Detection of non-melanoma skin cancer by in vivo fluorescence imaging with fluorocoxib A.

Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 μm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs

Identifying mechanism-of-action targets for drugs and probes

Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration—approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest

Regular use of aspirin and pancreatic cancer risk

BACKGROUND: Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been consistently associated with reduced risk of colorectal cancer and adenoma, and there is some evidence for a protective effect for other types of cancer. As experimental studies reveal a possible role for NSAIDs is reducing the risk of pancreatic cancer, epidemiological studies examining similar associations in human populations become more important. METHODS: In this hospital-based case-control study, 194 patients with pancreatic cancer were compared to 582 age and sex-matched patients with non-neoplastic conditions to examine the association between aspirin use and risk of pancreatic cancer. All participants received medical services at the Roswell Park Cancer Institute in Buffalo, NY and completed a comprehensive epidemiologic questionnaire that included information on demographics, lifestyle factors and medical history as well as frequency and duration of aspirin use. Patients using at least one tablet per week for at least six months were classified as regular aspirin users. Unconditional logistic regression was used to compute crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Pancreatic cancer risk in aspirin users was not changed relative to non-users (adjusted OR = 1.00; 95% CI 0.72–1.39). No significant change in risk was found in relation to greater frequency or prolonged duration of use, in the total sample or in either gender. CONCLUSIONS: These data suggest that regular aspirin use may not be associated with lower risk of pancreatic cancer

Aspirin-induced nuclear translocation of NFκB and apoptosis in colorectal cancer is independent of p53 status and DNA mismatch repair proficiency

Substantial evidence indicates nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC). However, the molecular basis for this anti-tumour activity has not been fully elucidated. We previously reported that aspirin induces signal-specific IκBα degradation followed by NFκB nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. We have also reported the relative specificity of this aspirin-induced NFκB-dependent apoptotic effect for CRC cells, in comparison to other cancer cell types. It is now important to establish whether there is heterogeneity within CRC, with respect to the effects of aspirin on the NFκB pathway and apoptosis. p53 signalling and DNA mismatch repair (MMR) are known to be deranged in CRC and have been reported as potential molecular targets for the anti-tumour activity of NSAIDs. Furthermore, both p53 and MMR dysfunction have been shown to confer resistance to chemotherapeutic agents. Here, we set out to determine the p53 and hMLH1 dependency of the effects of aspirin on NFκB signalling and apoptosis in CRC. We specifically compared the effects of aspirin treatment on cell viability, apoptosis and NFκB signalling in an HCT-116 CRC cell line with the p53 gene homozygously disrupted (HCT-116p53−/−) and an HCT-116 cell line rendered MMR proficient by chromosomal transfer (HCT-116+ch3), to the parental HCT-116 CRC cell line. We found that aspirin treatment induced apoptosis following IκBα degradation, NFκB nuclear translocation and repression of NFκB-driven transcription, irrespective of p53 and DNA MMR status. These findings are relevant for design of both novel chemopreventative agents and chemoprevention trials in CRC