Metalloproteinases Flashcards
(20 cards)
What are the key aims in studying metalloproteinases (MMPs) in cancer biology?
Understand the controversial roles of MMPs in cancer biology.
Demonstrate evidence that some MMPs are targets for therapeutic intervention.
Discuss why cancer trials using small synthetic MMP inhibitors were unsuccessful.
What are the main learning objectives (LOs) in studying MMPs in cancer?
Evaluate that MMPs have both pro- and anti-cancer activities.
Demonstrate knowledge of MMP-regulated signaling pathways in cancers.
Analyze treatment options centered on MMPs and interlinked signaling pathways.
What are the steps involved in the metastatic cascade?
- Clonal expansion, growth, diversification, angiogenesis
- Metastatic subclone formation
- Adhesion to and invasion of the basement membrane
- Passage through extracellular matrix (ECM)
- Intravasation
- Interaction with host lymphoid cells
- Tumor cell embolus formation
- Adhesion to basement membrane
- Extravasation
- Metastatic deposit formation
- Angiogenesis
- Growth
What are the two main types of extracellular matrix (ECM)?
Basement membrane - separates epithelium from surrounding stroma.
Interstitial connective tissue matrix - surrounds cells and provides structural support.
What fibrous components are found in the ECM?
Collagen
Elastin
Fibronectin
Laminin
What non-fibrous components are found in the ECM?
Proteoglycans
Polysaccharides
What were the first-generation MMP inhibitors used in early cancer trials?
Batimastat, BB94, Ilomastat, GM6001
What were the second-generation MMP inhibitors used in cancer trials?
Marimastat, BB25516, Prinomastat, BAY12-9566
What are some early failures in MMP inhibitor therapies for cancer?
Premature entry into clinical trials.
Lack of MMP subtype specificity.
Faulty clinical trial design (late-stage disease patients).
Inadequate clinical endpoints (tumor size reduction, markers in serum).
Dose-limiting toxicities.
MMPIs not reaching the tumor microenvironment.
What is the role of MMPs in cancer progression?
Promote tumor growth by regulating proliferation and apoptosis.
Create a tumor-promoting micro-environment: angiogenesis, vasculogenic mimicry, stromal cell activation.
Promote invasion and metastasis: ECM degradation, epithelial-mesenchymal transition, cell adhesion, migration.
What is an antitarget in drug development?
A molecule or protein with essential or protective roles in normal cell function. Inhibition results in unwanted side effects or initiation of disease.
What is a target in drug development?
A molecule or protein contributing to disease. Inhibition of a validated target reverses disease progression or at least slows it.
What are ADAMs in cancer biology?
A disintegrin and metalloprotease family of transmembrane glycoproteins.
Implicated in various functions like cell migration, axon growth, muscle development, immunity, and cell signaling.
How do ADAMs contribute to ECM remodeling in cancer?
ADAM12, ADAM13, ADAM15 contribute to ECM remodeling by cleaving proteins like fibronectin, collagen, and gelatin.
In cancer, this facilitates invasion, migration, and tumor progression.
What is the impact of ADAM15 in cancer?
Overexpressed in breast, prostate, and pancreatic cancers.
Enhances cell-cell interactions and regulates permeability in endothelial cells.
Associated with pathological neurovascularization.
What is the role of ADAM10/17 inhibition in cancer and inflammation?
Beneficial effects: Reduced tumor cell migration, decreased tumor proliferation, increased immune surveillance, reduced vascular permeability.
Side effects: Increased adhesiveness in inflammation, decreased neuroprotection in the brain.
What are protease-activated prodrugs (PAPs) and their characteristics?
PAPs are designed to be activated by proteases in the tumor microenvironment.
Ideal characteristics: Well-characterized enzyme cleavage preferences, selective activity in tumors, minimal systemic toxicity, high prodrug affinity for the enzyme.
How does MT1-MMP contribute to tumor invasion and metastasis?
MT1-MMP mediates migration, invasion, and metastasis by degrading ECM components and promoting focal adhesion and stress fiber formation.
What are the benefits of combining AXL inhibitors with MAPK inhibitors in cancer therapy?
Reduces tumor growth and metastasis.
AXL inhibitors block evasive signaling, enhancing the efficacy of MAPK inhibitors and reducing drug resistance.
What is the role of TIMPs (tissue inhibitors of metalloproteinases) in cancer therapy?
TIMPs can block the activity of ADAM10, preventing the shedding of receptor tyrosine kinases (e.g., AXL), thus reducing drug resistance and promoting tumor killing.
