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Maximizing Protein Production Efficiency in Cancer Therapeutics Katherine Thomas
Pancreatic Cancer
445,220
PANCAN Pancreatic Cancer Fact Sheet 2013
TRAIL • TNF-related apoptosis-inducing ligand • Induces apoptosis by binding to an
extrinsic death receptor • In order to be active, TRAIL must form a
homotrimer • TRAIL therapies are more effective in
cancer cells than human cells A Genetically Encoded Multifunctional TRAIL Trimer Facilitates Cell-Specific Targeting and Tumor Cell Killing;
2010
Shepard B et al. Anti-Infective Agents in Medicinal Chemistry 2010;8:87-101
TRAIL • Non-covalently bonded
TRAIL is sensitive to degredation
• Must form a homotrimer in order to become active
TR3 • Covalently-linked trimer
developed through genetic fusion
• Can be further genetically modified
TR3 is a powerful inducer of apoptosis.
Spitzer D et al. Mol Cancer Ther 2010;9:2142-2151
Target Proteins
• Surface proteins • Over-expressed in pancreatic and ovarian
cancer cells
Mesothelin MUC16
http://www.epitomics.com/images/IVD/AC-0130_ihc_17343_large.jpg http://www.mybiosource.com/images/tds/protocol_images/MBS245325_IH.jpg
FhMeso1-TR3
Targeting
Targeting
Meso-TR3 TR3
Garg et al
Need for Mass Production
Signal Peptides
• Leader sequences • Direct protein to
secretory pathway • Destination: Golgi
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1999/illpres/protein.html
Kozak Sequence • Initiation of translation • Contains start codon
http://www.biomedcentral.com/content/supplementary/1471-2164-13-21-s9.png
Results
pTR3
cd59 signal peptide cd59 signal peptide
Kozak sequence
pTR3-mod59
cd59 signal peptide Kozak sequence
pTR3-mod59
Honeybee melittin signal peptide
Kozak sequence
pTR3-Mel
LEX signal peptide Kozak sequence
pTR3-LEX
Future Research • Mass Drug Production
– In-vivo – Clinical Trials
• Genetic Modification – Target Proteins – Cancer Stem Cells – Additional Drugs
Acknowledgements
• Dr. Hawkins • Dr. Spitzer • Jesse Gibbs • Christy Hornick
Thank You
