There is currently only one approved molecular targeted HNSCC therapy: inhibition of the tyrosine kinase receptor, EGFR. However, EGFR inhibition benefits only a fraction of patients, and there are no reliable predictors of response. The underlying hypotheses of our study are that patient tumor cells grown on complex engineered in vitro microenvironment (ME) microarrays (MEMA) will: i) sufficiently mimic the tumor cell microenvironment in vivo to ii) allow for the development of accurate and clinically actionable predictors of response to targeted therapeutic agents to guide selection of patients likely to benefit from targeted therapy. As proof of principle, we will focus on inhibitors of EGF and PI3K/AKT/TORC1,2 pathways, according to two aims. First we aim to define stromal elements that impact individual patient tumor cell growth and response to targeted therapy. We will determine substratum and soluble factor combinations in MEMA that support adhesion and growth of HNSCC patient tumor cells, test response to inhibitors of EGFR and PI3K/AKT/TORC1,2, and validate predicted targets of inhibitors in patients'cells under ME conditions that show the highest (positive or negative) impact on patient responses. The results may uncover factors that favor or contraindicate treatment of a patient with the tested inhibitor, and suggest strategies for future therapeutic development. Secondly we aim to develop predictive HNSCC signatures for molecular targeted therapy response. We will evaluate the relevance of selected proteins on MEMA to original tumor biology. Results of 20 to 40 patients will be used to develop predictive tests, taking into account stromal dependent/independent tumor properties for stratification of patients to clinical trials of agents specifically likely tobenefit them. These will include HNSCC-specific microenvironment microarrays for prospective analysis of each HNSCC patient's viable tumor cells to determine response to inhibitors and for (epi)genetic signatures of response potentially applicable to uncultured tumor specimens (e.g., DNA sequence changes, RNA expression, and protein activation changes in validated target gene pathways). Our patient-centered team of scientists and HNSCC physicians will accelerate translation of our results for guiding treatment of individual HNSCC patients in """"""""real- time"""""""", whil developing protocols applicable more broadly to biopsy specimens. The public health benefit is the potential to change standards of care for HNSCC patients, who now face only a 50% 5-year survival rate, unchanged over the last four decades. Proof of principle of viable cell and/or molecular predictors of response in HNSCC also has the potential for broader impact on other cancers with similar signaling network defects.
The proposed project brings together physicians and scientists in a patient-centered team to evaluate the molecular characteristics of living tumor cells from head and neck squamous cell carcinomas (HNSCC) of the oral cavity (base of tongue, tonsil, oropharynx), using bioengineered cell culture conditions designed to mimic tumor microenvironments in the body that affect the cells'response to targeted therapy with cetuximab (the only approved agent for HNSCC) or with INK128 (found by us to be effective in HNSCC patient cells and currently being tested in clinical trials for other solid tumors). Our findings (decrease/no effect/increase of tumor growth upon treatment of patient cells with inhibitors) will be validated to develop tests of whether a patient's tumor will respond to inhibitors: i) HNSCC-specific microenvironment microarrays for plating of live tumor cells and ii) signatures of response such as changes in DNA sequence, RNA expression and protein activation of validated target genes that correlate with response to therapy. These tests will provide guidance on who will benefit from particular molecular targeted therapies, potentially changing the standard of care for the 250,000 newly-diagnosed HNSCC patients each year in the United States who face a 50% overall 5-year survival, unchanged over the last four decades.
