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1.  Targeting HER2+ breast cancer: the TBK1/IKKε axis 
Oncoscience  2014;1(2):180-182.
HER2+ breast cancer (BC) is a highly aggressive subtype, affecting ~20% of BC patients. Current treatments include adjuvant or neoadjuvant chemotherapy plus anti-HER2 agents such as trastuzumab, a monoclonal antibody directed against HER2. Despite improvement in disease free survival, most patients eventually succumb to metastatic disease, which is largely incurable. Consequently, there is an urgent need to identify novel drugs that can efficiently kill HER2+ BC and/or potentiate the effect of existing anti-HER2 therapies. We performed a lenti-viral shRNA kinome screen on non-adherent mouse Her2/Neu tumorspheres and identified TBK1, a non-canonical IκB kinase (IKK), as the most potent target [1]. TBK1 knock-down, or treatment with TBK1-II, a drug that efficiently inhibits TBK1 and its close relative IKKε (IKBKE), suppressed growth of human HER2+ BC cells and induced cellular senescence. Senescence was associated with inhibition of phosphorylated/active p65-NFkB and induction of the cell cycle inhibitor, p16ink4a. In addition, TBK1-II cooperated with lapatinib, a EGFR/HER2 inhibitor, to accelerate apoptosis in vitro and suppress tumor growth in a xenograft model of HER2+ BC. Thus, TBK1/IKKε inhibitors may improve treatment of HER2+ BC in cooperation with anti-HER2 therapy.
PMCID: PMC4278282  PMID: 25594009
Breast cancer; HER2; therapy; TBK1; IKKε
2.  Carcinoid and Neuroendocrine Tumors of the Colon and Rectum 
ABSTRACT
Carcinoid and neuroendocrine tumors of the colon and rectum arise from the amine precursor uptake and decarboxylation (APUD) cells of the intestine. Carcinoid tumors are most commonly found in the gastrointestinal tract and are located in decreasing order of frequency in appendix, ileum, rectum, stomach, and colon. The vast majority of lesions are asymptomatic and are found incidentally during endoscopy. The management of these lesions depends upon the size of the lesion, involvement of the muscularis, location, and presence of metastatic disease. Small lesions (1 cm) can often be treated locally, either endoscopically or transanally. However, larger lesions (> 2 cm) require a formal oncologic resection. Adjuvant therapy is indicated only for metastatic disease, and admirable advances have been made in the realm of chemotherapy for reduction of disease and palliation of the symptoms of carcinoid syndrome. In this article, we discuss the nature of these interesting and uncommon tumors, clinical presentation, treatment options, and prognosis.
doi:10.1055/s-2006-942343
PMCID: PMC2780103  PMID: 20011309
Carcinoid; neuroendocrine tumor; colon; rectum
3.  Mechanism-Based Pharmacodynamic Models of Fluoroquinolone Resistance in Staphylococcus aureus 
Pharmacodynamic modeling from earlier experiments in which two ciprofloxacin-susceptible Staphylococcus aureus strains and their corresponding resistant grlA mutants were exposed to a series of ciprofloxacin (J. J. Campion, P. J. McNamara, and M. E. Evans, Antimicrob. Agents Chemother. 49:209-219, 2005) and levofloxacin (J. J. Campion et al., Antimicrob. Agents Chemother. 49:2189-2199, 2005) pharmacokinetic profiles in an in vitro system indicated that the subpopulation-specific estimated maximal killing rate constants were similar for both agents, suggesting a common mechanism of action. We propose two novel pharmacodynamic models that assign mechanisms of action to fluoroquinolones (growth inhibition or death stimulation) and compare the abilities of these models and two other maximum effect models (net effect and MIC based) to describe and predict the changes in the population dynamics observed during our previous in vitro system experiments with ciprofloxacin. A high correlation between predicted and observed viable counts was observed for all models, but the best fits, as assessed by diagnostic tests, and the most precise parameter estimates were obtained with the growth inhibition and net effect models. All models, except the death stimulation model, correctly predicted that resistant subpopulations would not emerge when a high-density culture was exposed to a high initial concentration designed to rapidly eradicate low-level-resistant grlA mutants. Additional experiments are necessary to elucidate which of the proposed mechanistic models best characterizes the antibacterial effects of fluoroquinolone antimicrobial agents.
doi:10.1128/AAC.00736-05
PMCID: PMC1563538  PMID: 16940088
4.  Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus 
Previously, we demonstrated the importance of low-level-resistant variants to the evolution of resistance in Staphylococcus aureus exposed to ciprofloxacin in an in vitro system and developed a pharmacodynamic model which predicted the emergence of resistance. Here, we examine and model the evolution of resistance to levofloxacin in S. aureus exposed to simulated levofloxacin pharmacokinetic profiles. Enrichment of subpopulations with mutations in grlA and low-level resistance varied with levofloxacin exposure. A regimen producing average steady-state concentrations (Cavg ss) just above the MIC selected grlA mutants with up to 16-fold increases in the MIC and often additional mutations in grlA/grlB and gyrA. A regimen providing Cavg ss between the MIC and the mutant prevention concentration (MPC) suppressed bacterial numbers to the limit of detection and prevented the appearance of bacteria with additional mutations or high-level resistance. Regimens producing Cavg ss above the MPC appeared to eradicate low-level-resistant variants in the cultures and prevent the emergence of resistance. There was no relationship between the time concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of mutations that appeared in grlA/B or gyrA. Our pharmacodynamic model described the growth and levofloxacin killing of the parent strains and the most resistant grlA mutants in the starting cultures and correctly predicted conditions that enrich subpopulations with low-level resistance. These findings suggest that the pharmacodynamic model has general applicability for describing fluoroquinolone resistance in S. aureus and further demonstrate the importance of low-level-resistant variants to the evolution of resistance.
doi:10.1128/AAC.49.6.2189-2199.2005
PMCID: PMC1140504  PMID: 15917512

Results 1-4 (4)