Development of a companion diagnostic to predict response to cetuximab in patients with head and neck squamous cell carcinoma

ABSTRACT Head and neck squamous cell carcinoma HNSCC is the world s th leading cause of cancer accounting for of cancer mortality For many other cancers molecular characterization has led to sub classification of disease based on the status of oncogenic drivers in signal transduction pathways leading to the development of molecularly targeted agents MTAs targeting specific dysregulated proteins in these pathways HNSCC genetics are highly complex with no clinically actionable mutations or classification beyond HPV positive and HPV negative tumors Classification to improve therapeutic decision making is needed for HNSCC Cetuximab CTX an epidermal growth factor receptor EGFR binding monoclonal antibody mAb is FDA approved for HNSCC as a monotherapy or combined with radiation or platinum based therapy Though having a substantial clinical impact in a small proportion of patients treatment with CTX is associated with serious adverse reactions resulting in interrupted therapy in of patients Due to this high risk along with a high cost and the low response rate a companion diagnostic CDx to identify patients most likely to respond to CTX is urgently required We propose to develop a live tumor cell based CDx to guide the identification of CTX responsive patients based on tumor ex vivo functional responses which are predictive of clinical outcomes Since traditional tissue processing strips tumor cells of their biological integrity it is only suitable for histologic review not allowing analysis of dynamic biomarkers BioMarker Strategies is developing the SnapPath Process and Pathology Multi Analyte Profiles PathMAP technologies for live tissue processing of solid tumors using a single use cartridge which holds the sample and all the necessary reagents and consumables automating and standardizing tumor processing and treatment to enable highly predictive and standardized tests The tumor cellsandapos responses are scored against PathMAP a locked classification model PathMAP tests can help guide medical oncologists in their treatment decisions for cancer patients The proposed CDx will measure the pharmacodynamic response upon exposure to CTX of specific phosphoproteins in MAPK JAK STAT and PI K pathways the key pathways in HNSCC pathophysiology We propose to Optimize Conditions and Response Profile to Predict CTX Sensitivity to detect strong pharmacodynamic responses in sensitive cells and minimal responses in resistant cells Evoke Functional Signaling Profiles FSP Against CTX in Complex Samples by first using clinically relevant patient derived xenograft PDX samples and then human clinical samples The proposed research will serve as a feasibility study determining percent suppression cut off values for predictive biomarkers and confirming operationalization of the test in complex samples It will also determine the sample size for a future larger multisite sample collection in Phase II NARRATIVE Worldwide head and neck squamous cell carcinoma HNSCC is the sixth leading cause of cancer Cetuximab the first FDA approved molecularly targeted agent for HNSCC is expensive has potential adverse reactions and due to the absence of any companion diagnostic CDx test in HNSCC only yields responses in of patients The overall goal of our proposal is to develop a CDx for HNSCC to predict an individual s response to cetuximab