B-38. Chemo VI (Large molecule ST inhibitors. Antimetastatics and anti-vascularization)

Question 1

Large Molecule Signal Transduction Inhibitors

Answer 1

• Large Molecule Signal Transduction Inhibitors:

1. VEGF - Bevacizumab
2. Her2 - Trastuzumab
3. EGFR - Cetuximab, Panitumumab
4. CD20 - Rituximab
5. CD52 - Alemtuzumab
6. Asparaginase

Question 2

Large Molecule signal transduction inhibitor kinetics and side effects

Answer 2

Large Molecule Signal Transduction Inhibitors:

Kinetics: are all given as slow i.v. infusions; (as proteins, they would be degraded by gastric HCl)

Side Effects:

• Infusion reaction - any mAb can cause this (details under rituximab)
• Serum sickness - can occur with “-xi-” (chimeric) mAbs via antigenicity of non-human components

Question 3

• Bevacizumab
  
  • MOA
  • Indications
  • Contraindication
  • Side effects

Answer 3

Bevacizumab

• MOA: IgG mAb against VEGF-A → ↓ angiogenesis → ↓ tumor vascularization
• Indications:
  
  • Metastatic colorectal cc. - combo with 5-FU, irinotecan, oxaliplatin
  • Solid tumors - breast cc., NSCLC
  • (Wet macular degeneration - inhibits subretinal neovascularization)
• Contraindication: recent surgery - must wait ≥ 18 days to allow healing of surgical wounds first
• Side Effects:
  
  • Bleeding- epistaxis common; more rarely hemoptysis, hematemesis, cerebral bleeding, etc.
  • Thromboembolism- increased risk of TIA, stroke, angina, MI
  • Hypertension
  • GI perforation - rare, but may be fatal; (mostly with metastatic colorectal / epithelial ovarian cc.)

Question 4

• Trastuzumab
  
  • MOA
  • Indication
  • Side effects

Answer 4

Trastuzumab

• MOA: IgG mAb against HER2 (EGFR2) → inhibits Tyr kinase activity → ↓ MAPK / PI3K-AKT pathways
• Indication:
  
  • Breast cancer - Her-2/neu+ types
  • Her2+ adenocarcinomas - of ovaries, stomach, lung + salivary glands
• Side effects:
  
  • Fever, allergy, myelosuppression
  • Cardiotoxicity- can cause ↓ LVEF (rarely HF); same as lapatinib (other Her-2 drug)

Question 5

• Cetuximab and panitumumab
  
  • MOA
  • Indication
  • Side effects

Answer 5

Cetuximab and panitumumab

• MOA: IgG mAb against EGFR → inhibits Tyr kinase activity of EGFR
• Indication:
  
  • Metastatic colorectal cc. - combo with irinotecan / oxaliplatin
  • Solid tumors - NSCLC, squamous cell head + neck cancers
• Side effects:
  
  • Skin rash - acneiform eruptions due to effect on epidermal EGFRs
  • Serum sickness less likely than with rituximab

Question 6

• Rituximab
  
  • MOA
  • Indications
  • Side effects

Answer 6

Rituximab

• MOA: chimeric IgG that binds CD20 on B cells → complement + Ab-mediated cytotoxicity
• Indication:
  
  • Hematological malignancies - CD20+ non-Hodgkin lymphoma and CLL
  • Rheumatoid arthritis - usually with MTX in resistant cases
  • Other autoimmune disease - microscopic polyangiitis and Wegener granulomatosis
• Side Effects:
  
  • Infusion reaction - common within 1st hr; HA, fever, rash, dyspnea, pruritus, ↓ BP, swelling
    
    • due to cytokine release upon mAb interaction with its antigen
    • managed with antihistamines, paracetamol or NSAIDs
  • Serum sickness - later, in 7-10 days; fever, rash, arthralgia, proteinuria + swollen nodes (T3HS)
  • Tumor lysis syndrome - treat with allopurinol
  • Immunosuppression- only ↓ Ig levels when used repeatedly; late-onset neutropenia and hepatitis B reactivation may occur
    
    • Associated with ↑ risk of progressive multifocal leukoencephalopathy via JC virus

Question 7

• Alemtuzumab
  
  • MOA
  • Indications
  • Side effects

Answer 7

Alemtuzumab

• MOA: IgG mAb against CD52 (on B/T/NK cells + monocytes) → Ab / complement-mediated cytotoxicity
• Indications:
  
  • Hematological malignancy - CLL, cutaneous T-cell lymphoma
  • Transplants- BM, kidney, islet cell transplants for rejection prevention
• Side Effects: myelosuppression, ↑ infections and triggering of autoimmunity (via Treg suppression)

Question 8

Asparaginase

• MOA
• Indication
• Side Effects

Answer 8

Asparaginase

• MOA: degrades asparagine; ALL cells need exogenous asparagine → ↓ protein synth
• Indication: ALL
• Side Effects: nausea, vomit, HS rxn, skin rash

Question 9

Anti-metastatic drugs

Answer 9

Anti-metastatic Drugs:

1. Bisphosphonates
2. Bevacizumab + cetuximab
3. Lapatinib
4. Medroxyprogesterone acetate or megestrol
5. Fulvestrant
6. Vemurafenib

Question 10

Anti-metastatic drug indication:

• Bisphosphonates
• Bevacizumab + cetuximab
• Lapatinib
• Medroxyprogesterone acetate or megestrol
• Fulvestrant
• Vemurafenib

Answer 10

Anti-metastatic Drugs:

Bisphosphonates - against bone metastases from breast, prostate cc.

Bevacizumab + cetuximab for metastases of colorectal cc.

Lapatinib for brain metastases from Her2+ breast cc. (enters BBB well)

Medroxyprogesterone acetate or megestrol for metastases of breast cc.

Fulvestrant (ER atg) for ER+ breast cc. metastases

Vemurafenib for metastatic melanoma

Question 11

Vascularization inhibitor drugs

Answer 11

• Vascularization Inhibitors:
  
  1. includes VEGF(R) inhibitors bevacizumab, sorafenib + sunitinib
  2. Endo- and angiostatin**
  3. Thrombospondin

Question 12

Vascularization inhibitor indication

Answer 12

Vascularization inhibitors:

Sunitinib, sorafenib (VEGFR atg) and bevacizumab (anti-VEGF mAB) mentioned above.

Endostatin - fragment of type 18 collagen; under research; interferes with VEGF/FGF pro-angiogenesis effects

Angiostatin - endogenous anti-angiogenic cleaved from plasminogen; under research for cancer tx

Thrombospondin - isolated from platelets stimulated by thrombin; analog ABT-150 is in clinical trials