Report of the First International Symposium on NUT Carcinoma

Abstract

NUT carcinoma is a rare, aggressive cancer defined by rearrangements of the NUTM1 gene. No routinely effective treatments of NUT carcinoma exist, despite harboring a targetable oncoprotein, most commonly BRD4-NUT. The vast majority of cases are fatal. Poor awareness of the disease is a major obstacle to progress in the treatment of NUT carcinoma. While the incidence likely exceeds that of Ewing sarcoma, and BRD4-NUT heralded the bromodomain and extra-terminal domain (BET) inhibitor class of selective epigenetic modulators, NUT carcinoma is incorrectly perceived as "impossibly rare," and therefore receives comparatively little private or governmental funding or prioritization by pharma. To raise awareness, propagate scientific knowledge, and initiate a consensus on standard and targeted treatment of NUT carcinoma, we held the First International Symposium on NUT Carcinoma on March 3, 2021. This virtual event had more than eighty attendees from the Americas, Europe, Asia, and Australia. Patients with NUT carcinoma and family members were represented and shared perspectives. Broadly, the four areas discussed by experts in the field included (1) the biology of NUT carcinoma; (2) standard approaches to the treatment of NUT carcinoma; (3) results of clinical trials using BET inhibitors; and (4) future directions, including novel BET bromodomain inhibitors, combinatorial approaches, and immunotherapy. It was concluded that standard chemotherapeutic approaches and first-generation BET bromodomain inhibitors, the latter complicated by a narrow therapeutic window, are only modestly effective in a minority of cases. Nonetheless, emerging second-generation targeted inhibitors, novel rational synergistic combinations, and the incorporation of immuno-oncology approaches hold promise to improve the prognosis of this disease.

Fig. 1.

Mechanistic model of how BRD4-NUT drives growth and blocks differentiation in NUT carcinoma. Above, the normal function of BRD4 is to facilitate transcriptional elongation in a manner that can be regulated by changes in cell state, such as pro-differentiative signaling (i.e. TGF-beta signaling). Below, in the pathologic state, when BRD4 is fused to NUT, the recruitment of p300 leads to the formation of hyperacetylated megadomains whose transcriptional activation of oncogenic target genes are resistant to negative regulatory signals due to their large size. Ac, acetyl-lysine; MED, mediator complex. Material from: Eagen K and French CA, Supercharging BRD4 with NUT in carcinoma, Oncogene, 2021, Springer Nature (8).

Fig. 2.

Therapeutic vulnerabilities of NUT carcinoma to small molecule inhibitors. Shown are small molecule inhibitors of p300/CBP histone acetyltransferase (A485), p300/CBP bromodomains (GNE-781), BET bromodomains (BETi), p300/CBP and BET bromodomains (NEO2734), CDK4/6 (abemaciclib and palbociclib), and the CDK9 component of P-TEFb (CDK9i). Material from: Eagen K and French CA, Supercharging BRD4 with NUT in carcinoma, Oncogene, 2021, Springer Nature (8).

Fig. 3.

Initial paradigm for treatment of head and neck NUT carcinoma.