Improving Therapy for Breast Cancer and Melanoma by Transcriptome - Methylome Profiling, Integrative Network Inference, and Design of Novel Theranostic Tools of Optically active Drugs 

Activity period: 2015-2018

Research Line: Optical Nanosensing

Proposal core of the Encoder project is the development and characterization of complex nanostructures for therapy/sensing and multimodal diagnosis/imaging applications in pathologic cardiac hypertrophy.

Gene expression is modulated by multiple complex mechanisms, including epigenetic regulation. In particular, significant variation in gene expression is induced by DNA methylation, which is therefore thought to play a major role in tumorigenesis and cancer progression. Molecular profiling of coupled transcriptome and methylome can capture dynamics specifically correlated with disease states, and naturally complemented by interactomic data. The resulting network requires an integrative type of inference targeted to the selection of active modules indicating regions with marked changes in molecular activity and phenotypic signature linked to cellular response. The complexity of finding cancer profiles suggests that signatures of dysregulation involve possible interplay between protein coding genes and non-coding RNAs, whose mechanisms are yet to be understood in terms of functional significance for cancer.

The proposal addresses these challenging problems with regard to infiltrating and metastatic breast and melanoma cancers, two malignant diseases having generally poor prognosis. Risk factors and family history are considered to play a role in both cancers, which are already known to be mutually associated from epidemiologic studies. It is possible to hypothesize that pathways involved in the development of both cancers may overlap to a certain extent, involving complex regulatory mechanisms. Notably, the molecular events which lead to unresponsiveness are yet unknown, although hypermethylation of many genes in these malignant cancers has offered a strong rationale for treatment approaches based on the use of DNA demethylating agents. In parallel, an efficient therapeutic strategy combined with Decitabine (DAC) can lead to the design of novel theranostic tools in order to perform knock-down of overexpressed oncogenes. The expected impact of the results from this oncoepigenetic study is an acceleration of the translation of cancer markers and therapeutic signatures to clinical applications.

The main role in the project of the Chemical and Biochemical Optical Sensor Group is to validate the identified module markers in primary tumors and cancer cell lines by respectively high density cancer-specific Tissue MicroArray and oligonucleotide-based probes with twofold action (drug and sensor), thus contributing through theranostic tools to personalized medicine solutions.