Our bodies follow a 24-hour ‘biorhythm’ that affects most of our biological functions. This fact forms the basis of cancer chronotherapy, which takes time of day into account to plan cancer treatment. Administering cancer drugs at the right time can double effectiveness while reducing toxicity up to fivefold. However, individual differences in biorhythms mean that the ‘right time’ varies from one person to another. In a recent study, researchers linked gene expression in mice with the time point at which the chemotherapy agent irinotecan (Camptosar) produced the least toxicity. They developed a mathematical model that predicts each animal’s ideal time point based on the expression of two genes. In the future, they hope to develop similar tools to help predict the best time for cancer treatment in human patients.
Mutations in the KRAS gene are the most common cancer-driving mutations in all cancers; they occur in 20% of lung cancers and 40% of colon cancers. KRAS-mutant cancers are aggressive and do not respond well to current treatments. Although the importance of KRAS mutations in cancer has been known for over 30 years, scientists have so far not succeeded in developing a drug targeting them. Now researchers have located a previously undetected ‘pocket’ on a certain mutated form of the KRAS protein. The mutation, called KRAS(G12C), occurs in 7% of lung cancer and 9% of colorectal cancer patients. The researchers then created molecules that bind to the ‘pocket’ and inhibit the mutant KRAS, but not normal KRAS protein. They hope to develop these compounds into drugs against KRAS-mutant cancers.
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.
Past studies have suggested that the diabetes drug metformin (Glucophage) may make lung cancer tumors more susceptible to radiation and therefore, make radiation therapy more effective. Researchers therefore analyzed the medical records of patients with locally advanced non-small cell lung cancer (NSCLC) who had been treated with radiation and chemotherapy. Sixteen of these patients had been taking Glucophage at the time. All of the Glucophage-treated patients are still alive and the cancer has returned in only two so far (an average of 10.4 months after the treatment)–better outcomes than what was seen in the patients who were not on Glucophage. Glucophage also made tumors more sensitive to radiation treatment in a mouse model of lung cancer.
Drugs known as EGFR inhibitors—like erlotinib (Tarceva) and gefitinib (Iressa)—are used to treat non-small cell lung cancer (NSCLC) with so-called ‘activating mutations’ in the EGFR gene. Unfortunately, drug resistance develops relatively quickly in most patients. Resistance is often due to additional EGFR mutations, so-called ‘resistance mutations,’ such as EGFR T790M. Researcher have developed a new EGFR inhibitor, AZD9291, which targets both activating and resistance mutant forms of EGFR. AZD9291 inhibited the growth of EGFR-mutant NSCLC cell cultures and eradicated lung cancer tumors with either activating or resistance mutations in mice. Because AZD9291 is less active against normal, non-mutant EGFR, it may have fewer side effects than other EGFR inhibitors. Initial tests of AZD9291 in patients have been promising.
The drug crizotinib (Xalkori) is used to treat non-small cell lung cancer (NSCLC) with mutations in the ALK gene. However, most patients develop resistance to the drug, usually because of further mutations in the ALK gene. A new ALK inhibitor drug, PF-06463922, may offer a solution. PF-06463922 blocked a variety of Xalkori-resistant mutant versions of ALK in cell cultures, and inhibited the growth of Xalkori-resistant ALK-mutant tumors in mice. PF-06463922 also combated tumor cells driven by mutations in ROS1, a gene closely related to ALK, in mouse models. Like Xalkori, PF-06463922 may therefore also be effective for NSCLC patients with ROS1 mutations. Finally, PF-06463922 was able to penetrate into the brain in multiple animal species–important because lung cancer often spreads to the brain.
Two drugs that are currently approved to treat symptoms of depression may also be effective against small cell lung cancer (SCLC). Researchers used bioinformatics, which combines mathematics and computer science to analyze large amounts of biological data, to pinpoint drugs likely to act on pathways that are important in SCLC. They identified the antidepressant imipramine (Tofranil) and the sedative/anti-nausea medication promethazine (Phenergan). Both drugs killed SCLC cells both in cell culture and in mouse models of chemotherapy-resistant SCLC. SCLC tumors arise from cells that are part of the hormone and nervous system, which may explain the effectiveness of these drugs. A new clinical trial will explore the effectiveness of desipramine (Norpramin), a drug similar to Tofranil, in SCLC.
Notch genes are a family of genes that are involved in cancer growth. However, they also control many other biological functions, so drugs blocking all Notch genes are severely toxic. Now, researchers have identified one specific member of this gene family that plays a particularly important role in at least some cancers. Inhibiting this gene, Notch1, prevented tumor growth and caused cancer cells to die in both cell culture and animal models of lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). Drugs selectively targeting Notch1 may offer a less toxic approach to halting lung cancer growth.