Small cell lung cancer is an aggressive, highly lethal form of the disease that is linked with tobacco use. Researchers have now found mutations and other genetic interruptions occurring in the cancer's development that could translate to potential new drug targets for this disease.
The researchers, from the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) and geneticists from the Broad Institute, have published the results of their new study in the journal Cell.
They explain that as cancer cells grow and spread throughout the body, they go through genetic alterations. Some of these mutations are known as "drivers" and help cells grow out of control, while other "passenger" cells simply go along for the ride.
After performing the most complete analysis to date of these changes in mice that were programmed to develop cancer, the investigators say they were able to identify tumor cells that broke free and spread to other organs.
Lead author David McFadden speaks of the current lack of knowledge about this type of deadly cancer:
"Right now, small cell lung cancer is really lagging behind with respect to therapies that target a specific mutation or genetic alteration in the tumors, because we don't know a lot about the drivers in these cancers."
To investigate further, he and his team studied mice that lack two key tumor-suppressor genes, called p53 and Rb. This strain of mice develops lung cancer, but scientists do not understand how the cancer progresses or which genetic alterations drive their tumor growth.
An early mutating gene 'makes a good target'
The team says in previous studies, it has been difficult to pinpoint these driver mutations because cigarette smoke carcinogens produce many mutations - many of which do not actually affect tumor growth.
Studying small cell lung cancer in mice makes it easier to identify driver mutations because they are not exposed to cigarette smoke carcinogens.
This is why studying the disease in a mouse model is beneficial; the mice are not exposed to cigarette smoke, which makes it easier to identify the important drivers.
Additionally, mice that lack the p53 and Rb tumor-suppressor genes develop lung tumors that closely match the progression of small cell lung cancer in humans. These tumors are extremely metastatic, typically spreading to the lymph nodes near the lungs and then to the liver.
To study the genetic alterations that occurred in these tumors, the researchers isolated DNA from them. This included genetic mutations and changes in the number of copies of a gene or chromosome.
After comparing genetic alterations appearing in early and late cancer development, the team found that early on, tumors acquire several extra copies of a gene called Mycl1, which is a known oncogene that helps cells ignore signals sent to stop growing.
McFadden says that because this gene mutates so early, it is found in almost all of the tumor cells, which makes it a good target.
Although there are not any current cancer treatments that specifically target Mycl1, scientists are presently working on drugs that target MYC, a closely related oncogene.
The team traced tumor cell paths to find sources of metastases
In later tumor progression, the researchers say the mouse cancer cells lose a gene called Pten, which previous research has found mutated in around 20% of small cell lung cancer patients.
A critical signaling pathway called PI3K is regulated by Pten and influences certain aspects of cell growth and survival. The team says when Pten is lost, this pathway becomes overactive, allowing tumor cells to grow rapidly. As such, drugs that target this pathway are in early stages of clinical testing in humans.
Upon comparing genomes of cells from the original lung tumors with tumors that later appeared in other sites, the researchers were able to retrace the paths the tumor cells took, allowing them to determine which lung tumors were the sources of the metastases.
They say that although multiple subsets of cells from the lung tumors could move to the lymph nodes, only a single subset from the lymph nodes typically spread to the liver.
"Our data really add to this emerging idea that metastatic spread is quite complicated, and that there may be different populations within a single cancer moving around to different sites, which may complicate treatments."
The team now plans to conduct further genetic analysis to pinpoint which mutations make certain cells more likely to metastasize.
They say they also plan to treat small cell lung tumors with chemotherapy drugs to observe genetic changes that occur as cancer cells become resistant to the treatment.
Medical News Today recently reported on a study that suggested antioxidants may speed up lung cancer progression.