Tumor heterogeneity in lung cancer, recently described as a variety of distinct genetic and epigenetic profiles and expressions exists in both forms of inter and intra tumoral patterns resulting in differences in their morphology and biological behavior. Unfortunately, as much as our understanding of new targets in cancer is evolving, we still face a major challenge, we are unable to translate a “target response” to a “clinical response”. The critical question remains as we are not able to pinpoint the driver settings of genes which their alterations have the potential to correlate with survival. This problem is further complicated by implementing cytotoxic and targeted therapies. The first category, cytotoxic therapies, can cause activation of multiresistance genes, cause mutation in the tumor, and further stimulate the tumors stem cells. The second group, targeted therapies, can also cause resistance by inducing mutations in the DNA, as well as enhancing the process called “selective advantage” of the colonies that are not responding to the targeted therapy. This pattern is shown in lung cancer post-targeted-treatment circulatory DNA analysis with a wide range of mutations, confirming the fact that the drug itself has promoted “HETEROGENEITY”. “Sequential tyrosine kinase inhibition” is therefore suggested to reduce the potential of secondary mutations in DNA.
Here we propose a new strategy to use a “heterogenous” approach for a heterogenous tumor. In this approach we have looked in the literature in a systemic review for the mechanisms of resistance in targeted therapies and we have identified epigenetic key regulators that could be targeted. We were especially interested in the hypoxia response targets that were involved with the heterogeneity of the tumor. The more hypoxic tumors, the more they disseminate c DNA. Similarly, the more hypoxic a tumor, the more heterogeneity is seen. We believe that by changing the tumor's behavior, by epigenetic therapy, we can reduce the tumor's tendency for “genometastasis” (dissemination of the CTC and c DNA), and hence reduce the tumor's ability to metastasize.
Results and Discussion: Here we review a case series of patients with advanced metastatic non small cell lung cancer treated with a novel multi targeted epigenetic therapy with promising response.
Conclusion: Our preliminary findings on a subset of advanced heterogenous lung cancer treated with combinational epigenetic method deserves further investigation in a larger scale clinical trial, and can significantly improve the clinical outcome in widely metastatic disease.
Citation Format: M. A. Nezami, Daniel Stobbe, Aaron Gould-Simon, Steven Hager. Heterogenous approach for heterogenous disease, heterogeneity in cancer genomics and epigenetic approach. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C140.