Predicting lung cancers' response to treatment through 'co-clinical trials'
Researchers are able to predict how some lung cancer patients are likely to respond to treatment by identifying specific genetic markers in the patient's tumor. Published in Nature and funded in part by Uniting Against Lung Cancer, a team of scientists is speeding this process, investigating these markers in real-time by conducting 'co-clinical trials'. These studies enable researchers to dive deeper into testing a drug or drug combination being studied in human clinical trials by using laboratory animals genetically engineered to mimic human lung cancers. Dr. Kwok-Kin Wong (a member of the UALC Medical Committee) and his collaborators put theory into practice, identifying specific genetic markers in tumors that predicted lung cancer patient responses in an on-going clinical trial.
About 15-30% of lung cancer patients have tumors with mutations to the KRAS gene, but unlike tumors withEGFR or ALK mutations, there is no targeted therapy available. In addition, patients who have lung tumors with mutations to KRAS are likely to have poorer responses to traditional chemotherapy. Doctors are testing a combination of drugs in a clinical trial (docetaxel, a standard chemotherapy, and selumetinib, a MEK inhibitor), to improve how patients with KRAS-positive tumors respond to chemotherapy and fill a significant void in treatment options.
Using laboratory animals engineered to have KRAS-positive lung tumors, Dr. Wong and his team conducted a 'co-clinical trial', and were able to identify specific genetic markers in the tumors that correlated to improved patient responses or resistance to this treatment combination.
Tumors that had mutations to KRAS only or KRAS and p53 showed substantial improvement in response to the combination therapy, while tumors with KRAS and Lkb1 mutations were resistant to treatment. Human patients enrolled in the trial were only required to have tumors with KRAS mutations. But, the researchers were able to look at how patients were responding to treatment according to whether their tumors had KRAS, KRAS and p53, or KRAS and Lkb1 mutations. Excitingly, findings from the animal studies were also observed in human patients.
The success of this approach means that we have another tool to better design clinical trials, improving the likelihood that enrolled patients will benefit from treatment. The 'co-clinical trial' enables researchers to continue to gather information quickly, speeding the process of research.
In addition to funding Dr. Wong, Uniting Against Lung Cancer is also funding Dr. Katie Politi (Yale University), who is using this same strategy to understand how patients with EGFR-positive lung tumors respond and become resistant to another drug combination (BIBW-2992, an EGFR/HER2 inhibitor and Cetuximab, an EGFR antibody), used in an on-going clinical trial. Her studies will help us develop better treatments for lung cancer patients with tumors harboring EGFR mutations after they become resistant to current therapies.
And this approach doesn't stop with lung cancer - it's a tool we'll see used to improve treatments for many types of cancer, and we're happy to see lung cancer researchers blazing the trail.
- Chen et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613–617, 2012.