Credit: Aaron Logan
A small molecule targeting sphingosine kinase (SPHK) demonstrates considerable activity against virus-associated lymphoma, according to preclinical research published in Molecular Cancer Therapeutics.
The research focused on primary effusion lymphoma (PEL), a variant of diffuse large B-cell lymphoma etiologically linked to Kaposi’s sarcoma-associated herpesvirus (KSHV).
Investigators found that SPHK generates biologically active sphingolipids that keep PEL cells alive.
“It is still early in our understanding of how these special lipids contribute to viral cancers, but this is a major potential advance,” said senior study author Christopher Parsons, MD, of Louisiana State University Health Sciences Center in New Orleans.
“There are no therapies available to fight viral tumors by selectively blocking these pathways, all while not harming normal, uninfected cells.”
So the researchers decided to test ABC294640, a novel small molecule that selectively targets SPHK, in cells from PEL patients and mouse models of PEL.
ABC294640 induced dose-dependent apoptosis in a number of KSHV+ PEL cell lines: KSHV+/EBV- BCBL-1 cells, KSHV+/EBV+ BC-1 cells, KSHV+/EBV- BC-3 cells, and KSHV+/EBV- BCP-1 cells. But the drug showed little to no activity in KSHV-/EBV- BL-41 cells.
Further analyses revealed that ABC294640 induces apoptosis through suppression of KSHV-associated signal transduction.
The investigators observed dose-dependent suppression of ERK, Akt, and NF-kB p65 phosphorylation, as well as cleavage of caspase-3 and caspase-9, in BCBL-1 cells exposed to the drug. But the same effects did not occur in drug-resistant BL-41 cells.
Overexpression of either ERK or p65 in BCBL-1 cells partially suppressed apoptosis induced by ABC294640. And when the researchers used RNAi to target SPHK2, PEL cells exhibited reduced activation of ERK, Akt, and p65 phosphorylation, as well as a 5- to 6-fold increase in apoptosis.
Additionally, the team found that ABC294640 suppressed PEL progression and induced regression of PEL tumors in vivo.
The investigators injected BCL-1 cells into NOD/SCID mice and observed PEL expansion within 3 to 4 weeks. However, when they administered ABC294640 within 24 hours of PEL cell injections, they observed significant reductions in tumor expansion.
The researchers also evaluated ABC294640 activity after PEL tumors had been established. And treated mice showed significant tumor regression compared to untreated mice.
The investigators said these results suggest ABC294640 should be evaluated in clinical trials of KSHV-associated lymphoma.
“Our research thus far indicates that this molecule is safe, with the potential to stand alone as a single, orally administered drug,” Dr Parsons said.
