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Vascular changes in tumors resistant to a vascular disrupting nanoparticle treatment
Shweta Sharma1, Aman P Mann1, Tarmo Mölder2
1Sanford-Burnham-Prebys Medical Discovery Institute, Cancer Research Center, La Jolla, CA, USA.
Abstract:
Anti-angiogenic and vascular disrupting therapies rely on the dependence of tumors on new blood vessels to sustain tumor growth. We previously reported a potent vascular disrupting agent, a theranostic nanosystem consisting of a tumor vasculature-homing peptide (CGKRK) fused to a pro-apoptotic peptide [D(KLAKLAK)2] coated on iron oxide nanoparticles. This nanosystem showed promising therapeutic efficacy in glioblastoma (GBM) and breast cancer models. However, complete control of the tumors was not achieved, and some tumors became non-responsive to the treatment. Here we examined the non-responder phenomenon in an aggressive MCF10-CA1a breast tumor model. In the treatment-resistant tumors we noted the emergence of CD31-negative patent neovessels and a concomitant loss of tumor homing of the nanosystem. In vivo phage library screening in mice bearing non-responder tumors showed that compared to untreated and treatment-sensitive tumors, treatment sensitive tumors yield a distinct landscape of vascular homing peptides characterized by over-representation of peptides that target αv integrins. Our approach may be generally applicable to the development of targeted therapies for tumors that have failed treatment.
Insights
Tumor therapies targeting blood vessels can fail, leading to treatment resistance. Researchers identified new vascular targets in non-responsive tumors, offering hope for improved cancer treatments.
Area of Science:
- Oncology
- Nanomedicine
- Vascular Biology
Background:
- Anti-angiogenic and vascular disrupting therapies are crucial for cancer treatment, targeting tumor neovasculature.
- Previous theranostic nanosystems showed efficacy but faced challenges with treatment resistance in glioblastoma and breast cancer models.
- Tumor resistance can involve the emergence of new blood vessels that evade current therapies.
Purpose of the Study:
- To investigate the mechanisms of treatment resistance in aggressive breast tumors.
- To identify novel vascular targets in non-responder tumors for improved therapeutic strategies.
- To understand the changes in tumor vasculature associated with treatment failure.
Main Methods:
- Utilized an aggressive MCF10-CA1a breast tumor model to study treatment resistance.
- Analyzed tumor vasculature in non-responder tumors, focusing on CD31 expression and neovessel formation.
- Employed in vivo phage display screening to identify vascular homing peptides in non-responder tumors.
Main Results:
- Treatment-resistant tumors exhibited CD31-negative neovessels, indicating altered vascularization.
- The theranostic nanosystem lost its tumor homing capability in non-responder models.
- Phage screening revealed an over-representation of peptides targeting αv integrins in treatment-sensitive tumors compared to non-responders.
Conclusions:
- Tumor resistance to vascular-disrupting agents is associated with changes in neovasculature and loss of nanosystem homing.
- Identifying specific vascular targets, such as αv integrins, is crucial for overcoming treatment resistance.
- This research provides a framework for developing targeted therapies for refractory tumors.