Methods for the prediction of sensitivity of lung tumors to platinum compounds and other genotoxic or DNA damage response therapies
TS-038185 — Methods to predict the sensitivity of NSCLC tumors to platinum compounds and other genotoxic or DDR-targeting therapies
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (~ 85%) and nearly 190,000 new cases are diagnosed annually in the United States. In addition, 1 in 4 cancer deaths are from lung cancer. Approximately 1 in 14 men and 1 in 17 women will be diagnosed with lung/ bronchus canc…
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (~ 85%) and nearly 190,000 new cases are diagnosed annually in the United States. In addition, 1 in 4 cancer deaths are from lung cancer. Approximately 1 in 14 men and 1 in 17 women will be diagnosed with lung/ bronchus cancer in their lifetime.
Platinum-based therapies are currently the most utilized first-line treatment for NSCLC. The efficacy of platinum compounds depends on the activation of cellular DNA damage response (DDR), eventually resulting in cancer cell death. However, these treatments are limited by severe toxicity effects and cancer cells can develop resistance to the regimen. Thus, a better understanding of the molecular mechanisms of DDR and new prognostic and predictive biomarkers for these therapies are required to improve outcomes of NSCLC.
Researchers at The Ohio State University, led by Dr. Coppola, have previously reported that a RanBP9, a scaffold protein, participates in the DNA damage response, and that its down-regulation leads to enhanced sensitivity to DDR induced by ionizing radiation treatment (Palmieri, et al 2016). Overexpression of the RanBP9 protein is common in lung cancer. The researchers created knock-out NSCLC cells lines and demonstrated that treatment with cisplatin reduced DDR and resulted in higher levels of apoptosis both in vitro and in vivo. This led to finding that higher levels of the RanBP9 protein are associated with tumor stage and low response to platinum compounds as first-line treatments. They also found that downregulation of the protein is associated with over-activation for poly(ADP-ribose) Polymerase (PARP), and that use of PARP inhibitors enhances cisplatin anti-tumor efficacy. Based on the results of the study, the researchers have identified a new biomarker that can be used to measure response to genotoxic treatments in NSCLC.
- Clinical predict patient sensitivity to DNA-damaging agents
- Oncology treatment planning
- Pharmaceutical development
- Assessment of RanBP9 expression can be used to predict patient sensitivity to DNA-damaging treatments
- The protein could be used as a target to inhibit that sensitivity, improving outcomes for lung cancer patients
- Could identify patients who could benefit from therapies using PARP inhibitors alone or with cisplatin, or even with lower doses of platinum compounds to reduce the occurrence of strong side effects.