Diffuse large B-cell lymphoma (DLBCL) represents one of the most common variants of Non-Hodgkin's lymphoma (NHL), and oncogenic herpesviruses (EBV and KSHV) are the etiologic agents for the majority of these tumors in patients over 50 or those infected with the human immunodeficiency virus (HIV+). Despite modest improvements in outcomes for patients receiving standard therapy, patients with virus-associated DLBCLs exhibit more widespread ("extranodal") disease and less favorable outcomes. Notably, increased treatment failure and mortality have been observed for patients from urban, minority-predominant cohorts with high rates of virus-associated DLBCL and HIV infection who have been largely excluded from clinical trials. Apogee Biotechnology Corporation has developed the first non-lipid inhibitors of sphingosine kinase (SK) and has evaluated their biologic and therapeutic activity in a variety of models for cancer and inflammatory diseases. The first clinical compound in this series, ABC294640, is an orally-available selective inhibitor o SK-2 that attenuates signal transduction, induces tumor cell death, and inhibits host angiogenesis and inflammation in the context of solid tumor formation. We have found that ABC294640 induces apoptosis for virus-infected DLBCL lines, in part through attenuation of virus-associated signal transduction. Most importantly, ABC294640 significantly reduces virus-associated DLBCL tumor burden in xenograft models for both EBV+ and KSHV+ DLBCLs. Therefore, we hypothesize that ABC294640 will have significant clinical activity for many DLBCLs refractory to standard therapy, especially virus-associated DLBCLs. To begin development of ABC294640 as a new drug for DLBCL, we propose to conduct a Phase I/IIa clinical study of this agent enrolling patients with refractory/relapsed DLBCL from minority-predominant urban populations in Louisiana at high-risk for poor outcomes with this disease. In this open-label, dose-escalation study, ABC294640 will be given orally to HIVneg or HIV+ patients, with primary objectives including determination of the maximum tolerated dose (MTD), dose- limiting toxicities, and pharmacokinetics for ABC294640 in these patients. Secondary objectives will include determination of the effects of ABC294640 on plasma sphingosine 1-phosphate levels, PBMC- and tumor- associated viral load (EBV and KSHV), and tumor expression of S1P receptors as first steps toward identification of putative biomarkers for drug resistance. We will also evaluate antitumor activity for ABC294640 using objective radiographic and clinical assessments. Up to 21 patients will be enrolled in the dose-escalation phase of the study, and once the MTD has been established, up to 12 additional patients with DLBCL will be enrolled using this dose in order to obtain additional preliminary efficacy and safety data. This study will form the foundation for follow-on clinical trials of ABC294640 in patients with DLBCL, thereby expanding the commercial market for this agent to include hematologic malignancies and offering a new therapeutic approach for underrepresented patients for whom DLBCL incurs especially high mortality.
DLBCL incurs high mortality for patients with advanced or refractory disease, so new drugs that target critical pathways controlling growth and survival of DLBCL cells are desperately needed. Sphingolipid metabolism, and sphingosine kinases in particular, may play a critical role in DLBCL progression. ABC294640 is a novel sphingosine kinase inhibitor that has anti-DLBCL activity in mouse models as a single agent and can be used alone or in combination with standard drugs given to DLBCL patients to reduce tumor growth. The proposed Phase I/IIa clinical trial will establish the maximum tolerated dose, safety profile, and preliminary efficacy for ABC294640 in patients from an underrepresented, minority- predominant cohort with treatment-refractory DLBCL for whom the disease incurs especially high mortality.
|Dai, Lu; Trillo-Tinoco, Jimena; Bai, Aiping et al. (2015) Ceramides promote apoptosis for virus-infected lymphoma cells through induction of ceramide synthases and viral lytic gene expression. Oncotarget 6:24246-60|