Small Molecule Inhibitor-Mediated Chemotherapy

Aka: Small Molecule Inhibitor-Mediated Chemotherapy, Small Molecule Targeted Cancer Therapy, Protein-Tyrosine Kinase Inhibitor, Tyrosine Kinase Inhibitor, PTK Inhibitor, Protein Kinase Inhibitor, Nib Targeted Chemotherapy

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II. Definitions

  1. Protein Kinase
    1. Group of enzymes (e.g. Tyrosine Kinase) that transfer a phosphate group to a Protein
  2. Tyrosine Kinase
    1. Protein Kinase, that is a key enzyme in molecular signaling pathway
    2. Transfers a phosphate from ATP to a Protein's tyrosine Amino Acid
  3. Protein-Tyrosine Kinase Inhibitor (PTK Inhibitor)
    1. Agents that inhibit Tyrosine Kinase, suppressing cell growth and proliferation
    2. Many of the small molecule agents (suffixed with tinib) are inhibitors of Tyrosine Kinase
  4. Suffix Naming Conventions
    1. Nib: Small Molecule Agents overall
    2. Tinib: Tyrosine Kinase Inhibitors
    3. Anib: Angiogenesis Inhibitor
    4. Zomib: Protease or Proteasome Inhibitors (mib agents)

III. Mechanism

  1. See Tyrosine Kinase
  2. Targeted to Protein kinases (esp. Tyrosine Kinase), interfering with various markers (e.g. EGFR, HER2-neu and VEGF)
    1. Protein kinases targeted are active in promoting cell growth and exploited by cancers
  3. Primarily oral agents (contrast with other Chemotherapy which is primarily intravenous)
  4. Small molecules that principally act intracellularly
  5. Less specific than monoclonal antibodies
  6. Small molecules also effect healthy tissue, and therefore have systemic effects

IV. Pharmacokinetics

  1. Oral agents
  2. Very short half life (hours)

V. Advantages

  1. Much less expensive than monoclonal antibodies, but still >$5000 for a course of Chemotherapy

VI. Efficacy

  1. Widely variable efficacy depending on tumor type
  2. Highly effective agents
    1. Osimertinib is highly effective in metastatic EGFR Lung Cancer
    2. Alectinib is highly effective in advanced ALK Lung Cancer
  3. Poor efficacy agents
    1. PARP agents (e.g. Olaparib) do not appear to affect survival in BRCA Ovarian Cancer

VII. Medications: General

  1. ALK Inhibitor (CD246, Anaplastic Lymphoma Kinase Inhibitor)
    1. Alectinib (Alecensa), Brigatinib (Alunbrig), Ceritinib (Zykadia), Crizotinib (Xalkori), Lorlatinib (Lorbrena)
    2. Indications
      1. Lung Adenocarcinoma (ALK+ fusion, metastatic)
    3. Efficacy
      1. Alectinib is highly effective in advanced ALK Lung Cancer
    4. Adverse Effects
      1. Bradycardia
      2. Hepatotoxicity
      3. Nausea or Vomiting
      4. Ocular Toxicity
      5. QTc Prolongation
  2. BCL2 (B-Cell Leukemia/Lypmphoma 2)
    1. Venetoclax (Venclexta)
    2. Indications
      1. Chronic Lymphocytic Leukemia (17p deletion)
    3. Adverse Effects
      1. Pancytopenia (severe)
      2. Tumor Lysis Syndrome
  3. BCR-ABL Inhibitor
    1. Bosutinib (Bosulif), Dasatinib (Sprycel), Nilotinib (Tasigna), Ponatinib (Iclusig)
    2. Indications
      1. Chronic Myelogenous Leukemia
    3. Precautions
      1. Ponatinib is associated with serious cardiovascular events (CVA, MI, PVD) in 20-30% (1% death rate)
    4. Adverse Effects
      1. Congestive Heart Failure
      2. Diarrhea (Bosutinib)
      3. Edema
      4. Effusions (Dasatinib)
      5. Hematologic Effects
      6. Pancreatitis
      7. Prolonged QTc (Nilotinib)
      8. Thrombosis (Ponatinib)
  4. BRAF Inhibitor (B-raf proto-oncogene Inhibitor)
    1. Dabrafenib (Tafinlar), Vemurafenib (Zelboraf), Encorafenib (Braftovi)
    2. Indications
      1. Lung Adenocarcinoma (V600E Mutation, metastatic)
      2. Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
        1. BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
      3. Melanoma (V600E or V600k mutation, metastatic)
        1. BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
    3. Adverse Effects
      1. Colitis
      2. Congestive Heart Failure
      3. Fever
      4. Hepatotoxicity
      5. Hyperglycemia
      6. Rash
      7. Squamous Cell Skin Cancer
      8. Thrombosis
  5. BTK Inhibitor (Bruton Tyrosine Kinase Inhibitor)
    1. Ibrutinib (Imbruvica)
    2. Indications
      1. Chronic Lymphocytic Leukemia (17p deletion)
    3. Adverse Effects
      1. Atrial Fibrillation
      2. Diarrhea
      3. Edema
      4. Bleeding Diathesis
  6. c-KIT Inhibitor (Tyrosine Kinase KIT gene)
    1. Imatinib (Gleevec)
    2. Indications
      1. Gastrointestinal Stromal Tumor (c-KIT+, adjuvant after complete tumor resection)
    3. Adverse Effects
      1. Congestive Heart Failure
      2. Edema
      3. Hematologic Effects
  7. Cyclin-Dependent Kinase Inhibitor (CDK Inhibitor 4 and 6)
    1. Palbociclib (Ibrance)
    2. Ribociclib (Kisquali)
    3. Abemaciclib (Verzenio)
  8. EGFR Inhibitor (Epidermal Growth Factor Receptor Inhibitor)
    1. Afatinib (Gilotrif), Dacomitinib (Vizimpro), Erlotinib (Tarcerva), Gefitinib (Iressa), Osimertinib (Tagrisso)
    2. Indications
      1. Lung Adenocarcinoma (EGFR exon 19 deletion, exon 21 substitution)
    3. Efficacy
      1. Osimertinib is highly effective in metastatic EGFR Lung Cancer
    4. Adverse Effects
      1. Diarrhea
      2. Hepatotoxicity
      3. Prolonged QTc
      4. Rash
      5. Trichiasis
  9. FLT3 Inhibitor (FMS-like Tyrosine Kinase 3 or CD135)
    1. Gilteritinib (Xospata), Midostaurin (Rydapt)
    2. Indications
      1. Acute Myelogenous Leukemia (FLT3+ new or advanced/refractory)
    3. Adverse Effects
      1. Hepatotoxicity
      2. Prolonged QTc
      3. Rash
      4. Vomiting
  10. FGR2/3 Inhibitor (Fibroblast Growth Factor Receptor 1/2 Inhibitor)
    1. Erdafitinib (Balversa)
    2. Indications
      1. Bladder Cancer (FGR2/3+, advanced or metastatic)
    3. Adverse Effects
      1. Central Serous Retinopathy
      2. Hand-Foot Syndrome
      3. Hyperphosphatemia
      4. Oncholysis
  11. IDH1 Inhibitor (Isocitrate Dehydrogenase 1 Inhibitor)
    1. Ivosidenib (Tibsovo)
  12. IDH2 Inhibitor (Isocitrate Dehydrogenase 2 Inhibitor)
    1. Enasidenib (Idhifa)
    2. Indications
      1. Acute Myelogenous Leukemia (IDH1/2+ new or advanced/refractory)
    3. Adverse Effects
      1. Edema
      2. Hepatotoxicity
      3. Prolonged QTc
  13. MEK Inhibitor (MAP Kinase-ERK Kinase Inhibitor)
    1. Binimetinib (Mektovi), Trametinib (Mekinist), Cobimetinib (Cotellic)
    2. Indications
      1. Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
        1. BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
      2. Melanoma
        1. BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
    3. Adverse Effects
      1. Papulopustular rash
      2. Diarrhea
      3. Peripheral Edema
      4. Hypertension
      5. Ocular toxicity (uveal, Retinal)
  14. NTRK Inhibitor (Neurotrophic Tyrosine Kinase Receptor)
    1. Larotrectinib (Vitrakvi), Entrectinib (Rozlytrek, also targets ROS1)
    2. NTRK is also known as TRK (Tropomyosin Kinase receptor)
    3. Indications
      1. NTKR Fusion Solid Tumors
    4. Adverse Effects
      1. Cardiotoxicity
      2. Cognitive Impairment
      3. Fractures
      4. Hepatotoxicity
      5. Ocular Toxicity
  15. PIK3CA Inhibitor (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha)
    1. Alpelisib (Piqray)
    2. Indications
      1. Breast Cancer (PIK3CA mutation, metastatic)
    3. Adverse Effects
      1. Stevens-Johnson Syndrome
      2. Hyperglycemia
      3. Severe Diarrhea
  16. PARP Inhibitor (Poly ADP Ribose Polymerase)
    1. Olaparib (Lynparza), Talazoparib (Telzenna), Niraparib (Zejula), Rucaparib (Rubraca)
    2. Indications
      1. Breast Cancer (BRCA mutation, metastatic)
      2. Ovarian Cancer (BRCA mutation, advanced or metastatic)
    3. Efficacy
      1. PARP agents (e.g. Olaparib) do not appear to affect survival in BRCA Ovarian Cancer
    4. Adverse Effects
      1. Acute Myelogenous Leukemia (rare)
      2. Pneumonitis
      3. Pancytopenia
      4. Myelodysplastic Syndrome or Macrocytosis
  17. ROS1 Inhibitor (Receptor Tyrosine Kinase encoded by ROS1 gene)
    1. Crizotinib (Xalkori, also targets ALK), Entrectinib (Rozlytrek, also targets NTKR)
    2. Indications
      1. Lung Adenocarcinoma (ROS1+, metastatic)
    3. Adverse Effects (based on Entrectinib)
      1. Cardiotoxicity
      2. Cognitive Impairment
      3. Fractures
      4. Hepatotoxicity
      5. Ocular Toxicity
  18. Sonic Hedgehog Pathway Inhibitor (SHH Pathway Inhibitor)
    1. Vismodegib (Erivedge)
    2. Sonidegib (Odomzo)
    3. Glasdegib (Daurismo)
  19. VEGF Inhibitor (Vascular Endothelial Growth Factor) Receptor Inhibitor
    1. Axitinib (Inlyta), Cabozantinib (Cometrig), Lenvatinib (Lenvima), Pazopanib (Votrient), Regorafenib (Stivarga), Sorafenib (Nexavar), Vandetanib (Capreisa)
    2. Ponatinib (Iclusig)
      1. Also targets BCR-ABL (see BCR-ABL Inhibitor)
    3. Sunitinib (Sutent)
      1. Non-specifically targets many kinases

VIII. Medications: Multikinase Inhibitors ("Dirty Inhibitors")

  1. General
    1. Many small molecule agents act on more than one kinase
    2. These multi-kinase agents block multiple sites important in cancer growth and proliferation
    3. These agents also affect non-cancerous cells, and more targets result in potential for greater toxicity
  2. Examples of Multikinase Agents
    1. Afatinib (Gilotrif)
    2. Alectinib (Alecensa)
    3. Ceritinib (Zykadia)
    4. Dabrafenib (Taflinlar)
    5. Ibrutinib (Imbruvica)
    6. Idelalisib (Zydelig)
    7. Nintedanib (Olev)
    8. Ruxolitinib (Jakafi)
    9. Trametinib (Mekinst)
    10. Vemurafenib (Zelboraf)

IX. Drug Interactions

  1. Multiple Drug Interactions related to Cytochrome P450 enzymes
    1. Many Cytochrome P-450 3A3/4 Isoenzyme interactions (inducers and inhibitors)
  2. Histamine Blockers (H2 Blocks) and Proton Pump Inhibitors impact absorption
    1. Bosutinib
    2. Crizotinib
    3. Dabrafenib
    4. Dasatinib
    5. Erlotinib
    6. Gefitinib
    7. Nilotinib
    8. Ponatinib
  3. Warfarin Drug Interactions
    1. Dabrafenib
    2. Erlotinib
    3. Gefitinib
    4. Imatinib
    5. Vemurafenib
    6. Venetoclax

X. Safety

  1. Unless otherwise stated for specific agents, avoid these in pregnancy and Lactation
  2. Avoid in Lactation
  3. Avoid in pregnancy (all trimesters)
    1. Almost all agents are Pregnancy Category D or X
    2. Use reliable Contraception

XI. Labs: Monitoring

  1. Adverse Effects vary widely among agents (see preparations above)
  2. Typical monitoring
    1. Electrolytes, Glucose and Renal Function (e.g. basic chemistry panel, Chem8)
    2. Complete Bound Count (CBC)
    3. Liver Function Tests (esp. for agents with hepatotoxicity risk)
      1. Alkaline Phosphatase
      2. Total Bilirubin
      3. Alanine Transaminase (ALT)
      4. Aspartate Transaminase (AST)

XII. Diagnostics

  1. Agents with risk of Cardiomyopathy, Congestive Heart Failure
    1. Echocardiogram
  2. Agents with risk of QTc Prolongation or Atrial Fibrillation
    1. Electrocardiogram
  3. Agents with ocular toxicity
    1. Dilated Eye Exam by ophthalmology

XIII. Resources

  1. Tyrosine Kinase Inhibitors (StatPearls)
    1. https://www.ncbi.nlm.nih.gov/books/NBK563322/

XIV. References

  1. Imai (2006) Nat Rev Cancer 6:714-27 [PubMed]
  2. Pathak (2018) Vivechan Int J Res 9(1): 36-49 +PMID:30853755 [PubMed]
    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407887/
  3. Smith (2021) Am Fam Physician 103(3): 155-63 [PubMed]

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