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Matrix metalloproteinase inhibitors for cancer therapy:the current situation and future prospects
1Vanderbilt University Medical Center, Department of Cancer Biology, 736 PRB 23rd and Pierce Avenues, Nashville, TN 37232-6840, USA. Barbara.Fingleton@vanderbilt.edu
Abstract:
Inhibition of matrix metalloproteinases (MMPs), a family of proteolytic enzymes linked to many aspects of cancer progression, has been explored as a therapeutic goal for almost two decades. Thus far, all tested MMP inhibitors (MMPIs) have failed to reach primary end points in Phase III clinical trials, although secondary analyses suggest benefits in particular patient groups. The clinical development of these agents has been hampered by problems related to determination of effective dosages and side effects that necessitate dose lowering or drug holidays. Imaging technologies offer hope as a means to measure enzyme activity and hence effective enzyme inhibition in vivo. Meanwhile, recent results from genetic studies of both mice and man have given some clues to possible causes of musculoskeletal side effects. Future progress in the therapeutic use of MMPIs is dependent on the ability to selectively target cancer-associated MMPs at the correct stage in tumour progression and the development of surrogate markers of in vivo efficacy.
Insights
Matrix metalloproteinase inhibitors (MMPIs) show promise for cancer therapy but face challenges in dosage and side effects. Future success requires targeted MMPIs and reliable efficacy markers.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in cancer progression.
- Therapeutic inhibition of MMPs has been explored for nearly two decades.
- Despite extensive research, MMP inhibitors (MMPIs) have not met primary endpoints in Phase III trials.
Purpose of the Study:
- To review the challenges and future directions in the therapeutic use of MMP inhibitors for cancer.
- To highlight the potential of imaging technologies for measuring in vivo enzyme inhibition.
- To discuss genetic insights into musculoskeletal side effects associated with MMPIs.
Main Methods:
- Review of clinical trial data for MMP inhibitors.
- Analysis of genetic studies in mice and humans.
- Exploration of imaging technologies for assessing MMP activity.
Main Results:
- All tested MMPIs have failed to reach primary endpoints in Phase III clinical trials.
- Secondary analyses suggest potential benefits in specific patient subgroups.
- Genetic studies offer clues to the mechanisms behind musculoskeletal side effects.
Conclusions:
- Clinical development of MMPIs is hindered by dosage determination and side effect issues.
- Targeting cancer-associated MMPs selectively and developing surrogate markers for in vivo efficacy are crucial for future progress.
- Imaging technologies may aid in measuring enzyme activity and guiding treatment decisions.