like leukemia initiating cells are resistant to this treatmentThis proposal seeks to test a novel small molecule that is likely to target specifically the leukemia initiating cell population of CML thereby enhancing the efficacy of Bcr Abl inhibitors in achieving long term remission