Evidence linking dysregulation of cell cycle and Bcl-2 family proteins in the molecular pathogenesis of multiple myeloma (MM) has prompted intense interest in cyclin-dependent kinase (CDK) inhibitors and Bcl-2 antagonists in this disease. Furthermore, recent findings suggest that certain CDK inhibitors (e.g., flavopiridol;FP) act as transcriptional repressors by inhibiting the CDK9/cyclinT pTEFB complex, and by extension, phosphorylation ofthe carboxy-terminal domain of RNA Polll. Such agents down-regulate expression of short-lived proteins including Mcl-1, a critical survival factor in MM. Significantly, CDK inhibitors have recently been found to enhance the lethality of Bcl-2 antagonists (e.g. ABT-737) in human leukemia cells by unleashing Bak from Bcl-xL and Mcl-1, leading to a dramatic potentiation of apoptosis. Notably, a novel FP schedule has recently been developed which displays significant activity in another B-cell malignancy (CLL). We therefore hypothesize that clinically relevant CDK inhibitors such as FP, seliciclib (Rroscovitine), and SCH727965, an agent with an 1050 of 1 nM toward CDK9, represent logical candidate agents to enhance the activity of clinically relevant Bcl-2 antagonists (e.g., GX15-070, ABT-737) in MM. Indeed, preliminary evidence suggests a high degree of synergism between FP and GX15070, as well as other CDKI/Bcl-2 antagonist regimens, in MM cells. Evidence also suggests that such regimens induce upregulation of pro-apoptotic proteins (e.g., Bim, NOXA, and BIK) which may cooperate with Mcl-1 downregulation to trigger apoptosis.
In specific aim #1, we will employ genetic tools to test the hypothesis that synergistic interactions between CDK inhibitors and Bcl-2 antagonists stem from Mcl-1/XIAP downregulation, upregulation of Bim, NOXA, and BIK, release of Bak and BIM from both Bcl-xL and Mcl-1, Bax/Bak activation, and induction of mitochondrial injury. This information will guide the selection of correlative laboratory studies in subsequent planned clinical trials.
In Specific Aim #2, we will determine whether and by what mechanism(s) this strategy overcomes conventional drug resistance, stromal/cell adhesion- or growth factor-mediated drug resistance, and bortezomib or lenalidomide resistance in MM cells.
In specific aim #3, we will evaluate the selectivity of this strategy by comparing its activity against primary, patient-derived CDI38* MM versus their normal counterparts (e.g., CDI38"""""""", CD34* cells), and testing its in vivo efficacy using flank and systemic xenograft MM models.
In Specific Aim #4, we will use this information as a foundation for initiating one or more Phase I trials of CDKIs (e.g., FP) and Bcl-2 antagonists (e.g., GX15-070) in patients with refractory MM. Collectively, these studies will provide a rational foundation for a novel approach to MM therapy in which the activity of clinically relevant Bcl-2 antagonists (e.g., GX15-070 or ABT- 737) is enhanced through rational combination with transcriptionally repressive CDK inhibitors that disrupt the pTEFb complex (e.g., FP, seliciclib, or SCH727965) in patients with refractory MM.
Showing the most recent 10 out of 203 publications
