My main area of scientific interest lies in the development of novel direct acting protein based drugs to be utilized in the fight against disease. This interest has been addressed and will continue to be pursued through three distinct but related studies:
The development of novel protein based agents, understanding their mechanism of action and effect on disease
The delivery and efficient targeting of protein based therapeutics characterizing their biochemical and biophysical properties.
Modification of proteinsand gaining an understanding of their action for use as diagnostic and imaging agents in determination of disease progression.
My future research plans in the near term involve continued development of the snake venom disintegrin CN as a clinically applicable therapeutic agent both in collaboration with the Markland laboratory and as an independent investigator. In one study, we plan to biochemically, biophysically and biologically evaluate a recombinant version of contortrostatin (rCN) under production in Dr. Marklands laboratory. In addition to the rCN characterization development of assays to assure rCN batch-to-batch production quality and homogeneity are under way.
It has been observed that binding of CN to integrins produces an effect on a number of cellular processes including cell migration and cell cycle progression. However, the mechanism behind these effects is unknown. Elucidation of the effect of CN on signaling pathways within a cell will enhance our knowledge about cellular processes and may allow for the development of more effective anticancer therapy. In addition to delving into a mechanistic understanding of CN, I am focused on the development of disintegrin based imaging agents which will aid in diagnostics and evaluation of metastatic disease. These studies are possible because CN accumulates at the site of a tumor. By employing PET imaging (Positron Emission Tomography) of a radio-labeled CN in conjunction with 18Ffluorodeoxyglucose (18FDG) utilization, It is planned that an agent will be developed that is capable of identifying and evaluating metastatic tumor foci. Along these same lines I plan to develop a brachytherapeutic to be used in gliomas. CN or other similar proteins can be labeled with a radionuclide such as 131I and administered intrathecally. To act directly on the growing gliomas.
An additional project will involve screening venoms from different snake families and species to determine the protein composition of the venom (a snake venom proteomics project) in collaboration with Dr. Austin Yang of the USC School of Pharmacy who is interested in such a project. This screening will allow me to identify possible candidate proteins for development into therapeutic agents. All venom is different and understanding what is actually present and what can be used would be a great leap in understanding the biochemistry of venom proteins.
Multimeric disintegrin protein polymer fusions that target tumor vasculature. Biomacromolecules. 2014 Jul 14; 15(7):2347-58. View in: PubMed
Snake venom metalloproteinases. Toxicon. 2013 Feb; 62:3-18. View in: PubMed
Development of a chimeric recombinant disintegrin as a cost-effective anti-cancer agent with promising translational potential. Toxicon. 2012 Mar 15; 59(4):472-86. View in: PubMed
Development of a chimeric recombinant disiftegrin as a cost-effective anti%cancer agent with promising trafslational potential. Toxicon. 2012 Mar 15; 59(4!:472-86. View in: PubMed
Contortrostatin, a homodimeric disintegrin isolated from snake venom inhibits herpes simplex virus entry and cell fusion. Antivir Ther. 2012; 17(7):1319-26. View in: PubMed
The disintegrin contortrostatin in combination with docetaxel is a potent inhibitor of prostate cancer in vitro and in vivo. Prostate. 2010 Sep 1; 70(12):1359-70. View in: PubMed
Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities. PLoS One. 2010; 5(6):e10929. View in: PubMed
The use of pepsin in receptor internalization assays. Biochem Biophys Res Commun. 2009 Oct 16; 388(2):240-6. View in: PubMed
Structure of acostatin, a dimeric disintegrin from Southern copperhead (Agkistrodon contortrix contortrix), at 1. 7 A resolution. Acta Crystallogr D Biol Crystallogr. 2008 Apr; 64(Pt 4):466-70. View in: PubMed
Anti-angiogenesis and RGD-containing snake venom disintegrins. Curr Pharm Des. 2007; 13(28):2860-71. View in: PubMed
Development of a novel recombinant disintegrin, contortrostatin, as an effective anti-tumor and anti-angiogenic agent. Pathophysiol Haemost Thromb. 2005; 34(4-5):177-83. View in: PubMed
Contortrostatin, a snake venom disintegrin with anti-angiogenic and anti-tumor activity. Pathophysiol Haemost Thromb. 2005; 34(4-5):169-76. View in: PubMed
Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression. Mol Cancer Ther. 2004 Apr; 3(4):499-511. View in: PubMed
Purification, crystallization and preliminary X-ray analysis of the disintegrin contortrostatin from Agkistrodon contortrix contortrix snake venom. Acta Crystallogr D Biol Crystallogr. 2002 Dec; 58(Pt 12):2122-4. View in: PubMed
Molecular cloning and functional expression of contortrostatin, a homodimeric disintegrin from southern copperhead snake venom. Arch Biochem Biophys. 2000 Mar 15; 375(2):278-88. View in: PubMed
Contortrostatin, a homodimeric disintegrin, binds to integrin alphavbeta5. Biochem Biophys Res Commun. 2000 Jan 7; 267(1):350-5. View in: PubMed