Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

High Frequency of KRAS Codon 146 and FBXW7 Mutations in Thai Patients with Stage II-III Colon Cancer.

Background: KRAS, NRAS, and BRAF gene mutations are the most clinically relevant and frequently reported in colorectal cancer (CRC). Although data on these genes are frequently reported in several counties, data specific to these genes among Thai population are scarce. The aim of this study was to investigate and identify molecular alterations associated with colon cancer in Thai population, and to determine the impact of these genetic aberrations on clinical outcome. Methods: DNA from 108 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples that histologically confirmed adenocarcinoma of stage II-III colon cancer between 2010 and 2012 at Siriraj Hospital (Bangkok, Thailand) were extracted. Gene mutational analysis was performed by next-generation sequencing (NGS) using an Oncomine Solid Tumor DNA kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Results: A total of 22 somatic gene mutations were detected. The mutation frequency observed in KRAS, NRAS, BRAF, PIK3CA, and FBXW7 mutations was 47.2%, 1.9%, 1.9%, 12%, and 14.8%, respectively. KRAS mutation codon 12, 13, 59, 61, 117, and 146 mutations were identified in 29.6%, 8.3%, 1.8%, 0.9%, 0.0%, and 8.3%, respectively. KRAS Exon 4 had better DFS compared with Exon 2 and 3. Conclusions: This study is the first to comprehensively report hotspot mutations using NGS in Thai colon cancer patients. The most commonly identified gene mutation frequencies among Thai patients (KRAS, NRAS, BRAF, TP53, and PIK3CA) were similar to the gene mutation frequencies reported in Western population, except for subgroup of KRAS codon 146 and FBXW7 mutations that had a slightly higher frequency.

Post-Operative Concurrent Chemoradiation for Patients with Non-Squamous Cell Carcinoma of Head and Neck: A Retrospective Cohort of the Uncommon Cancers.

Background: Non-squamous cell carcinoma of the head and neck (HNnSCCA) is a rare tumor. Surgery is the standard treatment for resectable non-metastatic patients. Post-operative radiation (RT) is indicated for high-risk patients. No data from the randomized controlled trial utilizing post-operative concurrent chemoradiation (CCRT) is available. This study was aimed to determine the benefit of post-operative CCRT in the patients with resectable non-metastatic HNnSCCA. Methods: We retrospectively reviewed data of 139 patients with HNnSCCA (excluding nasopharyngeal, neuroendocrine, and skin cancers) who underwent surgery and post-operative radiation (RT) at Siriraj Hospital from 2009­2015. Results: Ninety-nine of the 139 patients had RT alone and 40 had CCRT. More patients receiving CCRT had ≥ one high-risk feature (80% CCRT vs. 57.6% RT; p=0.018). Five-year disease-free survival (DFS) and overall survival (OS) did not differ between the groups (58.6% CCRT vs. 68.2% RT; p=0.35 and 81.7% CCRT vs. 81.0% RT; p=0.35, respectively). Interestingly, post-operative CCRT was independently associated with significantly superior DFS (hazard ratio, HR 0.29; 95% confidence interval, CI 0.10 to 0.86; p=0.02) and OS (HR 0.08; 95% CI 0.01 to 0.43; p=0.003) according to multivariable analyses. Conclusion: Post-operative CCRT was associated with better survival in high-risk patients with resectable non-metastatic HNnSCCA comparing with post-operative RT alone. Post-operative CCRT might be considered as a treatment option for these patients.

Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study.

PURPOSE: The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. METHODS: We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5 days of each cycle. The primary outcome was reduction in nausea score. RESULTS: Thirty-four subjects (68 cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40-90). Thirty-three subjects (97 %) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95 % confidence interval, -3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. CONCLUSIONS: Ginger (500 mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.