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Method for Selecting Potential Ibrutinib-Based Combinations in CLL

By: Sarah Campen, PharmD
Posted: Wednesday, August 7, 2019

Investigators have developed an integrated analysis that may be useful to identify targetable pathways for new combination therapies to treat patients with chronic lymphocytic leukemia (CLL) who experienced disease progression with or resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib. By combining an assay to measure chromatin accessibility with a method for ex vivo single-cell synergistic chemosensitivity profiling, they established a comprehensive picture of the cellular responses to ibrutinib. The results were presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting in Atlanta (Abstract 319/10).

“Our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples,” stated Christoph Bock, PhD, principal investigator at the Research Center for Molecular Medicine, Vienna, and colleagues.

In this study, assay for transposase-accessible chromatin with high-throughput sequencing was used to evaluate peripheral blood specimens, collected before and after treatment with ibrutinib, from 24 patients with CLL; this assay measured chromatin accessibility “to gather the genome-wide regulatory landscape.” Pharmacoscopy, a method for ex vivo single-cell drug cytotoxicity profiling in primary samples, was used to measure chemosensitivity to more than 130 drugs on paired CLL samples.

Dr. Bock and colleagues integrated these two data sets and also performed a secondary combination screen of drugs with ibrutinib in samples from eight ibrutinib-naive patients to visualize changes in targeted sensitivity of key drugs with and without ibrutinib. They observed gained sensitivity to the proteasome PLK1 and mTOR inhibitors during ibrutinib treatment and validated their findings through image-based screening and classical CLL co-culture models.

Disclosure: The study authors’ disclosure information may be found at abstractsonline.com.



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