TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response.

Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53-mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for TRP53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease. Mol Cancer Ther; 16(12); 2913-26. ©2017 AACR.

Safety of cidofovir by intratympanic delivery technique.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is one of the most common infectious causes of congenital sensorineural hearing loss. To date, a safe and effective therapy for CMV-induced hearing loss does not exist. We hypothesize that the antiviral cidofovir (CDV) can be delivered to the inner ear via intratympanic (IT) injections to safely and effectively mitigate CMV-induced hearing loss. METHODS: To evaluate the safety of CDV IT injections, weanling guinea pigs with normal hearing were injected intratympanically with 3 mg or 5 mg concentrations of CDV and compared to control animals injected with sterile saline. A separate group of weanling guinea pigs were inoculated with CMV and a subset of this group was treated with CDV following inoculation. RESULTS: The 3 mg/ml and 5 mg/ml CDV concentrations resulted in hearing loss following IT injection into uninfected animals. No signs of inflammation or toxicity were noted on histologic analysis and there was no evidence of systemic toxicity in serology. Hearing loss induced as a result of guinea pig CMV infection recovered by day 21 in animals treated with IT injections of 5 mg/ml CDV. CONCLUSIONS: We provide promising evidence demonstrating both the efficacy and safety of IT CDV in the guinea pig animal model. This research further establishes a sound framework upon which ongoing investigations into drug delivery mechanisms for CMV-induced hearing loss will be based.