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Cancer Pharmacology

 

Cancer chemotherapy and pharmacology involves the pharmacological and oncological aspects of drugs at both an experimental and clinical level. New anticancer drugs require screening in terms of not only their pharmacokinetic and pharmacodynamic profiles but also single and combined drug administration modalities as well as the different phases of clinical trials. Importantly preclinical toxicology as well as drug interactions and indications for chemotherapy in cancer treatment are also investigated. 

Research in this area focuses on the study of “pro-growth/tumourigenic” serine/threonine kinases in an effort to delineate signalling pathways which may uncover new cellular targets for the pharmacological or genetic manipulation of cancer. In particular one area of research focuses on the role of p38 MAPKs, Paks and PKCs which exert a variety of cellular effects including changes in proliferation, malignant transformation, cell death and differentiation. We have performed extensive studies on one particular p38 MAPK isoform i.e. p38d MAPK which up until now has been largely understudied and ill-defined due to lack of specific activators and inhibitors being commercially available. Reports of the involvement of p38a and p38β MAPKs in a variety of pathological conditions is continuing to fuel interest in the development of potent and specific drugs for modulating the activity of these kinases. Interestingly, using a substrate fusion approach we have outlined that lack of expression specifically of the p38d MAPK isoform in different cancer types namely oesophageal, renal, prostate, lung and liver has profound effects on cancer cell proliferation and apoptosis.  We have also exploited the activation of PKCd as a pro-apoptotic and anti-proliferative agent in oesophageal cancer. Finally, we have identified different Pak isoforms which are pro-apoptotic in oesophageal and renal cancer. An important aspect of our research is to elucidate the signalling pathways underlying the apoptotic effect of these kinases using both pharmacological and molecular strategies. In addition the use of athymic nude mice to study their effects is necessary to translate in vitro results to in vivo models of tumourigenesis in order to validate our experimental hypothesis in a physiological setting. In summary, using siRNA technology and overexpression studies we have identified not only different kinase isoforms but in some instances the same kinase (p38d MAPK) involvement  in cell proliferation and cell death in different cancer types thus providing an important therapeutic  target for a range of cancers. Finally we have reported that the kinase status of the cancer may be a predictor of response to chemotherapy.