Investigators at the Sidney Kimmel Cancer Center at Jefferson have uncovered a new regulatory pathway with important implications for lung cancer. Lung cancer is the leading cause of all cancer-related deaths worldwide, with 85% of all cases consisting of non-small cell lung cancer (NSCLC). A major obstacle to successfully treating NSCLC is that many patients eventually develop resistance to chemotherapy, radiotherapy, and other therapies, allowing the cancer to progress and ultimately leading to decreased survival.
The new study, published in Molecular Cancer Research, was led by Bo Lu, MD, Professor in the Department of Radiation Oncology and Director of the Molecular Radiation Oncology Division at the Sidney Kimmel Medical College. The study centers on the Insulin-like Growth Factor Binding Protein 3 (IGFBP3), which influences cell growth through the Insulin-like Growth Factor 1 (IGF1) signaling pathway. Previous work indicated that low serum levels of IGFBP3 are associated with higher risk for several cancer types, including prostate, colorectal, and lung cancer, indicating that IGFBP3 might have an anti-tumor protective function.
Studies from the Lu laboratory and other groups have shown that in advanced NSCLC patients, high levels of IGFBP3 were linked to an improved prognosis, lending credence to the idea that IGFBP3 levels might affect a patient’s response to treatment. In the new study, Lu and colleagues demonstrate that mice harboring an oncogenic KRAS mutation exhibited accelerated lung tumorigenesis when the gene for IGFBP3 was deleted, providing direct genetic evidence for a protective function of IGFBP3. Following up these results in human NSCLC cells, the team found that over-expression of IGFBP3 led to increased cell death and improved sensitivity to the chemotherapy drug cisplatin. Taken together, these results confirm the importance of IGFBP3 for lung cancer progression and its response to treatment.
As Dr. Lu notes, “Our study illustrates that IGFBP3 modulates lung carcinogenesis driven by an oncogene mutation as well as therapeutic response to chemotherapy.” Dr. Lu also predicts that further research on IGFBP3 will lead to at least two significant translational developments for the clinical diagnosis and treatment of NSCLC and other cancers. First, IGFBP3 levels in a given patient could potentially be utilized as a biomarker to help predict therapeutic responses to specific chemotherapy regimens or other treatment options. Second, IGFBP3 can itself be investigated as a direct therapeutic target in the treatment of lung cancer and possibly other cancer types.
Read the full study here: http://mcr.aacrjournals.org/content/early/2017/03/22/1541-7786.MCR-16-0390