WNTS and WNT receptors as therapeutic tools and targets in human disease processes.

Cancer: When Growth Goes Rogue

Wnt dysregulation is a hallmark of cancers, especially colorectal cancer (CRC). Mutations in APC or β-catenin genes cause uncontrolled cell division. For example, 80% of CRC cases involve APC mutations . Prostate cancer, however, bypasses mutations, relying on crosstalk with androgen receptors .

Table 2: Wnt in Cancer

Cancer Type Key Wnt Component Therapeutic Approach
Colorectal APC mutations Porcupine inhibitors (e.g., LGK974)
Prostate β-catenin-AR interaction Anti-androgens + Wnt blockers
Liver (HCC) OIP5-AS1 lncRNA miRNA-300 mimics

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Cardiovascular Diseases: A Balancing Act

In atherosclerosis, Wnt5a disrupts cholesterol metabolism, while β-catenin activation worsens arterial stiffening . Conversely, boosting Wnt/β-catenin post-heart attack may aid repair by reducing inflammation .

Neurodegeneration: Lost Connections

Alzheimer’s patients show reduced Wnt activity, leading to amyloid plaque buildup. Enhancing Wnt/β-catenin could protect synapses . In Parkinson’s, Wnt agonists are being tested to rescue dopamine neurons .

Fibrosis: The Scarring Scourge

Overactive Wnt/β-catenin drives kidney and lung fibrosis. Inhibitors like ICG-001 (targeting β-catenin/CBP) reduce collagen deposition in preclinical models .

Table 3: Wnt in Non-Cancer Diseases

Disease Mechanism Therapeutic Candidate
Alzheimer’s Downregulated Wnt Lithium (GSK-3β inhibitor)
Pulmonary Fibrosis LRP6 activation DKK1 (LRP6 blocker)
Osteoporosis Sclerostin overexpression Romosozumab (anti-sclerostin)

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Therapeutic Strategies: Taming the Wnt Beast

Small Molecules:

  • Tankyrase inhibitors block β-catenin stabilization.
  • Porcupine inhibitors prevent Wnt secretion .

Antibodies:

  • Vantictumab targets Frizzled receptors in breast cancer .

Gene Therapy:

  • Delivering DKK1 silences Wnt in fibrosis .

Table 4: Wnt-Targeting Drugs in Clinical Trials

Drug Name Target Phase Condition
LGK974 Porcupine II Colorectal cancer
CBP/β-catenin inhibitor (ICG-001) β-catenin/CBP Preclinical Fibrosis, endometriosis
Romosozumab Sclerostin Approved Osteoporosis

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