Sir Peter MacCallum Department of Oncology - Theses

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Author: Bai, Yuchen × Start date: 2020 × Type: PhD thesis ×

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    Identifying Novel Markers for Therapeutic Stratification of Heterogeneous Head and Neck Cancer
    Bai, Yuchen ( 2022)
    Head and neck squamous cell carcinoma (HNSCC) is an aggressive heterogeneous disease that has had modest clinical improvement over the last decades. Standard first-line treatments for HNSCC including surgery, radiotherapy and chemotherapy are non-selective and are administered regardless of response biomarkers, resulting in a high recurrent and metastatic rate. Current therapeutic approaches to treat recurrent and metastatic diseases are limited, and their clinical outcome is dismal. Available targeted therapeutics have faced major roadblocks due to the lack of our understanding of HNSCC development. Additionally, the absence of therapy response or resistance biomarkers has hindered treatment stratification of HNSCC patients, with a random clinical benefit observed in a small subset of patients. This thesis has focused on addressing cellular and molecular mechanisms for the response of HNSCC to targeted therapy in addition to establishing a novel in vivo preclinical approach for modelling patient HNSCC. First, the functional GRHL3-FLG differentiation axis was established as a prognostic and predictive response biomarker to targeted therapy, highlighting a clinical value for differentiation-paired therapies against HNSCC. Second, YBX1 phosphorylation was identified as a regulator of the proliferation-invasion switch, providing a potential therapeutic target against metastatic HNSCC. Lastly, I generated a patient-derived orthotopic mouse model of HNSCC and confirmed its modelling of HNSCC metastasis in patients. This model serves as a promising platform to further validate the identified biomarkers for therapy stratification, facilitating their progression to clinical trials against HNSCC. Overall, this research reveals novel cellular and molecular features of heterogeneous and metastatic HNSCC that predict response to targeted therapy and provide a novel preclinical setting allowing validation of findings for a better understanding of HNSCC progression and metastasis, which will ultimately enhance patient survival outcomes.