Oncogenic Signaling in Cancer

The research conducted in my laboratory focuses on receptor tyrosine kinase signaling in normalcy and primary malignant brain cancer. Specifically, we are studying oncogenic epidermal growth factor receptor function during tumorigenesis, tumor maintenance and resistance to therapeutic treatments. Although the EGF receptor is one of the major oncogenes in primary malignant brain tumors, very little is known about the various signals that emanate from it and how these signals relate to therapeutic agents resistance. My laboratory uses state of the art genomic and genetic technologies to create genetically engineered mouse models of primary brain cancer that are built upon genetic mutation spectra observed in human patients.

Integrative Assessment of Oncogenic RTK Signaling in Brain Cancer

One of the most common genetic aberrations in glioblastoma multiforme (GBM) is the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR). A major aspect of our research focuses on deciphering the signaling networks within the CNS tumors that originate from EGFR. In collaboration with Forest White at MIT, we are undertaking a global phospho proteome approach aimed at establishing a functional relationship between activation of EGFR signaling networks and ensuing tumor phenotypes in an in vivo environment. We believe that this will generate invaluable information on EGFR's roles in GBM biology. The identification of signaling molecules necessary for critical aspects of GBM biology such as tumor initiation, maintenance and, most importantly, resistance to treatment in the context of integrative inputs from the extracellular milieu will offer unprecedented opportunities for pharmaceutical exploitation.

Figure 1. Schematic representation of the EGF receptor bound to its ligand and depicting intracellular phosphorylation sites along with activation of the signaling pathways associated with those sites.

In Vivo Use of Therapeutic miRNAs

Tremendous progress has been achieved in the recent years in our understanding of the ability of small interfering RNAs (siRNAs) to silence gene expression in mammalian cells. This has provided us with a revolutionary new tool to modulate the expression of disease-causing genes. My laboratory is realizing the therapeutic potential of RNAi by deciphering essential gene targets within our model systems and by utilizing potent and stable siRNA compounds that are silencing these genes. We strongly believe that siRNAs hold great potential as gene-specific therapeutic agents.

Nanoparticle-Based Delivery Vehicles

The use of nanoparticles for therapeutics targeting and delivery is hailed as one of the most exciting and clinically significant applications of nanotechnology. Targeted delivery of high-affinity drugs using nanoparticles promises to alleviate many of the difficulties associated with cross-reactivity, toxicity and misdistribution of conventional methods. In collaboration with members of the Harvard-MIT Nanomedical Consortium and David Kaplan’s group, my laboratory is testing various biodegradable non-toxic nanoparticles-based vehicles for efficient delivery of therapeutic siRNAs along with novel targeted chemotherapeutic agents. As such, we are concentrating our efforts on studying efficacy in relation to the physico-pharmacological properties of these nanoscale therapeutics.

Figure 2. Nanoparticle-based delivery of siRNA against the EGF receptor in vivo. Dendriworm nanoparticles (Dworm) (red) efficiently delivers EGFR siRNA to brain cancer tumor cells in vivo and mediate knock down of the EGFR (green). Taken from Agrawal et al 2009. Abstract