E-cadherin as a Biomarker of Response to Anti-IGF1R Inhibitors

University of Pittsburgh researchers have identified E-cadherin as a potential biomarker for predicting the response to anti-IGF1R inhibitors in cancer treatment. Insulin-like growth factor I (IGF1) and its receptor (IGF1R) play crucial roles in cancer progression, making IGF1R a significant therapeutic target. However, only a subset of patients responds to IGF1R inhibitors. The loss of E-cadherin, a key component of adherens junctions, hyperactivates the IGF1R pathway, enhancing sensitivity to IGF1R-targeted therapy in breast cancer cells. This discovery could lead to more effective and personalized cancer treatments.

Figure A: Loss or inhibition of E-cadherin (CDH1) expression enhances IGF1R signaling. Under stimulation with increasing doses of IGF1 (0-100nM) for 10 minutes, the siCDH1 group shows higher levels of IGF1R and Akt signaling compared to the control group. Figure B: Knockdown of E-cadherin increases sensitivity to IGF1R inhibitor (OS I-906) in breast cancer cells. 

Description

Disclosed herein are methods of treating a subject with an estrogen receptor-positive (ER+) breast cancer comprising obtaining a sample of the breast cancer from the subject; determining a level of E-cadherin in the sample is reduced compared to a control; and administering a therapeutically effective amount of an IGF1R pathway inhibitor and an endocrine therapeutic. Also disclosed herein are methods to treat a cancer in a subject comprising administering a therapeutically effective amount of an IGF1R pathway inhibitor and an E-cadherin inhibitor. Also disclosed are methods to predict the likelihood a subject with a breast cancer will respond therapeutically to a treatment comprising administering an IGF1R pathway inhibitor, the method comprising obtaining a sample of the cancer from the subject; and determining a level of E-cadherin in the sample.

Applications

• Biomarker for predicting response to anti-IGF1R therapy
• Personalized cancer treatment
• Enhancing the efficacy of existing cancer therapies

Advantages

This invention provides a novel biomarker (E-cadherin) for predicting the response to anti-IGF1R therapy, which currently lacks reliable biomarkers. The identification of E-cadherin levels as a predictor of therapy response can lead to more personalized and effective cancer treatments. Additionally, the combination of IGF1R inhibitors with standard anti-ER therapies shows synergistic effects, potentially improving treatment outcomes for patients with E-cadherin deficient breast cancers.

Invention Readiness

The invention has been validated through in vitro studies, demonstrating the role of E-cadherin in modulating IGF1R signaling and its potential as a biomarker for therapy response. Further research and clinical trials are needed to confirm these findings and develop diagnostic tools for clinical use.

IP Status

https://patents.google.com/patent/US11548939B2

Related Publication(s)

Nagle, A. M., Levine, K. M., Tasdemir, N., Scott, J. A., Burlbaugh, K., Kehm, J., Katz, T. A., Boone, D. N., Jacobsen, B. M., Atkinson, J. M., Oesterreich, S., & Lee, A. V. (2018). Loss of E-cadherin Enhances IGF1–IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors. Clinical Cancer Research, 24(20), 5165–5177. https://doi.org/10.1158/1078-0432.ccr-18-0279