Abstract
Purpose :
Thalidomide and its analogs have been shown to inhibit ocular and tumor angiogenesis. Currently, these compounds are FDA approved for the treatment of multiple myeloma. Thalidomide analogs have dual activity in myeloma in that they inhibit tumor angiogenesis and directly inhibit myeloma cell proliferation by altering the activity of cereblon. However, the role of cereblon in mediating the anti-angiogenic effects remains unknown. Here, we performed the cornealmicropocket assay in CRBN KO mice to evaluate the anti-angiogenic activity of the highly potent thalidomide analog pomalidomide.
Methods :
Using a widely adopted CRISPR/Cas9 system in mouse models, we generated a CRBN KO in C57BL/6J mice. Mutant mice were both genotyped and confirmed by Sanger sequencing. In addition, we confirmed the Crbn null allele in cornea and brain by Western blot. We performed the corneal micropocket assay in homozygous CRBN KO and C57BL/6J control mice using 80ng bFGF pellets. Pomalidomide was administered daily by intraperitoneal injection (100mg/kg). On day 5, new blood vessel growth area (VA in mm2) was quantified.
Results :
There was no significant difference in corneal neovascular response to 80ng bFGF between untreated CRBN KO mice and wild type controls. Further, pomalidomide inhibited corneal angiogenesis in CRBN KO mice to an equal extent as it does in wild type mice.
Conclusions :
Our results suggest that cereblon does not play a key role in corneal angiogenesis and is not involved in the anti-angiogenic activity of pomalidomide.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.