Biomarkers and new therapeutic targets in lung cancer

Surgery is currently the best option for treating lung cancer; however, less than 20% of patients with lung cancer are diagnosed in the early stages, when surgery is a potential treatment option. In other patients, when the disease is detected later, the alternative treatment currently available is more aggressive (chemotherapy, radiation therapy) and less effective. The use of molecular markers may make it possible to detect lung cancer in the early stages, which would help improve patient survival. These markers can be combined with imaging detection techniques, such as computed axial tomography, to increase their specificity. Furthermore, molecular characterization of the small lesions detected by means of imaging may help us understand the biology of the nodules found in screening programs. These markers could also be used to select high-risk populations, which would considerably reduce the cost of imaging-based cancer-screening programs. To this end, our group works basically on developing strategies for early detection of lung cancer based on the molecular changes that take place throughout the carcinogenesis process. To achieve this goal, our research is carried out on two levels:

1. Basic studies, in which we characterize the molecular changes in lung-cancer carcinogenesis in order to identify potential diagnostic and prognostic biomarkers.

2. Translational studies, in which we evaluate the candidate biomarkers in clinical samples and attempt to develop the right diagnostic and prognostic tools to allow them to be used in clinical practice.

The following are some of the projects currently being carried out in the laboratory:

• Study of the molecular mechanisms used by malignant lung cells to avoid activating the complement system.

• Changes in the processing of RNA associated with neoplastic transformation, and development of splicing microarrays to identify new molecular markers for lung cancer.

• Standardization and validation of molecular biomarkers in the context of early detection of lung cancer.

• Development of specific prognostic histology signatures based on protein-expression profiles.

• Application of genomic and cytogenetic techniques in the detection of lung cancer.

Thanks to advances in molecular and cell biology, and to state-of-the-art genomic techniques, the past 10 years have seen the discovery of new mutations and genetic alterations that are at the source of a certain proportion of lung-cancer cases. This has made it possible to develop more specific drugs that are aimed at the "molecular Achilles' heel" of those tumors. However, the key molecular alterations in approximately 50% of lung cancers are still unknown, which means that a huge number of patients are still not benefiting from "precision oncology." The goal of our group is to use high-performance genomic technologies to identify and validate new target molecules in tumors with few therapeutic options (tumors in nonsmokers, pan-negative tumors, and small-cell carcinoma) in order to improve survival and quality of life in these patients.

In our work, we use state-of-the-art genomic technology and samples from several independent cohorts of patients. We also carry out functional studies in cell and animal models to validate the potential targets identified. If we find sensitivity to the inhibition of these targets, we search for new drugs aimed at these molecular pathways.

The following are some of the areas in which our team is currently working:

• Characterization of new molecular profiles using genome data from the patients (copy-number variations and LOH) and data relating to splicing alterations. Identification of new therapeutic targets based on molecular profiles.

• Development of new therapeutic strategies aimed at specific mutations, which can improve survival in patients with lung cancer.

• Contribution of cancer stem cells (CSCs) to tumor onset, ability to recruit bone-marrow derived cells, induction of angiogenesis, and resistance to chemotherapy and radiation therapy. We are performing large-scale analyses (gene-expression and microRNA profiles) to try to understand the transcriptomic program that guides the acquisition of malignant properties in CSCs and to identify therapeutic targets specific to these cells.

• Characterization of the mechanisms of activation and regulation of the complement system with regard to the tumor cell. Identification and validation of therapeutic targets based on blockade of the complement system and its synergy by means of checkpoint inhibitors used in immunotherapy.