Targeted Therapy

Introduction to Targeted Therapy - Precision Power

• Drugs acting on specific molecular targets (proteins, genes) vital for cancer cell growth, progression, and survival.
• Mechanism: "Lock and key" model; drugs precisely interact with targets often unique to or overexpressed in cancer cells.
• Patient selection: Requires predictive biomarker identification (e.g., EGFR, HER2, BRAF mutations) via genetic/protein tests.
• Contrasts conventional chemotherapy, which non-selectively targets all rapidly dividing cells.
• Goal: Enhanced efficacy, reduced systemic toxicity ("Precision Medicine"), improving therapeutic index by sparing normal cells.

⭐ Many targeted therapies are monoclonal antibodies (suffix "-mab") targeting cell surface receptors or small molecule kinase inhibitors (suffix "-ib") affecting intracellular signals.

Tyrosine Kinase Inhibitors - Signal Jammers

• Small molecule inhibitors targeting intracellular kinase domains, blocking ATP binding sites.
• Interfere with signaling pathways essential for tumor cell proliferation and survival.
• Generally orally administered. Many end in "-tinib". 📌 (Imatinib)
• Common class side effects: GI toxicity, rash, fatigue.
• Resistance via gatekeeper mutations is a challenge.

Monoclonal Antibodies - Guided Missiles

• Large proteins targeting specific cell surface antigens (e.g., receptors) or circulating proteins.
• Nomenclature indicates origin & structure:
  • -omab: Murine (100% mouse)
  • -ximab: Chimeric (e.g., Rituximab; ~30% mouse)
  • -zumab: Humanized (e.g., Trastuzumab; ~5-10% mouse)
  • -umab: Human (e.g., Nivolumab; 100% human)
• Key Examples & Targets:

  mAb	Target	Key Indications
  Trastuzumab	HER2	Breast Ca, Gastric Ca
  Rituximab	CD20	NHL, CLL, RA
  Bevacizumab	VEGF	CRC, NSCLC, RCC, Glioblastoma
  Cetuximab	EGFR	CRC, H&N Ca
  Pembrolizumab	PD-1	Melanoma, NSCLC, RCC, Hodgkin
  Ipilimumab	CTLA-4	Melanoma

• Adverse Effects (AEs):
  • General: Infusion reactions, hypersensitivity (less with human/humanized).
  • Specific:
    • Trastuzumab: Cardiotoxicity (monitor LVEF).
    • Bevacizumab: Hypertension, bleeding, GI perforation, impaired wound healing.
    • Cetuximab/Panitumumab: Acneiform rash.
    • Checkpoint Inhibitors (CPIs): Immune-related AEs (irAEs) - colitis, hepatitis, pneumonitis, endocrinopathies.

⭐ Trastuzumab is only effective in HER2-positive cancers; HER2 testing is mandatory before therapy initiation.

Other Targets & Resistance - New Paths, Old Foes

• Key Alternative Targets & Agents:
  • PARP Inhibitors (Olaparib, Niraparib): BRCA1/2 mutated cancers (ovarian, breast, prostate). MOA: Synthetic lethality.
  • Proteasome Inhibitors (Bortezomib, Carfilzomib): Multiple Myeloma. MOA: Inhibit proteasome, ↑apoptosis.
  • mTOR Inhibitors (Everolimus, Sirolimus): Renal Cell Ca, HR+ Breast Ca. MOA: Block mTOR, ↓cell growth.
  • HDAC Inhibitors (Vorinostat): CTCL. MOA: Epigenetic modulation.
  • Hedgehog Pathway Inhibitors (Vismodegib): Basal cell carcinoma.
• Mechanisms of Acquired Resistance:
  • Target gene mutations (e.g., EGFR T790M).
  • Bypass pathway activation (e.g., MET amplification).
  • Drug efflux (P-glycoprotein).
  • Phenotypic transformation.
• Combating Resistance:
  • Next-gen inhibitors (Osimertinib for T790M).
  • Combination therapies.
  • Liquid biopsies for early detection.

⭐ Osimertinib, a 3rd-gen EGFR-TKI, is highly effective against the T790M "gatekeeper" resistance mutation in NSCLC.

High‑Yield Points - ⚡ Biggest Takeaways

• Imatinib: A TKI for CML (BCR-ABL) and GIST (c-KIT).
• Monoclonal antibodies: Trastuzumab (HER2+ breast cancer), Rituximab (CD20+ lymphomas).
• EGFR inhibitors: Gefitinib (NSCLC with EGFR mutation), Cetuximab (KRAS wild-type colorectal cancer).
• Angiogenesis inhibitors: Bevacizumab (anti-VEGF mAb), Sunitinib (multi-TKI).
• Immune Checkpoint Inhibitors: Pembrolizumab (anti-PD-1), Ipilimumab (anti-CTLA-4) boost T-cell activity.
• BRAF inhibitors: Vemurafenib for melanoma with BRAF V600E mutation.
• PARP inhibitors: Olaparib for BRCA-mutated ovarian/prostate cancers.