General Updates | The potential of stem-cell directed therapeutics in myelofibrosis: ONC201 + RG7112

Well, our present approach is to essentially create a paradigm shift in how we’re treating patients with myeloproliferative neoplasms. We and others have become increasingly aware that each of the myeloproliferative neoplasms originate at the level of the hematopoietic stem cell, which is corrupted by a number of driver mutations and also associated with additional myeloid gene mutations.

The present therapeutic approaches from my point of view are really palliative and do little to prolong the survival of patients with these myeloproliferative neoplasms. In order to explore this approach, we’ve really focused on patients who have high-risk or very high-risk myelofibrosis, that are refractory or resistant to ruxolitinib because their survival is essentially approximately 14 months. We’re trying to develop combinations of therapies that deplete stem cells that we think will not only reduce spleens, improve the symptoms of these patients, but also probably correct their cytopenias, but most importantly, will prolong the survival of these patients. Previous drugs that have been under development have been important contributions to the treatment of myelofibrosis, but unfortunately they don’t prevent disease evolution to more overt forms of myelofibrosis or a lethal form of leukemia called MPN blast phase. We feel in this high-risk group that has an adverse survival of 14 months, that we need to be much more aggressive, use combinations of drugs that essentially deplete stem cells for prolonged periods of time that will hopefully lead to prolongation of survival and elimination of the malignant clone.

We have been extremely interested in using the drug called ONC201. ONC201 is a novel compound that essentially stimulates apoptosis of malignant cells by promoting, by acting through the extrinsic apoptotic pathway. We previously had experience with RG7112, which is a nutlin that increases p53 and acts through the intrinsic pathway. Our hope was essentially to combine agents that induce malignant cell apoptosis by both promoting extrinsic and intrinsic apoptosis, therefore leading again to stem cell depletion, and hopefully prolongation of survival of patients with myelofibrosis. Our in vitro studies essentially showed that this was possible, and that this would be an excellent way of treating myelofibrosis since both of these drugs when used at low doses spare the reservoir of normal hematopoietic cells. We remain eager to do a Phase I trial with this combination of compounds, with the hope again, that this would change the natural history of patients with myelofibrosis, due to the high likelihood that this drug combination would deplete MF stem cells whilst sparing normal stem cells.