Medical Student Research Fellowship for Summer 2010
Mentor: Kathlynn Brown
Department: Internal Medicine
Room number: ND2.210F (office)/ ND2.136 (lab)
Mail Code: 9185
Phone number: 5-6348
Human subjects IRB approved project number (where applicable): N/A
Animal subjects IRB approved project number (where applicable): 0961-07-03
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)
Brief Description of Project:
The overarching goal of the Brown Laboratory is to discover ligands specific to receptors on the surface of cancer cells that will have a clinical impact in functional diagnosis and tumor-specific drug delivery. Towards this goal, our laboratory has employed biopanning of phage-displayed peptide libraries to isolate novel peptidic cell-binding reagents. We have isolated 11 different peptides that bind specifically to non-small cell lung cancer (NSCLC) cells while avoiding nonmalignant cells. The peptides are functional outside of the context of the phage and have cell binding affinities in the low picomolar to low nanomolar range. As such, these ligands are matching or even surpassing the affinities of antibodies which have served as the gold standard in targeted therapies. Our peptides mediate cellular uptake allowing for chemotherapeutics to be delivered intracellularly where they exert their action. We have coupled our peptides to drugs and drug carriers; these conjugates affect cell-specific death and widen the therapeutic window. Lastly, the peptides can home to a tumor in an animal model.
We have identified the cellular receptor of one of these peptides as the restrictively
expressed integrin ?v?6. We determined the expression of ?v?6 on 311 human lung
cancer samples. The expression of this integrin is widespread in early stage
NSCLC. Log-rank test and Cox regression analyses show that expression of this
integrin is significantly associated with poor patient outcome. Preferential
expression is observed in the tumors compared to surrounding normal lung tissue.
Additionally, ?v?6 has a clear stepwise increase in expression, which corresponded
to histopathologic severity (from normal and reactive bronchial epithelia to
squamous dysplasia and invasive squamous cell carcinoma). Thus, ?v?6 may be
a novel marker for monitoring the progression of centrally located preneoplastic
lesions in smokers. Our data indicate that ?v?6 is a prognostic biomarker for
NSCLC and may serve as a receptor for targeted therapies.
The goals of this summer project are to fully optimize this peptidic delivery reagent for targeted drug delivery. We will explore peptide-drug conjugates and peptide-guided liposomal formulations, focusing on the delivery of three clinically used chemotherapeutics: doxorubicin, paclitaxel, and gemcitabine. Constructs will be optimized for maximal anti-tumor effects while minimizing toxicity. Pharmacokinetic and pharmacodynamic studies will be performed. Additionally, we will explore the role of ?v?6 in NSCLC.
Previous Research Activities or Publications with Medical Students:
I have had 3 MDs as postdoctoral fellows in my laboratory. Their work has been published in the following manuscripts:
1. Li, Shunzi; McGuire, Michael J.; Lin, Mai, Liu, Ying-horng; Oyama, Tsukasa;
Sun, Xiankai; Brown, Kathlynn C. (2009) "Synthesis and Characterization
of a High Affinity ?v?6-Specific Ligand for In Vitro and In Vivo Applications"
accepted to Molecular Cancer Therapeutics.
2. Oyama, Tsukasa; Rombel, Irene T.; Samli, Kausar N.; Zhou Xin; Brown, Kathlynn C. (2006) "Isolation of multiple cell-binding ligands from different phage displayed-peptide libraries" Biosensors & Bioelectronics. 21, 1867-1875.
3. De, Jitakshi; Chang, Ya-Ching; Samli, Kausar N.; Schissler, Jonathan; Newgard, Christopher B.; Johnston, Stephen Albert; Brown, Kathlynn C. (2005) "Isolation of a Mycoplasma-specific binding peptide from an unbiased phage-displayed peptide library" Mol. Biosystems, 1, 149-157.
4. Zhou, Xin; Chang, Ya-Ching; Oyama, Tsukasa; McGuire, Michael J.; Brown, Kathlynn C. (2004) "Cell-Specific Delivery of a Chemotherapeutic to Lung Cancer Cells" J. Am. Chem. Soc. 126, 15656-15657.
5. Oyama, Tsukasa, Sykes, Kathryn F., Samli, Kausar, N., Minna, John D., Johnston, Stephen Albert, Brown, Kathlynn C. (2003) "Isolation of Lung Tumor Specific Peptides from a Random Library: Generation of Diagnostic and Cell-targeting Reagents" Cancer Lett. 202, 219-230.