Society-funded Research Sheds Light on Lung Cancer

More than 226,000 people will be diagnosed with lung cancer in 2012, according to estimates from the American Cancer Society. It is the leading cancer killer in the US, claiming both smokers and nonsmokers alike.

But new research funded by the American Cancer Society is helping scientists uncover more about what makes a lung tumor thrive – and what it will take to incapacitate this obstinate cancer.

"The work we're funding is not only helping us understand how lung cancer develops, but could one day lead to more tailored treatments for lung cancer," said Karl Saxe, PhD, Director of the Society’s Program in Cancer Cell Biology and Metastasis. Saxe and his colleagues are instrumental in helping the Society identify promising young investigators and projects.

New strategy may stop spread of lung cancer

Society-backed scientists have found that disrupting a specific protein may stop the spread of lung cancer. They are studying whether a class of diabetes drugs can throw a wrench into the tumor’s escape plan by keeping this protein in check.

The protein, called TGF-beta, normally keeps cell growth in check. But lung cancer cells cleverly develop a resistance to TGF-beta’s regulatory role and reprogram the protein to make the cancer cells mobile, thus triggering the process that allows the cells to spread – or metastasize – to other parts of the body.

Using diabetes medications called thiazolidinediones (TZDs), researchers effectively shut down TGF-beta in non-small cell lung cancer cells in mice. Without the cancer-promoting protein, the metastatic process came to a halt, researchers found.

The investigators are now looking at whether TZDs can inhibit TGF-beta in the normal cells surrounding a tumor to further quash cancer metastasis.

Normal cells initially rush to the cancer to fight it and repair the injury it causes. But the cells are quickly recruited by the tumor to help it survive. “Essentially, the tumor cells and [normal] cells cooperate with each other,” said Society grantee Venkateshwar G. Keshamouni, PhD, an assistant professor of internal medicine at the University of Michigan Health System.

This emerging area of research is based on the “seed and soil” hypothesis, where cancer is the seed and the hospitable environment around a tumor that helps it grow and spread is the soil.

Despite the promising results, Keshamouni said that because of safety concerns, drugmakers have been hesitant to test TZDs in lung cancer patients. Rezulin (troglitazone), one of the TZDs used in Keshamouni’s study, was removed from the market more than a decade ago because of a rare risk of liver failure. The other TZD used in the study, Avandia (rosiglitazone), can increase the risk of heart attack and stroke, and is available only through a restricted access program. However, lung cancer has far fewer effective treatments than diabetes, so the benefits for patients might outweigh these risks.

In the meantime, Keshamouni is looking for other ways to manipulate the TGF-beta protein to cripple the spread of lung cancer. His team recently discovered 2 genes that can restore TGF-beta’s normal role of controlling the growth – and death – of cells, including cancer cells.

“The goal would be to see if drugs are available to hit those targets, and if not, to develop new ones,” he said.

New gene mutations found in lung adenocarcinoma

Society-funded researchers have discovered several new faulty genes that allow lung cancer to flourish. Being able to identify which genetic errors – so-called gene mutations – are present in a tumor can help doctors match the right treatment to the right patient.

Recently, scientists probed 183 lung tumors for genetic abnormalities connected to lung adenocarcinoma, the most common type of lung cancer. They found the known offenders, including mutant versions of the EGFR and KRAS genes. But they also found some mutations in genes never before seen in lung cancer: U2AF1, RBM10 and ARID1A.

“It’s really showing us the complexity of this tumor type in a way that we weren’t able to see before,” said researcher Alice Berger, PhD, a postdoctoral fellow at Dana-Farber Cancer Institute in Boston. “We’re starting to see that there are a lot of different combinations of mutated genes in a tumor.”

The next step is to figure out what these mutant genes do and how they interact with each other, Berger said. “There may be something in their biology that will allow us to predict which patients will respond to certain drugs.”

This latest and most extensive probe of the genetics of lung adenocarcinoma also uncovered a hidden mutation in the EGFR gene. Mutant EGFR is the driving force behind roughly 1 in 6 lung adenocarcinomas.

Berger and her team used lab techniques to show that the EGFR-inhibiting drug Tarceva (erlotinib) can block the novel mutation. “If a doctor sees this mutation when a patient is being genotyped for EGFR and they aren’t sure what to do, there’s now a strong reason to put that person on an EGFR inhibitor. This could result in immediate benefit for patients,” Berger said.

Drug target identified in small cell lung cancer

Society-funded scientists have finally found a weak spot in small cell lung cancer. They also have a new type of drug to target the vulnerability: a Hedgehog inhibitor.

In the first part of the study, researchers used lab methods to genetically shut down the so-called Hedgehog signaling pathway in mice. The result was smaller and fewer small cell lung tumors. Investigators then tested whether a drug that turns off the Hedgehog signaling pathway could deliver a similar blow to human tumors growing under the skin of mice.

It worked, but only when the targeted agent followed chemotherapy. “The cancer cells that survive chemotherapy seem to have more Hedgehog activity. After chemotherapy is when these tumors are probably most sensitive to inhibition of the Hedgehog pathway,” said Society grantee Julien Sage, PhD, an associate professor of pediatrics and genetics at Stanford University School of Medicine.

Sage calls small cell lung cancer the nastiest of all lung cancers. It grows quickly and inevitably relapses with a newfound resistance to chemotherapy and radiation. “But now there’s hope that there’s something we can do to help these patients survive longer,” Sage said.

Normally, the role of the Hedgehog signaling pathway is to help an embryo develop and grow. Some small cell lung tumors hijack this process to spur the growth and spread of cancer cells, according to Sage’s research. But inhibiting the Hedgehog pathway may not be the answer for every patient, he said.

“We may find that not all patients benefit from a Hedgehog inhibitor,” Sage said. “A subset of patients may have higher activity of the pathway. Identifying those patients is the next challenge.”

Several Hedgehog inhibitors for small cell lung cancer are currently being tested in phase 1 and phase 2 clinical trials.

The American Cancer Society medical and editorial content team
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