Tumor selective targeting of a conserved scaffold domain
Abstract/Contents
- Abstract
- The extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) signaling cascade is pathologically activated in thirty percent of all human cancers. Therapeutics targeting this cascade have proven largely ineffective due to non-specific targeting, mutations in upstream or downstream kinases resulting in drug resistance, and gross tissue catastrophe. To investigate the possibility of targeting this cascade without generating these effects, we used siRNAs directed against ERK/MAPK scaffolds in a human tissue model system of epidermal neoplasia. IQGAP1 physically interacts with canonical ERK/MAPK pathway members in order to precisely modulate their signal output and in its absence, signaling through this pathway is severely diminished. Reducing IQGAP1 expression had no effect on normal tissue homeostasis or in vivo wound healing, but did effectively block invasive neoplasia and diminish tumor formation in an in vivo mouse model of cancer. This effect extended to a wide variety of tumor types with mutations in the ERK/MAPK pathway suggesting that selective therapeutics targeting IQGAP1 would be effective in a large percentage of human cancers. To identify the tumor-selective domain of IQGAP1, we ectopically expressed the ERK-binding WW domain. The IQGAP1 WW domain blocked neoplastic invasion, diminished ERK/MAPK signal transduction, blocked RAS-driven tumor formation in vivo, and caused regression of established RAS-driven tumors. Furthermore, this IQGAP1 WW domain can be synthesized as a purified 30-amino acid peptide, which retained its therapeutic effects when delivered ectopically. Overall, our results identify the IQGAP1 WW domain as a novel candidate for clinical drug development.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Jameson, Katherine LaRoque |
|---|---|
| Associated with | Stanford University, Cancer Biology Program |
| Primary advisor | Khavari, Paul A |
| Thesis advisor | Khavari, Paul A |
| Thesis advisor | Ferrell, James Ellsworth |
| Thesis advisor | Oro, Anthony, 1958- |
| Thesis advisor | Wong, Albert J |
| Advisor | Ferrell, James Ellsworth |
| Advisor | Oro, Anthony, 1958- |
| Advisor | Wong, Albert J |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Katherine LaRoque Jameson. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Ph.D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Katherine LaRoque Jameson
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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