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Dual targeting of the insulin-like growth factor and collateral pathways in cancer: combating drug resistance
Joseph A Ludwig1, Salah-Eddine Lamhamedi-Cherradi, Ho-Young Lee
1Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. jaludwig@mdanderson.org.
Abstract:
The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.
Insights
Targeting the insulin-like growth factor 1 receptor (IGF-1R) alone has shown limited success against cancer. Dual targeting of IGF-1R and other signaling pathways may overcome acquired drug resistance in carcinomas and sarcomas.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The insulin-like growth factor pathway is crucial for cancer hallmarks, including growth and resistance to therapy.
- Clinical trials targeting insulin-like growth factor 1 receptor (IGF-1R) and its mediators have yielded underwhelming and unsustained anticancer effects.
- Rapid acquisition of resistance to IGF-1R targeted agents is observed, even in patients with initial clinical responses.
Purpose of the Study:
- To present the rationale for dual targeting of IGF-1R and other signaling molecules.
- To explore a strategy for combating acquired drug resistance in carcinomas and sarcomas.
Main Methods:
- Review of existing clinical trial data on IGF-1R targeted therapies.
- Analysis of convergent intracellular signaling cascades downstream of IGF-1R.
- Hypothesizing dual-targeting strategies to overcome resistance mechanisms.
Main Results:
- Monoclonal antibodies targeting IGF-1R have shown dramatic responses in a small subset of patients.
- Overall anticancer effects of IGF-1R targeted therapies have been underwhelming and unsustained.
- Resistance to IGF-1R targeted agents develops rapidly, suggesting the need for combination therapies.
Conclusions:
- Effective targeting of IGF-1R likely requires simultaneous blockade of redundant signaling pathways.
- Dual targeting strategies hold promise for overcoming acquired drug resistance in carcinomas and sarcomas.
- Further research into combination therapies is warranted to improve cancer treatment outcomes.
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