Antioxidants are chemicals that neutralize particles called free radicals that can damage DNA. Preventing such damage may help lower cancer risk for some people. However, tumors themselves can contain high levels of free radicals; by eliminating these free radicals, antioxidants may help cancer cells grow. In a laboratory, lung cancer cells treated with the antioxidants vitamin E and acetylcysteine (ACC) multiplied faster than untreated cells. Vitamin E and ACC also increased tumor growth and decreased survival time in mice with lung cancer. The so-called ‘tumor suppressor’ protein p53 can sense certain free radicals to detect cells with DNA damage and stop their growth. Antioxidants may interfere with this cancer-suppressing mechanism by reducing free radical levels. Taking antioxidants may therefore not be recommended for lung cancer patients and smokers.
Abnormalities in the KRAS gene are the most common mutations in lung cancer, especially in lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). However, no effective targeted therapy directed at KRAS has been found. Instead, researchers have begun to focus on blocking molecules “downstream” in the chain of chemical reactions through which KRAS affects the cell. Two such molecules are TBK1 and MEK. A recent study found that the drug CYT387 blocks TBK1. CYT387 reduced tumor growth in mice with KRAS-mutant lung adenocarcinoma. Also in mice, CYT387 and the MEK inhibitor AZD6244, given together, shrank aggressive lung tumors with mutations in both the KRAS and the TP53 gene. Researchers now hope to investigate the two drugs in people.
The protein Axl has been associated with cell transformation processes that contribute to the spread of cancer through the body and to cancers becoming drug resistant. A recent study investigated the effect of the Axl inhibitor BGB324 on non-small cell lung cancer (NSCLC) cells that had become resistant to EGFR inhibitors like erlotinib (Tarceva). BGB324 restored the effectiveness of EGFR inhibitors against these cancer cells, which had been grown either in a matrix or as tumors in mice. BGB324 also appeared to enhance the effectiveness of the chemotherapy drug docetaxel (Taxotere) and of bevacizumab (Avastin). BGB324 may therefore be a promising new candidate for treating drug-resistant NSCLC. The drug will be tested in a phase Ib clinical trial for NSCLC in 2014.
E-cigarettes (electronic cigarettes that use a battery-powered system to deliver nicotine without producing smoke) are advertised as a safer alternative to tobacco cigarettes. However, very few studies have investigated how e-cigarettes affect lung function and lung cancer risk. Researchers examined human airway cells with mutations in the TP53 and KRAS genes, which are often mutated in the airways of current or former smokers at high risk of lung cancer. When the cells were exposed to e-cigarette vapor, they developed cancer-cell-like behaviors and gene expression changes very similar to what was seen when these cells were exposed to tobacco smoke. E-cigarettes may increase the risk of developing lung cancer in high-risk people, including current and former tobacco smokers.
More than one-third of melanomas are ‘pan-negative,’ meaning they lack known mutations that can be targeted for treatment. But now researchers have identified two new genetic abnormalities in pan-negative melanomas. These abnormalities consist of the BRAF gene joined with another gene (PAPSS1 or TRIM24), and so are called BRAF fusions. The new study showed that about 8% of pan-negative melanomas have BRAF fusions. Next, the researchers grew melanoma cells with these BRAF fusions in the lab and tested known targeted treatments on them. While these cultured cells were not sensitive to the BRAF inhibitor vemurafenib, they were sensitive to the MEK inhibitor trametinib, suggesting that MEK inhibitors could be used to target melanomas with these BRAF fusions.
As a byproduct of their rapid metabolism and growth, cancer cells frequently produce high levels of so-called free radicals–highly reactive particles that can damage cells. To protect themselves, cancer cells also produce antioxidants, which deactivate the free radicals. Drugs that block these antioxidants should therefore selectively impair cancer cells, while having relatively little effect on healthy cells that do not experience high levels of free radicals. Researchers found that the antioxidant-inhibiting drug ATN-224 induced the death of non-small lung cancer (NSCLC) cells in cell culture. ATN-224 also decreased the number and size of lung tumors in mice injected with NSCLC cells.
Tumors contain immune system cells that attack cancer cells but are present in very small numbers, leading to the hope that a flood of these antitumor cells might eradicate cancer. This approach can work in melanomas, but has not yet worked against other kinds of cancers. Now, there’s a better way to concentrate antitumor immune system cells: they have a protein called CD137 on their surfaces; researchers recently used this distinction to extract these antitumor cells quickly and easily from both melanomas and ovarian cancer. The new study showed that peoples’ own antitumor cells recognized their tumors and that injections of these cancer fighting cells kept tumors from growing in mice. If other types of cancer also contain these antitumor immune system cells, this new approach could hold promise for treating a wide range of tumors.
DNA analyses of lung adenocarcinomas, a type of non-small cell lung cancer (NSCLC), found that some tumors contain a kind of mutation called a gene fusion in a gene called NTRK1. The mutation consists of NTRK1, which is involved in cell growth, merging with a different gene. As a result, the gene’s product, a protein called TRKA, is continuously ‘switched on,’ independent of the signals that normally activate it. Treating cell cultures of lung cancer cells containing the NTRK1 gene fusion with TRKA inhibitors suppressed their growth. Patients with gene fusions in another gene, ALK, experience tumor shrinkage in response to treatment with the ALK inhibitor crizotinib (Xalkori). Similarly, TRKA inhibitors may act as targeted therapies for lung adenocarcinoma patients with NTRK1 mutations.
MicroRNAs are small molecules that turn down or switch off other genes and influence a wide range of processes in cells throughout the body. Researchers discovered that the microRNA 4423 (miR-4423) is found in higher levels in cells lining the airways of the lungs than in other parts of the body. But, levels of miR-4423 are lower in lung tumors and in otherwise normal-appearing airway cells of people with lung cancer. Because miR-4423 is found on the surface of the airways, measuring miR-4423 levels may serve as a relatively noninvasive test for lung cancer. Adding miR-4423 back inhibited the growth of lung cancer cells in cell cultures and decreased the size of lung cancer tumors implanted into mice. Increasing miR-4423 levels may therefore also form the basis of future lung cancer treatments.