Specialized fat molecules, called sphingolipids, play a key role in the survival of aggressive lymphomas caused by viruses, according to new research. The research also reveals a new therapy for preventing production of sphingolipids by lymphoma cells, thereby killing these cells, which are often resistant to standard therapies.
The research team, led by Christopher Parsons, MD, of Louisiana State University Health Sciences Center in New Orleans, focused on primary effusion lymphoma (PEL), an aggressive and deadly variant of diffuse large B-cell lymphoma that frequently occurs in people infected with HIV. Though scientists have known that the Kaposi sarcoma-associated herpes virus causes PEL, development of effective therapies has proven difficult.
PEL tumors arise within body cavities and progress rapidly with an average survival of approximately 6 months. Combination chemotherapy represents the current standard of care for PEL, but the effectiveness of standard therapy continues to be limited by side effects that include bone marrow suppression and drug resistance that is generated through virus-associated mechanisms.
After documenting the role of an enzyme called sphingosine kinase (SK) in the generation of biologically active sphingolipids in PEL tumors that keep the tumor cells alive, the researchers tested a novel clinical-grade small molecule that selectively targets SK. The molecule, called ABC294640, was developed by Apogee Biotechnology Corporation. Previous studies found antitumor effects for ABC294640 with kidney, prostate, and breast cancer cell lines. In the current study, ABC294640 not only inhibited SK function and induced PEL cell death, it worked selectively for virus-infected cells while sparing uninfected cells.
“It is still early in our understanding of how these special lipids contribute to viral cancers, but this is a major potential advance. There are no therapies available to fight viral tumors by selectively blocking these pathways, all while not harming normal, uninfected cells,” Parsons noted.
Parsons’ research group partnered with Apogee several years ago to develop and test new small molecules targeting lipid synthesis pathways, especially those in viral lymphomas, which have high rates of relapse or failure with standard therapies and higher mortality than nonviral lymphomas.
“Our research thus far indicates that this molecule is safe, with the potential to stand alone as a single, orally administered drug with no need to combine it with other toxic drugs now routinely used but which fail to work for many patients,” concluded Parsons. The study was published in Molecular Cancer Therapeutics (2014; 10.1158/1535-7163.MCT-13-0466).