There is a critical need for more effective therapies against metastatic colorectal cancer (CRC).
Guanylyl cyclase C (GCC) is a protein whose expression is normally restricted to the intestine
but is universally expressed by both primary and metastatic CRC cells, and therefore serves as a
tumor-specific antigen outside of the gastrointestinal tract. The development of a peptide:drug
conjugate (PDC) targeted against GCC will provide an important therapeutic for delivering a
cytotoxic agent directly to metastatic CRC cells.
A knottin peptide will be used as the targeting portion of the PDC because knottins naturally
have drug-like properties and are highly resistant to enzymatic degradation. In order to identify
a GCC-binding knottin I will work in Roland Strong’s lab to screen large, highly diverse knottin
libraries using affinity chromatography. The lead GCC-binding knottin candidates will then be
progressed to in vivo pharmacokinetic and biodistribution studies to identify peptides that
target preferentially to tumors with minimal binding to normal tissues. I will also test the
efficacy of various different conjugation strategies for extension of in vivo half-life. The in vivo
studies will be performed under the guidance of Jim Olson.
The development of a PDC that targets specifically to GCC-expressing cancer cells will require
significant expertise in protein production, purification, and biophysical characterization, as
well as in vivo pharmacology. Therefore, this represents an ideal opportunity to combine the
strengths of the Olson and Strong labs in order to generate a drug that has the potential to
provide significant survival benefit to cancer patients.