PlumX Metrics
Embed PlumX Metrics

Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

bioRxiv, ISSN: 2692-8205
2024
  • 0
    Citations
  • 0
    Usage
  • 0
    Captures
  • 1
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Mentions
    1
    • News Mentions
      1
      • 1

Most Recent News

Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

2024 FEB 19 (NewsRx) -- By a News Reporter-Staff News Editor at Clinical Oncology Daily -- According to news reporting based on a preprint abstract,

Article Description

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NF-κB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton-tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NF-κB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NF-κB signaling and the UPR, culminating in profound anti-tumor properties independent of TME stimuli.

Bibliographic Details

Alexandria P. Eiken; Audrey L. Smith; Sydney A. Skupa; Elizabeth Schmitz; Sandeep Rana; Sarbjit Singh; Siddhartha Kumar; Jayapal Reddy Mallareddy; Amarnath Natarajan; Dalia El-Gamal; Aguirre A. de Cubas; Akshay Krishna; Achyuth Kalluchi; M. Jordan Rowley; Christopher R. D'Angelo; Matthew A. Lunning; R. Gregory Bociek; Julie M. Vose

Cold Spring Harbor Laboratory

Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences; Immunology and Microbiology; Neuroscience; Pharmacology, Toxicology and Pharmaceutics

Provide Feedback

Have ideas for a new metric? Would you like to see something else here?Let us know