Rare but Deadly Cancer is Focus of First-Ever Conference and New Clinical Trials

With its deep experience in studying the rare, often lethal cancer known as NUT carcinoma, Dana-Farber Brigham Cancer Center attracts patients and families, some from far away. Unfortunately, NUT carcinoma is so rapidly aggressive that “sometimes patients get to Dana-Farber and become too sick to proceed with treatment,” which speaks to the urgent need for improved ways to approach this disease, says Geoffrey Shapiro, MD, PhD, senior vice president for Developmental Therapeutics at Dana-Farber.

Shapiro and Christopher French, MD, a pathologist at Brigham and Women’s Hospital, are corresponding authors of the First International Symposium on NUT Carcinoma published June 13 in Clinical Cancer Research. The virtual symposium in 2021 was sponsored by Dana-Farber, and attracted more than 80 attendees from several countries. It was designed to raise awareness of the disease and initiate a consensus on standard treatment of the cancer, which has a median survival of less than seven months.

French discovered the genetic abnormality that causes the malignant growth of NUT carcinoma, which begins in squamous cells that line hollow organs of the body. The disease stems from a translocation — a piece of the NUTM1 gene on chromosome No. 15 encoding a nuclear protein called NUT becomes fused with pieces of genes encoding bromodomain-containing proteins — chiefly BRD4 — to form a fusion cancer-causing protein called BRD4-NUT. This genetic mishap leads to the activation of an oncoprotein, MYC, which drives the aggressive growth of tumors.

It’s estimated that fewer than 200 cases of NUT carcinoma are diagnosed annually in the United States. A registry of NUT carcinoma cases has been established at Dana-Farber/Brigham and Women’s Hospital. Besides collecting information on cases, the registry web site offers updated information about NUT carcinoma, lists current clinical trials, tells stories of survivors, and offers opportunities to donate to support research.

The need for early detection and more treatment options

NUT carcinoma most often occurs in young adults but can develop at any age. It typically presents as a large mass in the thoracic cavity and exhibits signs and symptoms of lung cancer. Originally, it was called NUT Midline carcinoma, because it most often developed in the midline of the thoracic cavity or head and neck. But in recent years the “midline” term has been dropped, as NUT carcinoma has been found to develop almost anywhere in the body.

When thoracic NUT carcinoma is diagnosed at an early stage — which is rare — aggressive treatment with surgery and radiation provides the only chance for long-term survival. When this isn’t possible, doctors turn to potent chemotherapy regimens, which sometimes lengthen survival in pediatric patients. However, the symposium report said, “there is no consensus on optimal chemotherapy treatment — a huge problem that needs to be addressed through well-conducted preclinical and clinical studies.”

The genetic rearrangement that drives NUT carcinoma cells is also a vulnerability that scientists have been trying to exploit with precision drugs, including a class of small molecules called BET bromodomain inhibitors. In general, these drugs have shown “modest benefits,” the researchers say in the report. However, next generation BET inhibitors are under development. In addition, drugs that block immune system checkpoints are being tested in combination with BET bromodomain inhibitors and chemotherapy agents.

Jia Luo, MD, a thoracic medical oncologist at Dana-Farber, says several clinical trials of targeted agents alone or in combinations are under way or expected to launch later this year.

Shapiro says the symposium, which may be held again, perhaps every other year, “was the first time that this disease was addressed in this way — to pull together knowledge worldwide about NUT carcinoma. We very much want to get the word out and to develop a community of stakeholders.”