Impressions from a NUT carcinoma reading list

NUT carcinoma is a rare and very aggressive cancer which arises when the normally suppressed nuclear protein NUTM1 gets fused on any of a handful of partner proteins (such as BRD4, BRD3, NSD3, &c). The resultant fusion protein causes dramatic remodeling of chromatin state, opening up large stretches of normally inaccessible DNA for transcription and driving previously normal tissue to transform into a rapidly proliferating mass of small undifferentiated cells.

This type of cancer was originally discovered by Dr. Chris French in 2003, whose lab has since steadfastly worked to unravel the mysteries of what drives NUT carcinoma’s rapid proliferation and identify potential treatments. Other research groups have since joined the effort and there is an increasing awareness that NUT carcinoma is both under-diagnosed and part of a larger spectrum of rare cancers involving NUTM1. Unfortunately, good outcomes for patients with NUT carcinoma remain mostly limited to those who are able to completely remove it surgically and we don’t yet know a successful treatment regimen for metastatic disease.

Over the past year and a half, PIRL has been working on several different therapeutic ideas for NUT carcinoma which I’ll describe in future blog posts. For now, I wanted to take stock of the current landscape of options for patients with incomplete surgical resections and make sense of when existing therapies do in fact work for a small number of patients.

Important to note: I’m not a medical doctor but rather a Computer Scientist who went for a long professional sojourn into immuno-oncology. Please don’t take this blog post as medical advice when it’s actually an incomplete literature search by a non-MD researcher.

Impressions

With that caveat out of the way, I have pasted a reading list below and will attempt to summarize my impressions:

The presentation, response to treatment, and overall prognosis of NUT1 rearranged cancers depends heavily on the 5’ partner gene. Certain 5’ fusion partner genes (e.g. BRD4, BRD3, NSD3, YAP1, &c) are characteristic of cancers which look and act like NUT carcinoma, whereas others (e.g. RUNX1) only present in blood cancers and others (e.g. CIC) only in cancers which are categorized as sarcomas.

Among the diversity of malignancies involving NUTM1 rearrangements, it does seem that cancers driven by BRD4:NUTM1 fusions are particularly aggressive and unresponsive to chemotherapy. There are many case studies of surprisingly good response to various therapies and almost all of them involve 5’ fusion partners other than BRD4.

There was a lot of hope that the growth of NUT carcinoma could be significantly slowed by inhibiting the BRD4 portion of the drive oncogene using BET inhibitors such as molibresib and birabresib. Unfortunately, these drugs inhibit a broadly expressed family of proteins (BRD2, BRD3, BRD4, BRDT) and the resultant toxicity means existing BET inhibitors can’t be safely used at a dose level sufficient to fully arrest cancer growth. They do achieve a partial tumor shrinkage in a minority of patients, with some noteworthy case studies among patients with non-BRD4 fusion oncogenes.
There’s a new BET inhibitor, ABBV-744, which is more selective and designed to limit off-target toxicity. It does not, alone, seem very therapeutically exciting even in mouse models of NUT carcinoma. However, ABBV-744 does seem to synergize with the EZH2 inhibitor tazemetostat and, while not entirely eradicating NUT carcinoma growth in mice, it does at least delay progression for months. Whether this translates to humans remains to be seen.

For the most part, metastatic NUT carcinoma shrugs off most chemotherapy regimens and simply keeps growing, though there is modest evidence in retrospective studies that ifosfamide may be a better choice for chemotherapy.
The most remarkable thing I found in this literature search is several case studies of complete responses to the Scandinavian protocol for Ewing Sarcoma in NUT carcinomas with BRD4 as the 5’ fusion partner. The treatment consists of “two courses of VAI (vincristine, doxorubicin, ifosfamide) alternating with one course of PAI (cisplatin, doxorubicin, ifosfamide) at 3-weekly intervals”. That’s a very aggressive chemotherapy regimen and I’m way out of my expertise in trying to judge whether it’s generally applicable to NUT carcinoma patients (likely only pediatric patients would survive it). I will note that “I” in this VAI/PAI protocol stands for ifosfamide, so maybe that’s another clue that ifosfamide may have a role to play in treating NUT carcinoma. In any case, I hope someone elevates these anecdotal successes into some kind of prospective clinical trial.