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Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS or NOS III) has been implicated recently in the pathogenesis of PDAC. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDAC. Genetic deficiency in eNOS limited the development of pre-invasive pancreatic lesions and trended towards an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor L-NAME. Similarly, other transgenic models of oncogenic KRas-driven tumors responded to L-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which L-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose L-NAME for clinical investigations in treatment of PDAC and possibly other KRas-driven human cancers.

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Background Stomatitis is the most frequent adverse event reported in trials of mTOR-inhibitors, including EVE. In the pivotal phase 3 BOLERO-2 study, stomatitis incidence in the EVE + exemestane (EXE) arm was 59%. The BOLERO-4 study (NCT01698918) evaluated the efficacy and safety of first-line EVE + LET in postmenopausal pts with HR+, HER2− metastatic or locally advanced breast cancer (ABC). BOLERO-4 also assessed the effectiveness of an alcohol-free dexamethasone (0.5 mg/ 5ml; DEX) oral rinse for treating stomatitis in a subset of pts (USA). Methods Postmenopausal pts with HR+, HER2− ABC previously untreated for advanced disease received EVE (10 mg/day) + LET (2.5 mg/day).At disease progression, pts were offered EVE (10 mg/day) + EXE (25 mg/day). Pts who had at least one episode of stomatitis received oral stomatitis daily questionnaire (OSDQ), which is a 6 question pt-reported outcome (PRO) survey (Stiff et al, JCO. 2006). A subset of these pts (USA) was randomized (1:1) to receive DEX or standard of care (SOC). The primary objective of investigator-assessed progression-free survival in the first-line setting for ABC was presented previously. A secondary objective was to evaluate the effectiveness of the DEX oral rinse in reducing the severity and duration of stomatitis, using OSDQ data. Results Of the total 202 pts enrolled in this study, 52 pts were enrolled in USA, of which, 24 (46.2%) were randomized to receive DEX (n=11) or SOC (n=13), upon confirmation of stomatitis. The median duration of first stomatitis episode was longer per OSDQ (DEX, not estimable vs SOC, 13.7 wk) compared with physician-reported duration (DEX, 1.6 wk vs SOC, 1.9 wk). PRO OSDQ results were similar in both arms. Among the 202 pts enrolled, 89 (44.1%) filled the OSDQ at their first stomatitis episode. The median time from treatment initiation to first stomatitis episode was 1.7 wk; median duration of stomatitis was 13.7 wk (OSDQ) vs 2.1 wk (physician reported). The majority of pts experiencing stomatitis had moderate/little/no soreness, moderate/low/no pain, and stomatitis had low/no effect on daily activities (Table 1). Table 1. OSDQ Key Results (N=87)Questions (Score)First Day of Stomatitis Episode, n (%)End of First Stomatitis Episode, n (%)Overall healthPoor (0-4)20 (23.0)23 (26.4)Moderate (5-7)40 (46.0)32 (36.8)Perfect (8-10)27 (31.0)32 (36.8)Mouth and throat sorenessNo/a little/moderate (0-2)64 (73.6)84 (96.6)A lot or extreme (3-4)23 (26.4)3 (3.4)Mouth pain severityNo/low/moderate (0-4)51 (58.6)73 (83.9)Severe (5-7)24 (27.6)10 (11.5)Unbearable (8-10)12 (13.8)4 (4.6)Effect on daily activitiesNo/low (0-4)70 (80.5)78 (89.7)Moderate (5-7)11 (12.6)4 (4.6)High (8-10)6 (6.9)5 (5.7) Conclusions Overall, patient-reported median duration of stomatitis was longer than that reported by physicians, most likely due to differences in perceptions and the challenges in collecting and cleaning PRO data. Overall good health score was maintained in the majority of pts experiencing stomatitis and stomatitis had low/no effect on daily activities. However, these results, especially in the randomized subset need to be interpreted with caution owing to the small sample size, missing data and lack of commercially available DEX in most countries. Citation Format: Villanueva C, Tsugawa K, Toyama T, Noh W, Jeong J, Cardoso F, Sriuranpong V, Srimuninnimit V, Ozguroglu M, Kendall S, Falkson C, Cianfrocca M, Manlius C, Lin JCJ, Ringeisen F, Ridolfi A, Royce M. Stomatitis in patients treated with first-line everolimus (EVE) plus letrozole (LET): Results from BOLERO-4 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-08.

Pancreatic cancer has a very high mortality rate, and frontline therapy has not changed in over a decade indicating a need for novel therapeutics. In this regard, endothelial Nitric Oxide Synthase (eNOS) has emerged as a new target due to recent studies demonstrating elevated expression in human pancreatic cancers, and inhibition of pancreatic tumor growth with eNOS knockdown or knockout in xenograft and genetically engineered mouse models. By pharmacologically testing eNOS inhibition, we found that a non-selective NOS inhibitor, L-NG-Nitroarginine methyl ester (L-NAME), inhibited tumor growth of human pancreatic cancer cell lines and extended survival in the aggressive Pdx-1-CreTg/+;LSL-KRASG12D/+;LSL-Trp5R172H/+ (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC) by ∼30 days. This extended survival is particularly significant given that the current frontline therapy, gemcitabine, does not provide these mice with a similar survival advantage. While general inhibitors such as L-NAME are attractive molecules to explore, evidence has shown that targeting all three NOS enzymes can have undesirable off-target effects. As eNOS has been identified as the NOS family member required for pancreatic tumorigenesis, and there currently are no selective eNOS inhibitors, we have created and optimized a cell-based system to identify potent and selective compounds for eNOS inhibition. This assay uses a mammalian baculovirus expression system to distinguish the activity of eNOS, nNOS, and iNOS via measurement of the stable bi-products of nitric oxide synthesis, and has been tested with a variety of published NOS inhibitors including L-NAME, the iNOS specific inhibitor 1400W, and the nNOS specific inhibitor L-NPA. The assay is suitable for high throughput screening of small molecule libraries to identify novel eNOS inhibitors that, when paired with gemcitabine, may represent a novel combination therapy for pancreatic cancer therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2584. doi:10.1158/1538-7445.AM2011-2584

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