Identifying Novel Therapeutic Targets and Combination Strategies for Patients with BPDCN
Abstract
Project 1: We used CRISPR interference to perform an unbiased assessment of genes that confer sensitivity or resistance to tagraxofusp or to venetoclax and azacitidine when knocked down. We compared these data to RNA-sequencing of BPDCN cells at baseline and in the setting of MRD after treatment with the same drug. We identified hits in expected pathways that mediate resistance to venetoclax and tagraxofusp. One important hit was a largely uncharacterized RNA binding protein that confers sensitivity to both treatments when depleted. We performed eCLIP-seq to identify targets of this RNA binding protein and are currently performing experiments to understand the mechanism of sensitization. Project 2. We expanded efficacy study of the combination of IMGN632/VEN/AZA. By using large scale drug screen followed by BLISS independence analysis, we confirmed that triple treatment is synergistic at multiple of dosage levels and ratios in AML cell lines and primary samples. Mechanistically, BH3 profiling indicated that IMGN632 alone significantly primed AML cells to venetoclax-induced apoptosis, providing a strong rationale for tested combination. We also showed that IMGN632-indued DNA damage resulted in cell cycle arrest, blockade of DNA synthesis and activation of DNA damage response (DDR). Importantly, venetoclax impaired DDR triggered by IMGN632, which may additionally account for the increased efficacy of IMGN632/VEN combination. At clinical level, we opened the expansion cohorts for patients with BPDCN using the RPD2 of TAG/AZA/VEN: one cohort for first line treatment and second one for relapsed or refractory BPDCN. To date, 6 patients with r/r BPDCN and one patient with previously untreated BPDCN has been enrolled. Complete responses (CRs) were observed in 4 of 6 patients with r/r BPDCN who further proceeded to stem cell transplantation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1194698
Entities
People
- Andrew A Lane
- Marina Konopleva
- Omar Abdel-Wahab
Organizations
- The University of Texas MD Anderson Cancer Center