The drug discovery and development company Oncoceutics? lead molecule ONC201, a member of the ?Imipridone? family which targets specific G protein-coupled receptors (GPCRs) that control critical signaling pathways in cancer cells, has been investigated for the treatment of patients with multiple myeloma, leukemia, glioblastoma, and breast cancer. However, a newly published scientific manuscript focuses on ONC201?s anti-cancer effects in a type of lymphoma that had not previously been investigated.
ONC201 is an orally active DRD2 small molecule antagonist that is well-tolerated and effective against advanced cancers. Oncoceutics recently completed a successful Phase I study in solid tumors and has begun additional Phase I/II and Phase II clinical programs in both solid and hematological malignancies.
Figure 1.0: ONC201 is the founding member of the imipridone class, novel class of small molecule anti-cancer compounds that possess a unique three-ring heterocyclic core structure with two substitutable basic amines. The compound exhibits a number of attractive drug-like chemical and physical characteristics including excellent chemical stability, high aqueous solubility at low pH, and high lipophilicity at physiological pH. These attributes enable oral bioavailability that achieves therapeutic concentrations and wide distribution throughout the body to target tissues, including brain, bone marrow and lymph nodes. In pre-clinical models, ONC201 has exhibited excellent activity in advanced cancers that no longer respond to standard-of-care treatments. The anti-tumor activity of ONC201 is achieved without any signs of toxicity, which is likely caused by the ability of ONC201 to target dopamine receptor D2 (DRD2) with a high degree of selectivity and a rapid dissociation rate. Additionally, decades of clinical experience with selective G protein-coupled receptors (GPCR) antagonists for indications outside of oncology have proven that drugs which target this superfamily are generally well tolerated, unlike most cancer therapies. A number of clinical trials have shown the exceptional clinical safety of ONC201 along with a therapeutic pharmacokinetic (PK) profile, induction of pharmacodynamic (PD) markers, and early efficacy signals in a number of different types of cancer, including acute myeloid leukemia, non-Hodgkin?s lymphoma, prostate and endometrial cancers.Interest in ONC201 and Imipridones has led to several research projects alliance agreements between Oncoceutics and leading comprehensive cancer centers, including The University of Texas MD Anderson Cancer Center and the Fox Chase Cancer Center.
Earlier this week Oncoceutics confirmed the publication of a scientific manuscript from collaborators at the University of Texas MD Anderson Cancer Center (MDACC) that describes ONC201?s ability to control a set of anti-cancer signaling pathways to induce cell death in tumor, but not normal cells.
The publication, from the laboratory of Madeleine Duvic, MD a Principal Investigator and Professor of Dermatology at MDACC, focuses on the mechanism and efficacy of ONC201 in cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin?s lymphoma where ONC201 had not been previously investigated.
In vitro efficacy and mechanistic experiments
The researchers carried out a series of in vitro efficacy and mechanistic experiments with ONC201 in CTCL cell lines and patient-derived samples.
The studies documented the established mechanism of ONC201 that involves integrated stress response and inactivation of pro-survival kinases to induce anti-cancer effects in CTCL.
Additional anti-cancer activity
In addition, the researchers uncovered new aspects of the established mechanism of ONC201 that likely contribute to its anti-cancer activity in this tumor type. These new findings include inactivation of the JAK/STAT pathway and downregulation of NF?B, both playing an important role in tumor growth control and immune system modulation. The researchers posit that JAK/STAT and NF?B downregulation seen with ONC201 is a downstream consequence of the integrated stress response.
?The pathways that are controlled by ONC201 in this disease deepen our understanding of how ONC201 imparts multi-modal therapeutic effects through tumor cell death, the immune system, and the tumor microenvironment,? said Wolfgang Oster, MD, Ph.D, CEO of Oncoceutics.
?These data support our understanding of ONC201?s unique mechanism of killing tumor cells downstream of its target and suggest that compound may be effective in diseases where the Jak/STAT pathway is dysregulated,? Oster added
“Duvic’s expertise in the field of CTCL is exceptional, and her careful work with ONC201 reassures us that patients suffering from non-Hodgkin?s lymphomas may greatly benefit from this new therapeutic option,? said Martin Stogniew, Ph.D., Chief Development Officer of Oncoceutics.
?Having introduced drugs to this market space before with Duvic as the principal investigator, I am thrilled that to see her being a pioneer for ONC201 in CTCL,” Stogniew further noted.
Last editorial review: July 15, 2017
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