ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

Abstract

Abbreviations: TRAIL, TNF-related apoptosis-inducing ligand; DR5, death receptor 5; TNF, tumor necrosis family; NHL, non-Hodgkin's lymphoma.ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies

“…In accordance with ONC201-mediated activation of the ISR that B cells are highly sensitive to, lymphoma and myeloma were identified as the most ONC201-sensitive tumor types in a >1000 cell line screen [1]. ONC201 in vitro efficacy was confirmed in pediatric NHL cell lines that involved TRAIL-and caspase-dependent cell death [20]. ONC201 has demonstrated in vivo efficacy with prolongation of survival in an Em-myc transgenic B-cell lymphoma model [2].…”

The role of the TNF receptors and apoptosis inducing ligands in tumor growth

“…The anti-tumor activity of ONC201 has been demon strated in seve ral preclinical models of cancer, including refractory solid tumors, a transgenic lymphoma mouse mode land pediatric non-Hodgkin's lymphoma (NHL) cell lines. ONC201 caused a dosedependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis [27]. An induction of TRAIL and its receptor TRAILR2/ DR5 was also observed in these cell lines.…”

“…It has been shown that Xenografting TNFRSF10B silenced pancreatic cancer cells in SCID-mice indicated that there was notable suppression of tumor growth [26]. Recently, it was shown that the TRAIL pathway is selectively activated by small molecule ONC201/TIC10 in tumor cells [27]. The anti-tumor activity of ONC201 has been demon strated in seve ral preclinical models of cancer, including refractory solid tumors, a transgenic lymphoma mouse mode land pediatric non-Hodgkin's lymphoma (NHL) cell lines.…”

TIC10/ONC201—a potential therapeutic in glioblastoma

“…provided proof for the anti-neoplastic activity of TIC10/ONC201 in different cancer entities including data showing enhanced therapeutic efficacy in an orthotopic glioblastoma model in vivo . More studies followed to confirm and extend the initial findings providing further proof for the anti-cancer activity of TIC10/ONC201 in colorectal cancer stem cell, pancreatic cancer or non-Hodgkin’s lymphoma models (3–5). In a multi-targeting approach, our own group was able to show that TIC10/ONC201 synergizes with ABT263, an inhibitor of anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL, against glioblastoma and that the combination therapy causes tumor regression in vivo (6).…”