Understanding Drug Resistance to Targeted Therapeutics in Malignant B-Cell Lymphoproliferative Disorders (B-LPDs)
Annual rept. 15 Sep 2013-14 Sep 2014
DUKE UNIV DURHAM NC
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Small molecule inhibitors of B cell receptor BCR mediated signaling broadened therapeutic alternatives for patients with Bcell lymphoproliferative disorders B-LPDs, but understanding of drug resistance mechanisms is needed. We studied correlative samples from 15 subjects enrolled on the clinical trial of the novel microenvironmentally targeting combination of lenalidomide and plerixafor. We discovered increasing longitudinal CXCR4 expression as a possible mechanism enabling cells to migrate along the CXCR4-CXCL12 axis to the protective niches of the microenvironment. Surface CD52 decreases in those remaining on therapy, and soluble APRIL increased in a subject previously progressing on a PI3Kdelta inhibitor may be biomarkers to risk for primary or secondary resistance. We also studied primary CLL cells exposed to tyrosine kinase inhibitors of interest including those that target BTK, PI3K, and MEK and to caspase inhibitors as a marker of apoptotic machinery. Surprisingly caspase inhibition induced CLL cell death, rather than protecting, and does not appear that the mechanism for this finding is necroptosis. Finally we established co-culture stromal systems and flow based assays of drug induced apoptosis or death to evaluate the selected therapeutic inhibitors. Our ED50 and 50 reduction in target p-protein lowering may be due to patient selection. Ongoing experiments are detailed to confirm and expand these findings.
- Medicine and Medical Research