Through its work advancing bold therapeutic solutions to a complex range of adult leukemias and myeloproliferative neoplasms (MPNs) that compromise the lives of millions of patients, a 15-member team of investigators from Mount Sinai’s Department of Medicine continues to burnish its international credentials.

Reinforcing that reputation was the recent renewal for the fourth time of a National Cancer Institute (NCI)-funded grant supporting the Mount Sinai-led Myeloproliferative Neoplasm Research Consortium (MPN-RC), a unique group of translational researchers from 13 institutions across North America that has driven innovative clinical trials for such breakthroughs as Janus kinase 2 (JAK2) inhibitors for treating myelofibrosis, and restoring the tumor suppression activity of the TP53 gene, which encodes the p53 protein, through small-molecule inhibitors of the MDM2 protein.

The focus of the renewed NCI grant, which originated in 2006, is to improve the median six-year survival rate of individuals with myelofibrosis, a chronic leukemia characterized by excessive production of inflammatory cytokines. Under the leadership of Principal Investigator Ronald Hoffman, MD, Albert A. and Vera G. List Professor of Medicine (Hematology) and Director of the Myeloproliferative Disorders Research Program at the Icahn School of Medicine at Mount Sinai, scientists are attempting to deplete the pool of cancer stem cells by targeting malignant hematopoietic stem cells and reversing their tumor-promoting microenvironment.

“Our combination laboratory-clinical team is trying to effectively eliminate the malignant stem cell from which the disease is derived and, ultimately, change the natural course of lethal blood cancers,” says John Mascarenhas, MD, Professor of Medicine (Hematology and Medical Oncology) at Icahn Mount Sinai, and Director of the Adult Leukemia Program and of the Center of Excellence for Blood Cancers and Myeloid Disorders. As evidence of that dogged scientific pursuit he points to the team’s rational approaches to silence such cytokines as IL-1 and IL-8, which are pathologically overexpressed in myelofibrosis, with canakinumab and reparixin, respectively.

Just as importantly, MPN researchers have built on Dr. Hoffman’s considerable body of work over the years by activating the p53 pathway. These prior studies led to the observation that MDM2, a negative regulator of p53, is highly expressed in the CD34+ cells of patients with myeloproliferative neoplasms, and that it could be targeted by small-molecule antagonists known as nutlins, which occupy the p53 binding pocket of MDM2. From this seminal work has emerged a number of phase 3 registration trials for similar class compounds, as well as the development of cutting-edge combination approaches with BET protein inhibitors designed to dampen the myelofibrosis environment, which are poised to move from laboratory to the clinic.

Another way Mount Sinai researchers are taking combination therapy to new levels is through the development of targeted protein degraders, which have become one of the hottest fields of cancer drug discovery in recent years. Partnering with Jian Jin, PhD, Mount Sinai Professor in Therapeutics Discovery and Director of the Mount Sinai Center for Therapeutics Discovery, myeloid researchers have developed MDM2 and PPM1D protein degraders that are part of a new therapeutic class known as proteolysis-targeting chimeras (PROTACs). Dr. Jin’s pioneering work with PROTACs has created numerous degraders of a wide range of oncogenic proteins, including some considered undruggable for decades. The hope is that ongoing laboratory evaluation and agent optimization will soon lead to clinical testing in patients with blood cancers.

Among the most recent pivotal trials from the MPN/leukemia research program were those leading to approval of the JAK2 inhibitor pacritinib for patients with myelofibrosis and thrombocytopenia. “Previously these patients had an extremely poor prognosis,” explains Dr. Mascarenhas, who was lead investigator for the agent’s phase 3 registration trial. “The results of our PERSIST-2 study provided for the first time a promising therapeutic option for patients who are ineligible due to low platelets, or have failed therapy with the JAK1-JAK2 inhibitor ruxolitinib.”

Amid its flurry of past and current clinical work to arrest deadly blood cancers, Mount Sinai is also eagerly looking to the future.

“If we’re going to change the trajectory of acute leukemia and myeloid disease, we need to train and promote the next generation of clinical and laboratory scholars,” Dr. Mascarenhas says. “For that reason, we’re particularly proud of our talented team of junior faculty and fellows who have been awarded grants by the American Society of Hematology and Leukemia and Lymphoma Society to push the research envelope, and to hopefully develop curative approaches in our lifetime.”