Cancer researchers at Cold Spring Harbor Laboratory have identified a new form of lung cancer, a discovery that not only shakes up previous concepts about the disease but ultimately could spur the development of highly tailored therapies to address it.
For decades doctors have broadly divided lung cancers between small cell and non-small cell lung malignancies. Now, cancer biologists, led by Dr. Chris Vakoc, an associate professor at the laboratory, have unmasked a previously unrecognized form of the disease. They define it as a subtype of small cell lung cancer.
Among cancers of all kinds, small cell lung cancer has long borne a grim reputation: notoriously aggressive, prone to recurrence and tough to treat. Only 6 percent of patients who undergo therapy for the disease — surgery, chemo and radiation — are alive five years after diagnosis.
The Cold Spring Harbor team is estimating the newly identified subtype likely accounts for as many as 20 percent of all cases of small cell lung cancer, a disease overwhelmingly associated with smoking.
“We would like to develop an encyclopedic body of knowledge about it,” Vakoc said of the subtype. Already, his research suggests treatments that work best on the 80 percent of small cell lung cancers have virtually no impact on the recently discovered form.
Lung cancer, regardless of the cells in which it emerges, is a global public health concern. The World Health Organization estimates the disease causes about 1.7 million deaths worldwide annually, more than any other form of cancer.
In the United States, the American Cancer Society defines lung cancer as the second most common cancer in men and women after prostate and breast cancers. And while that incidence pattern also exists in New York, lung malignancies are the most common cause of cancer deaths in the state for both genders.
The subtype develops in an obscure population of cells — tuft cells — which were identified just a little more than a dozen years ago. Their relative newness to medicine, as well as the cancer that affects them, provides fresh insight into the complexity of malignancies that develop in the lungs, Vakoc said.
He’s now on the hunt for what he calls the “Achilles heel” in this form of cancer, the key weakness that can make tuft-cell lung cancer easily succumb to treatment. He’s also pursuing potential treatments. At the same time, Vakoc and his colleagues are searching for better ways to address the larger percentage of small cell lung cancers.
“Now that we have this new knowledge, we are looking for drugs that are preferentially active in the 20 percent and the 80 percent. No one knew these differences existed until a few days ago,” Vakoc said.
He and his colleagues turned to the breakthrough gene-editing tool called CRISPR-Cas9, which allowed them to screen a multitude of samples for specific proteins crucial to cancer growth. During that search, serendipity intervened: “The surprise is that in the process, we discovered a new form of lung cancer,” Vakoc said.
Word of his findings already has spread.
“This is very exciting,” said Jennifer King, science and research director for the Lung Cancer Alliance in Washington, D.C., a nonprofit patient advocacy organization.
“Small cell [lung cancer] is a very tough disease,” added King, previously a researcher at Memorial Sloan Kettering Cancer Center in Manhattan.
“We haven’t seen a new drug in more than 30 years. So having a better understanding of small cell lung cancer is the way we need to go for now,” King said.
Small cell lung cancer differs from its non-small cell lung counterpart in a variety of ways. First, it begins in the core region of the lungs, the bronchi, also known as the airways. Second, despite its relentless aggression and connection to smoking, it’s not the most common form of lung cancer: non-small cell lung cancer holds that distinction.
Overall, non-small cell lung cancers account for about 85 percent of all lung malignancies diagnosed in the United States. These cancers can begin in the outer tissue layers of the lungs, and there are several known subtypes, according to the National Cancer Institute.
While smoking may be a cause of non-small cell lung cancer, other adverse exposures and causes may also underlie the disease.
A recent breakthrough in treatment, called immunotherapy, is effective against non-small cell lung cancer but has no effect on small cell tumors. The medication known as Keytruda is such a treatment. Immunotherapy recruits the body’s immune system to aid the fight against cancer.
Despite immunotherapy's promise, medical investigators will have to find customized agents to address lung cancers that emerge in tuft cells.
Until he embarked on a series of intense molecular investigations to learn more about lung cancer, Vakoc acknowledged that he initially was unfamiliar with tuft cells. “I never learned about tuft cells in medical school, and I graduated in 2007.”
A 2005 scientific report in the American Journal of Respiratory and Critical Care Medicine was the first to introduce the medical community to “mysterious cells in search of a function.” That major report on tuft cells was authored jointly by scientists from Harvard Medical School, the National Jewish Medical and Research Center in Denver and the National Heart, Lung and Blood Institute in Bethesda, Maryland.
Since that time, medical investigators have learned that these brush-like cells are located throughout the respiratory and gastrointestinal tracts. Their vulnerability to tumor development may be linked to the staggering assaults related to smoking, experts have hypothesized.
“Virtually 100 percent of small cell lung cancer is caused by smoking,” said Dr. Roger Keresztes, a hematologist and oncologist at Stony Brook University Hospital. He was not involved with the Cold Spring Harbor research.
“I can say that in my career, there have been very few cases that have not been related to smoking, and it doesn’t surprise me that they have found a new subtype,” Keresztes said. .
Small cell lung cancer usually has spread to distant sites — such as the bones, liver or brain — by the time it is diagnosed. And while patients may initially respond to chemotherapy and radiation, the cancer often rebounds within a year, he added.
One reason the Cold Spring Harbor team has been able to identify a new subtype, Keresztes added, is because emerging molecular techniques are allowing medical scientists to gain new insights into the cancer in ways that were impossible in the past.
5 basic primers on lung cancer
1. New cases of lung cancer will be diagnosed in about 234,030 people nationwide this year. The disease is expected to affect 121,680 men and 112,350 women.
2. About 85 percent of people who have lung cancer develop a form called non-small cell lung cancer. The other 15 percent have small cell lung cancer.
3. Three types of non-small cell lung cancer:
Adenocarcinoma, the most common form diagnosed in smokers and nonsmokers alike. Grows slowly and is 40 percent of lung cancers;
Undifferentiated, or large cell carcinoma, grows and spreads faster than adenocarcinoma and is 10 to 15 percent of lung cancers ;
Squamous cell carcinoma begins in the flat cells that look like fish scales and is 30 percent of lung cancers.
4. Small cell lung cancer is strongly related to smoking and starts in the bronchi in the center of the chest. May be referred to as oat cell or combined cell. Spreads quickly. These cancers produce hormone-like neuroendocrine proteins.
5. Newly identified small cell lung cancer begins in tuft cells. Isolated at Cold Spring Harbor Lab. May account for one-fifth of small cell lung cancers.