Abstract B120: In vivo evaluation of dovitinib (TKI258) alone and in combination in patient-derived salivary gland tumor models: Identification of a potential treatment for adenoid cystic carcinoma.
Authors: Wick Michael J. , Nieves Francis , Estrada Vanessa , Kelly Scott , Kaufman Jeffrey , Moskaluk Christopher A. , Tolcher Anthony W. , Patnaik Amita , Shi Michael , Papadopoulos Kyriakos P. 
Published: June 2012

Background: Adenoid Cystic Carcinoma (ACC) is an uncommon cancer of the head and neck which typically originates in the salivary glands. We and others have previously performed preclinical and clinical screens of FDA-approved and investigational agents in an attempt to identify useful therapies for ACC. However, to date no approved standard of care drug therapy exists. Fibroblast growth factors (FGF) and their receptors (FGFR 1–4) are a highly conserved group of functional proteins involved in cell migration, proliferation and survival and have been found important in initiation and progression of certain cancer types. Recently FGFR1 has been found over-expressed and phosphorylated in a majority of ACC tumors and FGF2, a known ligand of FGFR1, is a known downstream target of MYB which is rearranged in most ACC tumors. These data provide the rationale for testing the efficacy of FGFR inhibitors in ACC.

Dovitinib (TKI-258) is an orally bioavailable multi-tyrosine kinase inhibitor (TKI) selectively targeting a number of proteins including VEGFR, PDGFR and FGFR. Preclinical and clinical activity of this agent has been demonstrated in solid tumors including breast and renal cancers. However, whether dovitinib is active towards ACC is unclear.

Methods: We have developed and characterized a panel of patient-derived ACC tumor models including ACC×5M1, ACC×6, ACC×9, ACC×14 and ACC×16. To evaluate potential activity of dovitinib towards ACC we tested this agent alone and in combination with docetaxel, a taxane previously found active in our preclinical ACC screens, in these five models. Single agent and combination tumor growth inhibition was evaluated with a mean control tumor volume of 1cm3 or seventy-days following treatment initiation as study endpoints.

Results: In these studies dovitinib was well tolerated at the evaluated treatment regimens. Dovitinib alone demonstrated statistically significant (p&lt;0.05) tumor growth inhibition in four of five tested models (TGI&gt;58%) and combination with docetaxel resulted in additive tumor growth inhibition in sensitive models, including partial and compete tumor responses in some models. Dose and schedule-dependent activity was also demonstrated with dovitinib in these studies.

Conclusion: These results identify dovitinib as a potential treatment for ACC and suggest combination benefit with docetaxel. Based on these studies and correlative molecular characterization data clinical trials have been initiated to evaluate dovitinib in patients with ACC. These studies further demonstrate the utility of patient derived tumor models as translational tools for improved identification of potential anticancer therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B120.