The epidermal growth factor receptor (EGFR) is an important target forthe treatment of head and neck squamous cell carcinoma (HNSCC). Clinical strategies to target EGFR have focused on monoclonal antibodies (mAbs), such as cetuximab. Cetuximab executes its antitumor effect in vivo via blockade of receptor-ligand interactions and engagement of Fcgamma receptors on immune effector cells which trigger antibody-dependent cell-mediated cytotoxicity (ADCC). Our preliminary studies demonstrate that tumor cell-autonomous expression of TGF-beta is a key molecular determinant of the de novo or acquired resistance of cancers to EGFR-targeted mAb, and provide a rationale for enhancing the antitumor efficacy of anti-EGFR mAb by combinatorial- or bi-functional antibody-based strategies to simultaneously counteract TGF-beta in the tumor microenvironment.
The aims of the project are designed to advance the clinical translation of this strategy for treatment of HNSCC;
Specific Aim I : Determine whether tumor cell-autonomous expression of TGF-beta inhibits cetuximab-induced ADCC in patients with HNSCC.
Specific Aim II : Determine the in vivo antitumor efficacy and toxicity of dual blockade of EGFR and TGF-beta using HNSCC patient-derived tumor xenografts in mice.
Specific Aim III : Determine the clinical relevance of TGF-beta as a molecular determinant of resistance to cetuximab in patients with HNSCC, and evaluate the clinical safety of a novel bi-functional anti-EGFR antibody that can sequester and block TGF-beta in the tumor microenvironment. This project addresses the urgent need for effective tumor-targeted therapeutic strategies against HNSCC by: (1) Establishing the role of tumor cell-autonomous expression of TGF-beta as a key mechanism and clinical biomarker of resistance to cetuximab in patients with HNSCC;(2) Improving the treatment of patients with HNSCC and other cancers via novelcombinatorialor bi-functional antibody-based strategies that simultaneously target and counteract EGFR and TGF-beta in the tumor microenvironment. The project will leverage the expertise and resources of the JHU Tissue Core, Biostatistics Core, and will interact with Projects 1 and 4 of the SPORE-Head and Neck Cancer.
This research and clinical project is designed to establish the role of tumor cell-autonomous expression of TGF-beta as a clinical determinant and biomarker of resistance of head and neck cancers(HNSCC) to cetuximab, and improve the treatment of HNSCC via novel combinatorial- or bi-functional antibody-based strategies that simultaneously target and counteract EGFR and TGF-beta in the tumor microenvironment.
|Guo, Theresa; Sakai, Akihiro; Afsari, Bahman et al. (2017) A Novel Functional Splice Variant of AKT3 Defined by Analysis of Alternative Splice Expression in HPV-Positive Oropharyngeal Cancers. Cancer Res 77:5248-5258|
|Kang, Hyunseok; Tan, Marietta; Bishop, Justin A et al. (2017) Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma. Clin Cancer Res 23:283-288|
|Bishop, Justin A; Westra, William H (2017) MYB Translocation Status in Salivary Gland Epithelial-Myoepithelial Carcinoma: Evaluation of Classic, Variant, and Hybrid Forms. Am J Surg Pathol :|
|Zhang, Hongzheng; Kim, Sungjin; Chen, Zhengjia et al. (2017) Prognostic biomarkers in patients with human immunodeficiency virus-positive disease with head and neck squamous cell carcinoma. Head Neck 39:2433-2443|
|Bishop, Justin A; Rooper, Lisa M; Chiosea, Simion I et al. (2017) Clear Cell Carcinoma of Salivary Glands is Frequently p16 Positive: A Pitfall in the Interpretation of Oropharyngeal Biopsies. Am J Surg Pathol :|
|Anagnostou, Valsamo; Smith, Kellie N; Forde, Patrick M et al. (2017) Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer Discov 7:264-276|
|Walline, Heather M; Carey, Thomas E; Goudsmit, Christine M et al. (2017) High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV. Mol Cancer Res 15:179-188|
|Peri, Suraj; Izumchenko, Evgeny; Schubert, Adrian D et al. (2017) NSD1- and NSD2-damaging mutations define a subset of laryngeal tumors with favorable prognosis. Nat Commun 8:1772|
|Weidhaas, Joanne B; Harris, Jonathan; Schaue, Dörthe et al. (2017) The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 3:483-491|
|Guerrero-Preston, Rafael; White, James Robert; Godoy-Vitorino, Filipa et al. (2017) High-resolution microbiome profiling uncovers Fusobacterium nucleatum, Lactobacillus gasseri/johnsonii, and Lactobacillus vaginalis associated to oral and oropharyngeal cancer in saliva from HPV positive and HPV negative patients treated with surgery and Oncotarget 8:110931-110948|
Showing the most recent 10 out of 122 publications