Tumor-Targeted Chemotherapy: Role in Oral Squamous Cell Carcinoma (OSCC) Management
While surgery remains the primary treatment modality for OSCC, tumor-specific inductive chemotherapy has the potential to spare vital oral tissues. Although currently employed chemotherapeutics provide specificity for cancer-protein overexpression (e.g. cetuximab - EGFR), the variable results in OSCC clinical applications suggests the “one-size fits all” treatment paradigm is outdated. Targeted screening to match treatment with patient and tumor-specific protein profiles would advance OSCC chemotherapeutic applications. This study assessed the effects of two drugs currently used in OSCC patients i.e. Afatinib (inhibits EGFR tyrosine kinase) and the triple angiogenic signaling kinase inhibitor, Vargatef on tumor-matched, authenticated (Hopkins Genetic Resources Core DNA evaluation) freshly isolated OSCC cell lines. Treatment effects were assessed at the protein level: immunoblotting (growth factor signaling cascades) and proteome profiling (cytokines and growth factors) (Table I) [Holpuch, Phelps et al., 2012]. This experimental design matched Afatinib and Vargatef's membrane receptor blockade with corresponding signaling proteins EGF and/or VEGF, enabling precise dissection of treatment effects on membrane-associated and downstream tumorigenic signaling pathways. Conceptually, combined membrane receptor blockade as achieved with Afatanib+Vargatef should suppress EGF/VEGF-mediated activation of an integral downstream signaling protein, STAT3. Our data demonstrate extensive inter-tumor heterogeneity and the presence of compensatory signaling pathways. Combined blockade failed to suppress STAT3 activation in JSCC1 and JSCC2 cells (Table I); findings that suggest need for supplemental STAT3 inhibition [Sen et al., 2012]. Interestingly, proteome profiling revealed only three unique proteins expressed by JSCC1 and JSCC2 (angiogenin, CXCL1, PDGF-AA), implying STAT3 activation by unique protein-mediated intracrine/autocrine signaling. Protein profiling of corresponding tumor tissues is ongoing. Optimally, tissues obtained from diagnostic incisional biopsies would be characterized to develop: 1) tumor-specific induction chemotherapy to reduce tumor mass (sparing vital oral tissues) and 2) secondary chemoprevention to reduce loco-regional OSCC recurrences.
Tumor Characterization | Tumor-Derived Cell Line | Treatment Effects: EGFR-Mediated Signaling | Growth Factor Production (Bold= JSCC1/2-Unique) |
JSCC1 Tumor Location: Tonsil/Hypopharynx Perineural Invasion: Yes Lymphovascular Invasion: Yes Nodal Involvement: 2 of 104 HPV: Negative
| JSCC1 | EGFR - Negligible autologous activation - Activation via EGF stimulation - Activation with VEGF stimulation+ vargatef treatment ERK1/2 - Negligible autologous activation - Activation via EGF stimulation - Complete inhibition with afatinib treatment STAT3 - Moderate autologous activation - Non-responsive to afatinib/vargatef treatment, constant activation | SerpinE1 Macrophage Migration Inhibitory Factor PDGF-AA Monocyte Chemotactic Protein-1 (CCL2) |
JSCC2 Tumor Location: Tongue Perineural Invasion: Yes Lymphovascular Invasion: Yes Nodal Involvement: 0 of 50 HPV: Negative
| JSCC2 | EGFR - Moderate autologous activation - Increased activation via EGF stimulation - Partial inhibition with afatinib treatment - Increased inhibition with afatinib+ vargatef treatment ERK1/2 - Strong autologous activation - Activation via EGF stimulation - Partial inhibition with afatinib/vargatef treatment - Substantial inhibition with afatinib+ vargatef treatment STAT3 - Strong autologous activation - Non-responsive to afatinib/vargatef treatment, constant activation | Angiogenin Dickkopf-1 EMMPRIN ENA-78 (CXCL5) Fibroblast Growth Factor 19 GRO-alpha (CXCL1) Intercellular Adhesion Molecule-1 Insulin-like Growth Factor Binding Protein -3 Interleukin-1alpha Urokinase Receptor Interleukin-8 Interleukin-17A Lipocalin-2 Macrophage Migration Inhibitory Factor PDGF-AA SerpinE1 Transferring Receptor Thrombospondin-1 Interleukin-6
|
JSCC3 Tumor Location: Floor of Mouth Perineural Invasion: Yes Lymphovascular Invasion: No Nodal Involvement: 1 of 27 HPV: Negative
| JSCC3 | EGFR - Moderate autologous activation - Increased activation via EGF stimulation - Partial inhibition with afatinib treatment - Increased inhibition with afatinib+ vargatef treatment ERK1/2 - Minimal autologous activation - Activation via EGF stimulation - Partial inhibition with afatinib treatment - Substantial inhibition with afatinib+ vargatef treatment STAT3 - Negligible autologous activation - Complete inhibition with afatinib treatment | Dickkopf-1 Insulin-like Growth Factor Binding Protein -2 Interleukin-8 SerpinE1 Macrophage Migration Inhibitory Factor Monocyte Chemotactic Protein-1 (CCL2)
|