Introduction Tinnitus is a debilitating auditory symptom that globally impacts the quality of life of patients. Sound exposure, stress, and somatosensory stimuli (e.g. neck and jaw movements) are tinnitus modulators that have been commonly described and studied. Napping may also increase tinnitus loudness upon awakening in a minority of subjects. To our best knowledge this modulation and its potential pathophysiological mechanisms has never been systematically assessed. Methods For this observational prospective study, we studied 37 tinnitus subjects complaining of significant naps-related tinnitus modulations. All subjects performed 6 naps attempts under polysomnography over 2 days. Audiological, electrophysiological as well as jaw and neck muscles mobility and sensitivity assessments were completed before and after each nap. In addition, subjects filled a screening questionnaire and underwent a tinnitus pitch-matching procedure. Results 197 naps attempts were collected. It was confirmed that overall naps were increasing tinnitus loudness (p< 0.001). First naps of the day yielded more important tinnitus modulations than second (p< 0.05) and third naps (p< 0.01) suggesting a saturation effect. Analyses conducted so far highlight that nap sleep duration correlates with observed tinnitus modulation (p< 0.05) and that audiometric thresholds at tinnitus closest frequency do not seem to be affected by tinnitus modulation. Neither jaw mobility nor sensitivity were correlated with tinnitus modulation. Analyses to come will assess if sleep apnea, sleep bruxism, cervical mobility or sleep position may correlate with tinnitus nap modulations. Conclusion This study demonstrated that in a subgroup of tinnitus patients naps may modulate tinnitus. Nap sleep duration more than jaw muscles sensitivity seem to be correlated with these modulations. Support (if any) This study was supported by Felicia and Jean-Jacques Lopez-Loreta Foundation, Robin Guillard EIRL and Université Paris Cité VIFASOM

Solid tumors at the advanced stages are often characterized by the overexpression of tyrosine kinase receptors that stimulate growth through the MAP kinase pathway and activate antiapoptotic signaling through the PI3K kinase pathway. One such receptor is the epidermal growth factor receptor (EGFR) that is overexpressed in many tumors including brain, lung, breast, ovarian and prostate carcinomas. EGFR can synergize with other tyrosine kinases such as Src to promote invasion and metastasis. However, despite the implication of EGFR in multiple processes, inhibitors of its tyrosine kinase activity such as ZD1839 or erlotinib showed moderate antiproliferative activity against certain tumor types in the clinic. It has been reported that EGFR expressing cells that harbor dysfunctional PTEN, are moderately sensitive to EGFR inhibitors. Given the complexity of cell response the latter class of inhibitors, we thought it of interest to investigate agents that are not only directed at EGFR but also to divergent targets such as Src or DNA, with the purpose of producing single compounds with greater potency than their single inhibitor counterpart. These molecules termed “combi-molecules” were designed to remain small enough for their quinazoline moiety to be able to bind to the ATP site of EGFR and to block a divergent target such as Src or DNA. Using molecular modeling, a structure-based drug design program was used to identify a linker that could be placed between the quinazoline moiety required for binding in the ATP site and the appendage directed at the divergent target. A solvent exposed ASP residue near the opening of the EGFR ATP binding pocket was used to optimize interaction with ionizable linkers. This interaction was found to be tolerant of bulky substituents and was exploited to append other pharmacophores to the combi-molecules. The results showed that in the category of mixed EGFR-DNA targeting molecules, the EGFR inhibitory potency of EGFR was in the low micromolar to nM range and the compounds also retained significant DNA damaging potential. In the category of EGFR-Src targeting molecules, we identified SB163 that contained a quinazoline moiety, the ionizable spacer and an analogue of PP2. SB163 showed significant antiproliferative and antimetastatic property in a Boyden Chamber assay and its activity was superior to that of a combination of known Src inhibitor PP2 + ZD1839, a clinical inhibitor of EGFR. Furthermore, sub-cellular distribution studies, using a fluorescent probe containing the optimized ionizable spacer showed that their biodistribution is unique with preferential localization in the perinuclear region. The results in toto suggests that in the design of promiscuous molecules, an ionizable basic arm linked to the aminoquinazoline moiety preserves EGFR inhibitory potency and allow freedom to append other moiety directed at the cross- target. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A142.