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New approaches to selectively target cancer-associated matrix metalloproteinase activity
Marilena Tauro1, Jeremy McGuire, Conor C Lynch
1Departments of Tumor Biology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., SRB-3, Tampa, FL, USA.
Abstract:
Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.
Insights
Matrix metalloproteinases (MMPs) play key roles in cancer progression. New, highly selective MMP inhibitors (MMPIs) offer improved cancer treatment strategies by targeting tumor microenvironment activity.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Matrix metalloproteinases (MMPs) are crucial in the tumor microenvironment, processing extracellular matrix (ECM) and regulating growth factors.
- MMPs' role in cancer progression has been recognized for decades, making them attractive therapeutic targets.
- Early matrix metalloproteinase inhibitor (MMPI) trials in the 1990s failed due to a lack of selectivity among MMPs and related enzymes.
Purpose of the Study:
- To review the advancements in targeting MMPs and their potential for novel cancer therapies.
- To explore how improved selectivity in MMPIs can overcome limitations of earlier trials.
- To discuss the potential of using MMP activity for targeted drug delivery in cancer.
Main Methods:
- Review of historical clinical trial data for MMP inhibitors.
- Analysis of recent innovations in chemical design, antibody-based strategies, and nanotechnologies for MMP targeting.
- Examination of the role of MMPs in the tumor microenvironment and their implications for drug delivery.
Main Results:
- Early MMPIs lacked the specificity required for effective cancer treatment.
- Recent technological advancements have enabled the development of highly selective MMPIs.
- Targeting specific MMPs offers potential for improved cancer patient survival and targeted drug delivery.
Conclusions:
- Selective targeting of MMPs represents a promising strategy for future cancer therapeutics.
- Leveraging MMP activity in the tumor microenvironment can enhance drug delivery and efficacy.
- Advanced MMPIs hold the potential to significantly improve outcomes for cancer patients.
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