Efficacy of Combining GMX1777 with Radiation Therapy for Human Head and Neck Carcinoma

Abstract

Purpose: Rapidly metabolizing tumor cells have elevated levels of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD + biosynthesis, which serves as an important substrate for proteins involved in DNA repair. GMX1777, which inhibits nicotinamide phosphoribosyltransferase, was evaluated in two human head and neck cancer models in combination with radiotherapy. Experimental Design: Effects of GMX1777-mediated radiosensitization were examined via metabolic and cytotoxicity assays in vitro; mechanism of action, in vivo antitumor efficacy, and radiosensitization were also investigated.Results: IC 50 values of GMX1777 for FaDu and C666-1 cells were 10 and 5 nmol/L, respectively, which interacted synergistically with radiotherapy. GMX1777 induced a rapid decline in intracellular NAD + followed by ATP reduction associated with significant cytotoxicity. These metabolic changes were slightly increased with the addition of radiotherapy, although poly(ADP-ribose) polymerase activity was significantly reduced when GMX1777 was combined with radiotherapy, thereby accounting for the synergistic cytotoxicity of these two modalities. Systemic GMX1777 administration with local tumor radiotherapy caused complete disappearance of FaDu and C666-1 tumors for 50 and 20 days, respectively. There was also significant reduction in tumor vascularity, particularly for the more sensitive FaDu model. Conclusions: Our data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Therefore, GMX1777 combined with radiotherapy definitely warrants clinical evaluation in human head and neck cancer patients. Clin Cancer Res; 16(3); 898-911. ©2010 AACR.Head and neck cancer is the fifth most common neoplasm worldwide (1, 2), with an estimated 644,000 new cases diagnosed each year wherein 60% of such patients present with stage III or IV disease (1, 2). Such locally advanced head and neck squamous cell cancers are treated with either hyperfractionated radiotherapy (3) or chemoradiotherapy (1, 2) but still associated with >50% mortality rate (1, 2), underscoring an urgent need to develop novel molecular therapies.Cancer cells have a dysregulated metabolism, which provides a survival advantage despite a noxious environment (4, 5). Consequently, there is increased demand for energy consumption and DNA repair. One of the key cofactors in cellular respiration is NAD + , which plays several essential roles, including serving as a coenzyme in redox reactions, providing substrates for the poly(ADP-ribose) polymerase (PARP), and sirtuins (6), a newly described group of proteins involved in multiple functions including DNA repair that requires NAD + to deacetylate (7). All these processes are involved in stress response, genomic instability, and apoptosis. In the mammalian system, the three major precursors of NAD + synthesis are tryptophan, nicotinic acid...

NAMPT Inhibitor GMX1778 Enhances the Efficacy of177Lu-DOTATATE Treatment of Neuroendocrine Tumors

“…shown to have a synergistic chemosensitizing effect, both in vitro and in vivo (16). Radiosensitizing effects of NAMPT inhibitors FK866 and GMX1777 have also been demonstrated experimentally in breast cancer and head and neck cancer models, respectively (6,17).…”

“…Radiotherapy causes DNA damage, which in turn induces activation of poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP-1) and consumption of NAD 1 (5). Inhibition of NAD 1 regeneration has been suggested as a radiosensitizing strategy (6).…”

Synergy between the NAMPT Inhibitor GMX1777(8) and Pemetrexed in Non–Small Cell Lung Cancer Cells Is Mediated by PARP Activation and Enhanced NAD Consumption

“…GMX1777 is a soluble prodrug of GMX used for in vivo studies (5,6). NAMPT inhibitors, including GMX1778 (GMX) and FK866, have shown preclinical activity alone and in combination with several therapeutic DNA-damaging agents, but the mechanism of synergy has not been clearly elucidated (7)(8)(9)(10).…”

An Orthotopic Model of Metastatic Nasopharyngeal Carcinoma and Its Application in Elucidating a Therapeutic Target That Inhibits Metastasis

“…[8][9][10][11][12] To date, most NPC xenograft studies have involved the growth of a mass of tumor cells, often subcutaneously, that do not recapitulate human disease because they remain discrete and encapsulated. [8][9][10] In comparison, clinically advanced NPC is characterized by aggressive invasion with erosion and remodeling of facial and skull base cranial bones 13 as well as distant metastasis to solid organs, most commonly bone, lung, and liver. 14,15 To more accurately replicate advanced human disease, we have developed an orthotopic mouse xenograft model of NPC by inserting luciferasetagged tumor cells into the nasopharyngeal region and then following patterns of growth and metastasis over time.…”