New Discovery Could Stop a Rare Cancer in Its Tracks

By Alan Dove

May 8, 2023

Collage of headshots of Sara Viragova, PhD and Piero Dalerba, MD. — Sara Viragova, PhD (left), and Piero Dalerba, MD (right), led a multi-disciplinary team uncovering a potential new therapeutic target for adenoid cystic carcinoma (ACC).

A multi-institutional team led by scientists at the Herbert Irving Comprehensive Cancer Center has found a promising new strategy for targeting adenoid cystic carcinoma (ACC), a rare but lethal form of cancer that often develops in the salivary glands. Their research reveals that the two sub-types of malignant cells that are known to co-exist in these tumors are linked by a “mother-daughter” relationship, and identifies a new class of drugs that could halt the disease’s progression.

About 1,300 people in the US are diagnosed with ACC each year. “Although rare, it’s really a dangerous disease, that is usually diagnosed at a young age, which can have a serious impact on both the quality of life and life expectancy of patients,” says Piero Dalerba, MD, assistant professor of pathology and cell biology at Columbia University and senior author on the new study, which appears in the current issue of the Journal of the National Cancer Institute. Dalerba adds that, because of its rarity, the condition is an “orphan disease” that has received relatively little research attention. There are no approved medical treatments, and surgery alone often does not achieve a permanent cure.

Understanding malignant cell sub-types for a potential therapeutic target

Adenoid Cystic Carcinomas (ACCs) are known to contain two distinct populations of malignant cells: myoepithelial-like cells and ductal-like cells. The two populations can be clearly distinguished based on the differential expression of a marker called TP63, which is present in myoepithelial-like cells (nuclei stained in brown) and absent in ductal-like cells (nuclei stained in blue).

Pathologists have found that ACCs contain two types of malignant cells, classified based on their appearance: myoepithelial-like and ductal-like. In the new paper, Dalerba’s team, along with collaborators at the University of Virginia School of Medicine and the University of California San Diego, used cutting-edge RNA sequencing techniques and cell sorting to purify the two cell types, study their molecular differences, and clarify their origins.

“We observed that the two cell-types do not behave as independent entities, but are related to each other, so that one acts as the progenitor of the other,” says Dalerba, who is also a member of the Tumor Biology and Microenvironment program at the Herbert Irving Comprehensive Cancer Center. Myoepithelial-like cells give rise to ductal-like "daughter" cells. Using animal models and sophisticated cell culture systems, in which cancer cells are allowed to grow as three-dimensional structures, called organoids, the researchers also found the cellular signals that drive that transition: retinoids, a group of chemical compounds related to vitamin A.

The team then exploited those findings to attack the tumors. “We can manipulate the cell composition of the tumor pharmacologically, so that if we give agonists or activators of retinoid signaling, we can force the myoepithelial-like cells to differentiate into the ductal-like cells. When we poison the same pathway, using suppressors of retinoid signaling, we can actually selectively kill the ductal-like ‘daughter’ cells,” says Sara Viragova, a PhD student in Dr. Dalerba’s laboratory and first-author of the study.

Suppressors of retinoid signaling could extend disease-free state

While selectively killing one of the two cell types in a tumor doesn’t eliminate it, in the case of ACC, such an intervention could be life-saving. The early stage of the disease, consisting of mixed populations of myoepithelial-like and ductal-like cells, tends to be slow-growing. That phase can persist for a decade or more, until tumors acquire additional genetic mutations that allow ductal-like cells to grow much faster and become dominant.

“It is against these more aggressive forms of the disease that suppressors of retinoid signaling are positioned to be very effective, because they are able to selectively kill the ductal-like population,” says Dalerba. Postponing this late, aggressive stage could extend the period during which patients remain disease-free, perhaps even indefinitely.

Dalerba and his colleagues are now characterizing the two cell types in more detail, and also working to develop and test clinical therapies based on their findings. “So far, we have preclinical evidence that the drugs [inverse agonists of retinoid signaling] are active, and our dream is to bring them into clinical trials and test them for antitumor activity in patients,” says Dalerba.