The innovative idea behind the EPIPHARM (EPIgenetics of PHARMacogenetics) project is to develop a package demonstrating the feasibility of a high-throughput tool for epigenotyping Cancer of Unknown Primary (CUP) to identify a drug sensitivity fingerprint based in the DNA methylation profile of non-coding RNA (ncRNA) loci. CUPs are a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary tumor at presentation. The CUP outcome is extremely poor with an expected death within the first six months of the diagnosis. CUP has been reported to comprise approximately 5% of all cancer cases in the world. Despite the introduction of new image technologies and immunohistochemistry methods, more than 50% of CUPs remain anonymous regarding their primary tumor site of origin and, as mentioned, their prognoses are dismal. For most patients with CUP, recommended treatments involves just empiric chemotherapy, usually with a taxane/platinum or gemcitabine/platinum regimens that achieve the described modest clinical benefit. Thus, it is necessary to have better tools to guide the pharmacological treatment of CUP cases. As part of the ERC Advanced Grant “Epigenetic Disruption on Non-Coding RNAs in Human Cancer” (EPINORC) we identified CpG methylation changes in a wide variety of ncRNAs (microRNAs, lincRNAs, T-UCRs, snoRNAs, piRNAs...) that showed a tumor-type specific pattern that has allowed the successful development of the EPICUP assay for the diagnoses of CUPs that it has been licensed and it is undergoing final clinical validation. In the current EPIPHARM Proof of Concept (PoC) proposal, we plan to optimize a ncRNA DNA methylation assay that includes a user-friendly and cost effective approach to improve the therapy of CUP cases by providing a more personalized drug treatment to an extent that will make it interesting commercially for the health providers and their associated company partners.