A common objective for all cell types is to identify the cellular receptor(s) that are bound by the cell-targeting peptide. The cell specificity demonstrated by these peptides indicates that they are recognizing distinct cell surface receptors that may be of clinical value. We envision using the cell-targeting peptide to map out the landscape of the cell surface. While it is certainly true that we can utilize the cell-targeting peptides for delivery without knowing their cellular targets, receptor ID is a critical component of our research for the following reasons:
- It will yield important biological information about the status of the cell surface and how the cell surface topography changes during a disease process.
- Identifying the cellular receptor is critical in terms of developing new diagnostic and targeting reagents. Antibodies can be generated to unique receptors and used as diagnostic and perhaps clinical reagents. Furthermore, it will lead the way into developing non-peptidic targeting molecules. Non-peptidic molecules typically have longer in vivo half-lives and better bioavailability than peptides.
- This knowledge will provide insight into why the targeting peptides display their remarkable cell specificity and may shed light on why we isolate peptides that recognize unique cellular features.
However, to identify the cellular target of a ligand selected from a library screen has been a challenge in chemical biology. We are currently developing new chemical and molecular biology based technologies for the systematic isolation of the cellular target of the cell-homing peptides. Once identified, we will:
- Determine the biological role the cell surface plays in the disease state.
- In the case of cancer, determine the expression patterns of the receptor in human samples and determine if the presence of the receptor correlates to drug sensitivity, patient prognosis, stage or pathological classification, and patient relapse.
- Probe how the underlying gene expression patterns affect the cell surface topography.
- Screen small molecule libraries for receptor binding as a transition to nonpeptidic cell targeting reagents.
We have identified the receptor for one of the lung adenocarcinoma targeting peptides as the restrictively expressed integrin and have shown that it is a poor prognostic factor for patients with NSCLC. We are currently probing its biological role in NSCLC.
More information can be found in the following publication:
Elayadi, Anissa N.; Samli, Kausar N.; Prudkin, Ludmila; Liu, Ying-horng; Bian, Aihua; Xie, Xian-Jin; Wistuba, Ignacio I.; Roth, Jack A.; McGuire, Michael J.; Brown, Kathlynn C. (2007) "A peptide selected by biopanning identifies the integrin avß6 as a prognostic biomarker for non-small cell lung cancer" Cancer Res. 2007; 67:5889-5895.