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Updated: May 20, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Global quantitative phosphoproteome analysis of human tumor xenografts treated with a CD44 antagonist
Stefan Weigand1, Frank Herting, Daniela Maisel
1Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany. Stefan.weigand@roche.com
Abstract:
The cell surface glycoprotein CD44 plays an important role in the development and progression of various tumor types. RG7356 is a humanized antibody targeting the constant region of CD44 that shows antitumor efficacy in mice implanted with CD44-expressing tumors such as MDA-MB-231 breast cancer cells. CD44 receptor seems to function as the main receptor for hyaluronic acid and osteopontin, serving as coreceptor for growth factor pathways like cMet, EGFR, HER-2, and VEGFR and by cytoskeletal modulation via ERM and Rho kinase signaling. To assess the direct impact of RG7356 binding to the CD44 receptor, a global mass spectrometry-based phosphoproteomics approach was applied to freshly isolated MDA-MB-231 tumor xenografts. Results from a global phosphoproteomics screen were further corroborated by Western blot and ELISA analyses of tumor lysates from CD44-expressing tumors. Short-term treatment of tumor-bearing mice with RG7356 resulted in modifications of the MAPK pathway in the responsive model, although no effects on downstream phosphorylation were observed in a nonresponsive xenograft model. Taken together, our approach augments the value of other high throughput techniques to identify biomarkers for clinical development of targeted agents.
Insights
RG7356, an antibody targeting CD44, demonstrated antitumor effects in mice. Phosphoproteomics revealed MAPK pathway modulation in responsive tumors, highlighting potential biomarkers for targeted cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- CD44, a cell surface glycoprotein, is crucial in tumor development and progression.
- RG7356 is a humanized antibody targeting the constant region of CD44, showing antitumor efficacy.
- CD44 interacts with hyaluronic acid, osteopontin, and growth factor pathways, influencing cell signaling.
Purpose of the Study:
- To investigate the direct impact of RG7356 binding on the CD44 receptor.
- To identify molecular changes associated with RG7356 treatment using phosphoproteomics.
- To explore potential biomarkers for predicting response to CD44-targeted therapies.
Main Methods:
- Global mass spectrometry-based phosphoproteomics on MDA-MB-231 tumor xenografts.
- Western blot and ELISA analyses of tumor lysates.
- Treatment of tumor-bearing mice with RG7356.
Main Results:
- RG7356 treatment modulated the MAPK pathway in responsive tumor models.
- No significant downstream phosphorylation effects were observed in nonresponsive models.
- Phosphoproteomic data were corroborated by Western blot and ELISA.
Conclusions:
- The study elucidates the molecular effects of RG7356 on CD44-expressing tumors.
- MAPK pathway alterations suggest a mechanism of action for RG7356.
- The findings support the use of phosphoproteomics for identifying biomarkers in targeted cancer therapy development.
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