KU PPB 423 Lesson 7 B- Targeted antineoplastic drugs - Part 1

TARGETED ANTINEOPLASTIC DRUGS

  • Lesson 7B PPB 423 – Neoplastic Diseases & Anticancer Drugs

  • Instructor: Dr. Hilda Nderitu

  • Date: 23rd February 2022

INHIBITORS OF GROWTH FACTORS & RECEPTORS IN CANCER CELLS

  • Presentation Date: 12th February 2021

1. Introduction to Growth Factor Inhibitors

  • Target: Cancer cells

  • Drug Classes and Examples:

    • Epidermal Growth Factor Receptor (EGFR)

      • Function: EGFR inhibitors

      • Type: Small molecule protein tyrosine kinase inhibitors

      • Examples: Erlotinib, Gefitinib, Afatinib, Osimertinib

      • Antibody Inhibitors: Cetuximab, Panitumumab, Necitumumab

    • Human epidermal growth factor receptor 2 (HER2/Neu)

      • Type: HER2/Neu Inhibitors

      • Examples: Trastuzumab, Pertuzumab,

        • Small molecule inhibitors of EGFR & HER2 tyrosine kinases: Lapatinib, Neratinib

    • Platelet-Derived Growth Factor Receptor (PDGFR)

      • Type: PDGFR Inhibitors

      • Examples: Olaratumab

    • Hedgehog Pathway Inhibitors

      • Examples: Vismodegib, Sonidegib

2. Epidermal Growth Factor Receptor (EGFR) Inhibitors

  • Types of EGFR Inhibitors:

    • Small molecule protein tyrosine kinase inhibitors: Erlotinib, Gefitinib, Afatinib, Osimertinib

    • Antibody inhibitors: Cetuximab, Panitumumab, Necitumumab

3. Rationale for use of EGFR Inhibitors

  • Importance of EGFR:

    • Part of the Erb-B family (specifically ErbB1 or HER1).

    • Activated by ligands, essential for epithelial cell growth & differentiation.

    • Overexpression in various solid tumors, including:

      • Colorectal cancer

      • Head & neck cancer

      • Non-small cell lung cancer

      • Pancreatic cancer

4. Mechanism of Action of EGFR Inhibitors

  • EGFR Activation:

    • Ligand binding induces receptor dimerization leading to intracellular signaling activation.

    • Mutations enhance signaling for growth & survival advantage for cancer cells (e.g., T790M mutation).

5. Specific Drugs - Erlotinib

  • Mechanism of Action: Reversible inhibitor of EGFR, competitively inhibits ATP binding.

  • Pharmacokinetics:

    • Absorption: Bioavailability ~ 60%, peak plasma levels after 4 hours.

    • Metabolism: CYP3A4, CYP1A2, CYP1A1.

    • Elimination: Half-life ~36 hours, primarily hepatic clearance.

6. Clinical Indications for Erlotinib

  • Advanced or metastatic non-small cell lung cancer post platinum-based treatment failure.

  • Newly diagnosed non-small cell lung cancer with EGFR mutations.

  • Unresectable or metastatic pancreatic cancer (with gemcitabine).

7. Drug Interactions of Erlotinib

  • Avoid: grapefruit products, PPIs (reduce bioavailability).

  • Interactions with CYP3A4 inducers/inhibitors (e.g., warfarin – caution advised).

8. Adverse Effects of Erlotinib

  • Common: Rash, Diarrhea, Anorexia, Fatigue, Dyspnea, Nail disorders.

  • Serious: Severe rash, interstitial lung disease.

9. Other EGFR Inhibitors

  • Gefitinib:

    • Similar action as Erlotinib, indication for EGFR-mutated non-small cell lung cancer.

    • Adverse effects: Respiratory issues, skin reactions.

  • Afatinib:

    • Irreversible EGFR inhibitor, used for non-small cell lung cancer.

    • Adverse Effects: Diarrhea, skin rash, lung disease.

10. Resistance to EGFR TKIs

  • Resistance often arises from T790M mutation in EGFR, seen in ~60% of cases after prior treatments.

11. HER2/Neu Inhibitors

  • Mechanism and importance of HER2 in breast cancer.

  • Drugs: Trastuzumab, Lapatinib, Neratinib, Pertuzumab.

  • Rationale for use: Overexpression in 20-30% of breast cancers leads to aggressive tumors.

12. Summary of Adverse Effects

  • Trastuzumab: Cardiotoxicity, infusion reactions.

  • Lapatinib: Skin reactions, diarrhea.

  • Clinical monitoring required for cardiac effects.

13. Platelet-Derived Growth Factor Receptor Inhibitors

  • Inhibit PDGFR signaling, involve Olaratumab for treatment of sarcomas.

14. Hedgehog Pathway Inhibitors

  • Role in basal cell carcinoma and examples like Vismodegib and Sonidegib.

15. Tumor Angiogenesis Inhibitors

  • Overview of VEGF and angiogenesis in tumor growth.

    • Key drugs: Bevacizumab, Aflibercept.

    • Mechanism: Inhibit blood vessel formation to starve tumors.

16. Conclusion

  • Targeted therapies are vital in managing specific cancer types by blocking growth factors and their pathways.

  • Ongoing research and monitoring for resistance and adverse effects is crucial for optimizing cancer treatment.