Gillian Murphy, Ph.D.
Professor, Department of Oncology, University of Cambridge, UK
A novel strategy for targeting metalloproteinases in cancer
Epithelial tumours evolve in a multi-step manner, involving both inflammatory and mesenchymal cells. Although intrinsic factors drive malignant progression, the influence of the micro-environment of neoplastic cells is a major feature of tumorigenesis. Extracellular proteinases, notably the metalloproteinases, are key players in the regulation of this cellular environment, acting as major effectors of both cell-cell and cell-extracellular matrix (ECM) interactions. They are involved in modifying ECM integrity, growth factor availability and the function of cell surface signalling systems, with consequent effects on cellular differentiation, proliferation and apoptosis.This has made metalloproteinases important targets for therapeutic interventions in cancer and small molecule inhibitors focussed on chelation of the active site zinc and binding within the immediate active site pocket were developed. These were not successful in early clinical trials due to the relative lack of specificity and precise knowledge of the target proteinase(s) in specific cancers. We can now appreciate that it is essential that we understand the relative roles of the different enzymes (of which there are over 60) in terms of their pro and anti tumour activity and their precise sites of expression The next generations of metalloproteinase inhibitors need the added specificity that might be gained from an understanding of the structure of individual active sites and the role of extra catalytic domains in substrate binding and other aspects of their biology. We have prepared scFv antibodies to the extra catalytic domains of two membrane metalloproteinases, MMP-14 and ADAM17, that play key roles in the tumour microenvironment. Our rationale and experiences with these agents will be presented in more detail.
Manzoor K, Ph.D.
Professor, Centre for Nanoscience & Molecular Medicine, Amrita University
Targeting aberrant cancer kinome using rationally designed nano-polypharmaceutics
Manzoor Koyakutty, Archana Ratnakumary, Parwathy Chandran, Anusha Ashokan, and Shanti Nair
`War on Cancer’ was declared nearly 40 years ago. Since then, we made significant progress on fundamental understanding of cancer and developed novel therapeutics to deal with the most complex disease human race ever faced with. However, even today, cancer remains to be the unconquered `emperor of all maladies’. It is well accepted that meaningful progress in the fight against cancer is possible only with in-depth understanding on the molecular mechanisms that drives its swift and dynamic progression. During the last decade, emerging new technologies such as nanomedicine could offer refreshing life to the `war on cancer’ by way of providing novel methods for molecular diagnosis and therapy.
In the present talk, we discuss our approaches to target critically aberrant cancer kinases using rationally designed polymer-protein and protein-protein core-shell nanomedicines. We have used both genomic and proteomic approaches to identify many intimately cross-linked and complex aberrant protein kinases behind the drug resistance and uncontrolled proliferation of refractory leukemic cells derived from patients. Small molecule inhibitors targeted against oncogenic pathways in these cells were found ineffective due to the involvement of alternative survival pathways. This demands simultaneous inhibition more than one oncogenic kinases using poly-pharmaceutics approach. For this, we have rationally designed core-shell nanomedicines that can deliver several small molecules together for targeting multiple cancer signalling. We have also used combination of small molecules and siRNA for combined gene silencing together with protein kinase inhibition in refractory cancer cells. Optimized nanomedicines were successfully tested in patient samples and found enhanced cytotoxicity and molecular specificity in drug resistant cases.
Nano-polypharmaceutics represents a new generation of nanomedicines that can tackle multiple cancer mechanisms simultaneously. Considering the complexity of the disease, such therapeutic approaches are not simply an advantage, but indispensable.
Acknowledgements:
We thank Dept. of Biotechnology and Dept. Of Science and Technology,Govt. of India for the financial support through `Thematic unit of Excellence in Medical NanoBiotechnology’ and `Nanomedicine- RNAi programs’.
H S M Kort, J-W J Lammers, S N W Vorrink, T Troosters
Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a disabling airway disease with variable extrapulmonary effects that may contribute to disease severity in individual patients (Rabe et al. 2007). The world health organization predicts that COPD will become the third leading cause of death worldwide by 2030. Patients with COPD demonstrate reduced levels of spontaneous daily physical activity (DPA) compared with healthy controls (Pitta et al. 2005). This results in a higher risk of hospital admission and shorter survival (Pitta et al. 2006). Pulmonary rehabilitation can help to improve the DPA level, however, obtained benefits decline after 1–2 years (Foglio et al. 2007).
Purpose
In order to maintain DPA in COPD patients after rehabilitation, we developed a mobile phone application. This application measures DPA as steps per day, measured by the accelerometer of the smartphone, and shows the information to the patient via the display of the mobile phone. A physiotherapist can monitor the patient via a secure website where DPA measurements are visible for all patients. Here, DPA goals can be adjusted and text messages sent.
Method
Three pilot studies were performed with healthy students and COPD patients to test the application for usability, user friendliness and reliability with questionnaires and focus groups. Subjects also wore a validated accelerometer. For the Randomized Controlled Trial (RCT) 140 COPD patients will be recruited in Dutch physiotherapy practises. They will be randomised in an intervention group that receives the smartphone for 6 months and a control group. Measurements include lungfunction, dyspnea, and exercise capacity and are held at 0, 3, 6 and 12 months.
Results and Discussion
The application was found to be useful, easy to learn and use. Subjects had no problems with health care professionals seeing information on their physical activity performance. They do find it important to be able to determine who can see the information. Correlations between the accelerometer and the measurements on DPA of the smartphone for steps per hour were 0.69 and 0.70 for pilot studies 1 (students) and 2 (COPD patients) respectively. The version of the application in pilot study 3 contained an error, which made correlations with the accelerometer unusable. The RCT study is now being executed.