Aug
12
Mon
2013
Invited Talk: Epigenetic Changes due to DNA Methylation in Human Epithelial Tumors @ Acharya Hall
Aug 12 @ 12:18 pm – 12:39 pm

sathyaK. Satyamoorthy, Ph.D.
Director, Life Sciences Centre, Manipal University, India


Epigenetic Changes due to DNA Methylation in Human Epithelial Tumors

Extensive global hypomethylation in the genome and hypermthylation of selective tumor specific suppressor genes appears to be a hallmark of human cancers.  Data suggests that hypermethylation of promoter region in genes is more closely related to subsequent gene expression; contrary to gene-body DNA methylation.  The intricate balance between these two may contribute to the progressive process of development, differentiation and carcinogenesis.  Epigenetic changes encompass, apart from DNA methylation, chromatin modifications through post-translational changes in histones and control by miRNAs.  At the genome level, effects from these are compounded by copy number variations (CNVs) which may ultimately influence protein functions.    From clinical perspective, changes in DNA methylation occur very early which are reversible and are influenced by environmental factors.  Therefore, these can be potential resource for identifying therapeutic targets as well as biomarkers for early screening of cancer.  Our current efforts in profiling genome wide DNA methylation changes in oral, cervical and breast cancers through DNA methylation microarray analysis has revealed number of alterations critical for survival, progression and metastatic behavior of tumors.  Bioinformatics and functional analysis revealed several key regulatory molecules controlled by DNA methylation and suggests that DNA methylation changes in several CpG islands appear to co-segregate in the regions of miRNAs as well as in the CNVs.  We have validated the signatures for methylation of CpG islands through bisufite sequencing for essential genes in clinical samples and have undertaken transcriptional and functional analysis in tumor cell lines.    These results will be presented.

Aug
13
Tue
2013
Invited Talk: Targeting aberrant cancer kinome using rationally designed nano-polypharmaceutics @ Acharya Hall
Aug 13 @ 2:05 pm – 2:29 pm

ManzoorManzoor 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’.

Manzoor

Invited Talk: Nanoscale Simulations – Tackling Form and Formulation Challenges in Drug Development and Drug Delivery @ Sathyam Hall
Aug 13 @ 2:15 pm – 2:40 pm

lalithaLalitha Subramanian, Ph.D.
Chief Scientific Officer & VP, Services at Scienomics, USA


Nanoscale Simulations – Tackling Form and Formulation Challenges in Drug Development and Drug Delivery

Lalitha Subramanian, Dora Spyriouni, Andreas Bick, Sabine Schweizer, and Xenophon Krokidis Scienomics

The discovery of a compound which is potent in activity against a target is a major milestone in Pharmaceutical and Biotech industry. However, a potent compound is only effective as a therapeutic agent when it can be administered such that the optimal quantity is transported to the site of action at an optimal rate. The active pharmaceutical ingredient (API) has to be tested for its physicochemical properties before the appropriate dosage form and formulation can be designed. Some of the commonly evaluated parameters are crystal forms and polymorphs, solubility, dissolution behavior, stability, partition coefficient, water sorption behavior, surface properties, particle size and shape, etc. Pharmaceutical development teams face the challenge of quickly and efficiently determining a number of properties with small quantities of the expensive candidate compounds. Recently the trend has been to screen these properties as early as possible and often the candidate compounds are not available in sufficient quantities. Increasingly, these teams are leveraging nanoscale simulations similar to those employed by drug discovery teams for several decades. Nanoscale simulations are used to predict the behavior using very little experimental data and only if this is promising further experiments are done. Another aspect where nanoscale simulations are being used in drug development and drug delivery is to get insights into the behavior of the system so that process failures can be remediated and formulation performance can be improved. Thus, the predictive screening and the in-depth understanding leads to experimental efficiency resulting in far-reaching business impacts.

With specific examples, this talk will focus on the different types of nanoscale simulations used to predict properties of the API in excipients and also provide insight into system behavior as a function of shelf life, temperature, mechanical stress, etc.