March 04 Lecture-Targeted therapy

TARGETED THERAPIES

  • Definition and Purpose: Targeted therapies are designed to target unique properties (hallmarks) of cancer cells with the aim to suppress tumor growth, offering a more precise treatment than traditional chemotherapy.

  • Reduction of Toxicity: Generally, targeted therapies are less toxic to normal cells, making them suitable for long-term cancer treatments.

  • Administration: Some therapies can be administered orally.

TODAY’S LEARNING OBJECTIVES

  • Classes to Discuss:

    • Immunomodulators (immune checkpoint inhibitors, T Cell transfer therapy)

    • Hormone therapies

    • Kinase inhibitors

  • Key Elements: For each class, identify drug names, mechanism of action, clinical use, and major side effects.

TUMOR IMMUNE ENVIRONMENT

  • Immunosuppressive Cells:

    • MDSC: Myeloid-derived suppressor cells

    • MC: Mast Cells

    • Treg: T regulatory cells

  • Immunostimulating Cells:

    • TIL: Tumor Infiltrating Lymphocytes (CD4+ and CD8+)

    • NK Cells: Natural Killer Cells / ILC1

    • DC: Dendritic Cells

IMMUNE CHECKPOINTS

  • Natural Regulation: Immune cells require regulatory mechanisms to avoid hyperactivation. Key checkpoints include:

    • CTLA-4: Inhibits T cell activation by binding to B7 molecule on antigen presenting cells.

    • PD-1: Provides inhibitory signals to T cells through interaction with PD-L1, a molecule secreted by cancer and immunosuppressive cells.

IMMUNOMODULATORS - CHECKPOINT INHIBITORS

  • Ipilimumab: Monoclonal antibody against CTLA-4, maintaining T cell activity in tumors.

    • Approved for: Colorectal cancer, melanoma, lung cancer.

  • Pembrolizumab & Nivolumab: Monoclonal antibodies against PD-1, used for various cancers like melanoma and lung cancer.

SIDE EFFECTS

  • Immune-Related Adverse Events: Include autoimmune reactions such as colitis and thyroiditis.

  • Challenges: Variability in patient response depending on immune cell types and tumor microenvironment.

T CELL TRANSFER THERAPY

  • CAR-T Therapy: Involves collecting T cells, modifying them to recognize cancer antigens, expanding them, and reintroducing them to the patient.

  • Products:

    • Tisagenlecleucel (KYMRIAH): Targets CD19.

    • Ciltacabtagene autoleucel (CARVYKTI): Targets BCMA.

  • Adverse Effects: Includes cytokine release syndrome and neurological toxicity.

HORMONE THERAPIES - BREAST CANCER

  • Selective Estrogen Receptor Modulators (SERM):

    • Tamoxifen: Partial agonist for ER, used for ER+ breast cancer. Risks include uterine cancer and thromboembolic events.

  • Aromatase Inhibitors: Block estrogen synthesis (e.g., Letrozole) effective for breast cancers with estrogen receptor expression.

  • Hormone Therapy Limitations: Ineffective for Triple Negative Breast Cancer (TNBC).

HORMONE THERAPIES - PROSTATE CANCER

  • Androgen Deprivation Therapy (ADT): Mainstay for metastatic prostate cancer. Achieved by surgical or medical means, mostly using LHRH analogs (e.g., Leuprolide).

  • Androgen Receptor Antagonists: Including Flutamide and Enzalutamide, used to counteract testosterone effects in prostate cancer.

KINASE INHIBITORS

  • Role of Tyrosine Kinases: Essential in providing growth signals to cancer cells. The Philadelphia chromosome's BCR-ABL kinase is a key target in CML treatment with drugs like Imatinib.

  • Examples of Kinase Inhibitors:

    • Generic end: Usually end with ‘nib’ (e.g., Nilotinib, Dasatinib).

    • Common Side Effects: Rash and diarrhea.

HER TARGETED THERAPIES

  • EGFR and HER2 Kinase Inhibitors: Effective in certain cancers. Tyrosine kinase inhibitors (e.g. Gefitinib for lung cancer) and monoclonal antibodies (e.g. Trastuzumab for HER2+ cancers).

SAMPLE QUESTIONS

  1. Question on immune checkpoint inhibitors`:

    • A 65-year-old patient prescribed an antibody that enhances T cell function is most likely receiving Nivolumab.

  2. Question on breast cancer drugs:

    • The drug inhibiting the conversion of androstenedione to estrogen is Anastrozole.

REFERENCES

  • Robert A. Weinberg. The Biology of Cancer.

  • Lippincott's Illustrated Reviews: Pharmacology, 5e.

  • Brody's Human Pharmacology: Mechanism-based therapeutics.