June 1, 2016

First clinical proof-of-concept that targeting BRD4-NUT with a BET inhibitor results in rapid antitumor activity in Nut Midline Carcinoma.

A recent study in collaboration with the Nut Midline Carcinoma (NMC) registry describes the antitumor activity of a novel BET inhibitor, OTX015/MK-8628, on four patients with advanced stage NMC. The role of OTX015/MK-8628 has previously been shown to inhibit proliferation and tumor growth in cells and mouse models, respectively. This study is the first to describe the effects of OTX015/MK-8628 in NMC patients. Two patients responded rapidly to treatment, as evidenced by tumor regression and symptomatic relief. A third patient demonstrated disease stabilization with a minor metabolic response. Increased survival was observed in two of the four patients (longer than 17 months compared to the median survival of 6.7 months after the initial diagnosis). However, due to the small number of patients in this current study, additional research is needed to establish the direct impact of BET inhibitors on survival in advanced NMC patients. Despite rapid antitumor activity, transient disease progression following short interruptions was observed, suggesting that continuous drug exposure is needed to maintain antitumor pharmacodynamic activity in this aggressive disease.

NMC is a very aggressive tumor and an optimal approach to treat this cancer has not been developed.  While response to standard chemotherapy or chemo-radiotherapy does occur, patients invariably relapse and are refractory to subsequent treatments.  Growing evidence that BRD-NUT fusion drives tumor growth and BET inhibition causes growth arrest, suggest the need for further clinical evaluation of BET inhibitors in NMC.  This study supports a strong potential for a targeted treatment approach, whereby a small molecule directly targets the causative oncoprotein, either alone or in combination with other treatment approaches in NMC patients.

OTX015/MK-8628 is currently in Phase I of a clinical trial to determine the maximum tolerated dose and to evaluate the safety and efficacy of single-agent administration in adults with selected advanced solid tumors, including NMC. Click here for more information.

Stathis A., Zucca E., Bekradda M., Gomez-Roca C., Delord J.P., de La Motte Rouge T., Uro-Coste E., de Braud F., Pelosi G., French C.A. Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628. Cancer Discov. 2016 May;6(5):492-500. [pdf]

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