Identifying Novel Therapeutic Targets and Combination Strategies for Patients with BPDCN
Abstract
Project 1: We measured characteristics of leukemia cells before and after treatment tagraxofusp (SL401) and determined that diphthamide pathway genes are silenced after tagraxofusp exposure. We also measured up-front markers of leukemia cell sensitivity to tagraxofusp and found that CD123 level correlates with baseline sensitivity but ADP-ribosylation activity of diphthamide on eEF2 by TAG does not. This suggests that diphthamide activity mediates resistance but is not a biomarker of baseline sensitivity in untreated leukemias. We also developed a BPDCN cell system for CRISPR/deadCas9 interference and performed a genome-wide CRISPRi screen for genes that affect sensitivity and resistance to tagraxofusp or venetoclax plus azacitidine. In Project 2, we have demonstrated synergistic activity combining anti-CD123 targeting agents (IMGN632 or SL401) with venetoclax and with VENetoclax and AZAcitidine, in BPDCN and AML cell lines. Mechanistic studies focusing on IMGN632/venetoclax combination have shown upregulation of apoptotic markers, profound cell cycle arrest and induction of DNA damage, which were reduced upon p53 silencing. IMGN632/venetoclax combination eradicated BPDCN in a PDX BPDCN model. We have determined the recommended phase 2 dose (RP2D) for the TAG/AZA/VEN triplet in AML/MDS trial and have recently received IRB and HRPO approval for amendment to add BPDCN cohort. We plan to initiate BPDCN enrollment in year 2 of funding period. Project 3: We determined that ZRSR2 mutations in BPDCN cells promote evasion of apoptosis by missplicing of genes in the toll-like receptor pathway, particularly the interferon response gene IRF7. This renders BPDCN cells hypoactive compared to normal pDCs in the setting of inflammation and protects them from activation-induced cell death.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1199631
Entities
People
- Andrew A Lane
- Marina Konopleva
- Omar Abdel-Wahab
Organizations
- Dana–Farber Cancer Institute
- Memorial Sloan Kettering Cancer Center
- University of Texas at Austin