Tumor Genomics and Therapeutic Mechanism as Revealed by Patient-Derived Oral Cancer Xenografts

Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer and the fourth leading malignancy among males in Taiwan. OSCC has a poor prognosis and remains a lethal disease more than 50% in OSCC patients diagnosed. The management of advanced OSCC consists of multiple therapies with surgery, radiation, and chemotherapy. Most recurrence occurs within 2 to 3 years. Cetuximab is the only targeted molecule approved by the US Food and Drug Administration (FDA) for the treatment of advanced HNSCC. However, the side effects and efficacy of the Cetuximab in OSCC still need to be improved. The poor prognosis of OSCC is mainly due to a low response rate to current therapeutic strategies. Thus, development of target therapy with precision medicine for OSCC are urgent need. Also, no useful genetic biomarkers are reliable for OSCC patient selection. PDX tumors maintain the molecular, genetic and histological features of origin patients’ tumor through serial passaging in mice. The PDX models can provide a more-relevant system to test clinically directed questions. Only one report identified the PDX model of head and neck squamous cell carcinoma (HNSCC) and none of the OSCC PDX model are reported. In this study, we will establish and standardize the patient-derived oral cancer xenografts model (OSCC-PDX) in our lab. The histopathological features between primary patient’s tumor and xenografts will be characterized. We will perform genomics study in primary patient’s tumor and xenografts by RNAseq platform we already established in our lab. Furthermore, we will perform an integrative approach, combining transcriptome analysis, bioinformatics analysis, and clinical information assessment to reveal molecules signatures for oral cancer subtyping, pinpoint novel therapeutic targets, and predicative signatures for OSCC. The tumor associated biosignatures will be integrated with the drug response predicated software built from DAISY, SynLethDB, and DeSigN and we should be pinpoint the potential predicated markers for drug responses and select useful therapeutic targets in OSCC. OSCC primary cell cultures and PDX models as well as appropriate functional assays will be established. We intend to clarify the useful biomarkers for predicating drug response and mechanisms underlying drug resistance. These integrated studies are expected to have tremendous potential for the development of new therapeutic interventions for OSCC. More significantly, the design and outcome of our proposed research can be extended to clinical trial and also to the development of personalized medicine schemes.

Project ID:PC10901-1978
External Project ID:MOST107-2314-B182-075-MY3