Posted November 4, 2014
Pier Scaglioni, M.D., from the University of Texas Southwestern Medical Center, is a recipient of a Fiscal Year 2011 Lung Cancer Research Program (LCRP) Investigator-Initiated Translational Research Award.
1. What is the most important thing that stakeholders should know about your research?
We decided to focus our research on non-small cell lung cancer (NSCLC) because it is the leading cause of cancer-related deaths in the world. Notably, Veterans, service members, their family members, and other military beneficiaries may have higher incidences of lung cancer than the general population due to higher smoking prevalence as well as an increased likelihood to being exposed to environmental carcinogens. Therefore, there is an urgent need for novel and effective treatment options for this devastating disease.
Lung cancer cells contain myriads of mutations that are thought to be caused by carcinogens present in tobacco smoke and/or the environment. Some of these mutations are deleterious in that they allow the cells to acquire aberrant behaviors, such as uncontrollable proliferation and migration to other organs, and ultimately cause cancer. Because cancer cells grow rapidly and uncontrollably, they become addicted to the cellular networks that fuel their growth - a phenomenon called "oncogene addiction." For instance, certain lung tumors harbor mutations that activate the epidermal growth factor receptor (EGFR), which drives their proliferation and allows their survival. This dependence on EGFR is being exploited in cancer therapy with drugs that inhibit EGFR and has been especially effective in lung cancer patients with EGFR-mutant tumors.
However, only a small number of the cellular networks that cancer cells are "addicted" to is known, which has impaired the development of potent and specific cancer drugs. As a result, therapies that target cellular networks that cancer cells rely on for survival and growth are available only for a small percentage of lung cancer patients.
The goal of the research funded by the LCRP is to make progress toward this unmet need by identifying novel cellular networks that, when inhibited, cause the death of NSCLC cells. We focused on NSCLC with oncogenic KRAS mutations, which affects 40,000 patients per year in the United States alone and does not yet have effective therapies. We discovered that NSCLC cells with oncogenic KRAS mutations rely on a cellular network that depends on focal adhesion kinase (FAK), a protein involved in cell migration. Importantly, FAK can be inhibited by an existing drug, defactinib (VS-6063; Verastem, Inc.), that has already been found to be safe in patients. We tested the effect of defactinib in preclinical models of lung cancer and demonstrated that defactinib specifically inhibits high-grade lung cancer. These results provided the rationale to start a Phase II multi-institutional clinical trial of defactinib in NSCLC patients harbouring KRAS mutations, which is currently accruing patients.
2. How did you arrive at this information or approach?
We identified the cellular networks that support the growth and survival of KRAS-mutant NSCLC cells by systematically inhibiting them to identify those that could be therapeutically targeted through preclinical studies involving patient-derived cell lines and clinically relevant genetically engineered mouse models. We determined that genetic or pharmacological inhibition of FAK has potent anticancer effects.
3. What is the next step to bringing your research closer to helping lung cancer patients?
The clinical trial of defactinib is ongoing in KRAS-mutant NSCLC patients. This is the first trial of a FAK inhibitor in lung cancer patients. Prior to enrollment, a patient is tested for the presence of the oncogenic KRAS and other critical mutations through a biopsy. Should the disease progress despite treatment, we will potentially obtain an additional biopsy to determine the molecular mechanisms underlying treatment resistance.
In the interim, we are testing therapies that cooperate with defactinib and other FAK inhibitors in preclinical models of lung cancer. In addition, we are also assessing the effects of FAK loss on the behavior of lung cancer cells. We will use this information to design new clinical trials of combinatorial therapies.
Konstantinidou G, Ramadori G, Torti F, Kangasniemi K, Ramirez RE, Cai Y, Behrens C, Dellinger MT, Brekken RA, Wistuba II, Heguy A, Teruya-Feldstein J, Scaglioni PP. 2013. RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discovery 3(4):444-457.
Schuster K, Venkateswaran N, Rabellino A, Girard L, Pe�a-Llopis S, Scaglioni PP. 2014. Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis. Molecular Cancer Research 12(6):912-923.
Phase II Study of VS-6063, A Focal Adhesion Kinase (FAK) Inhibitor, in Patients With KRAS Mutant Non-Small Cell Lung Cancer.
Researchers uncover a genetic vulnerability of lung cancer.