Anti-Cancer Drugs - Targeted Cancer Therapy Overview

Anti-Cancer Drugs - Targeted Cancer Therapy

1. Steroid Inhibitors

  • Presenter: Dr. J Haylor, Department of Medicine, UCLan

2. Steroid-Dependent Cancer

  • Testosterone: Linked to Prostate Cancer
  • Involved in driving cancer progression.
  • Oestrogen: Linked to Breast Cancer
  • Also fuels cancer cell growth in estrogen receptor-positive cases.

3. Prostate Cancer Overview

  • Androgen synthesis inhibitors include:

  • CYP17A1 Inhibitor: e.g., Abiraterone.

  • GnRH Agonists and Antagonists: Act on GnRH receptors to manage androgen levels.

  • Statistics:

  • 2nd leading cause of male cancer deaths.

  • 10,000 deaths per year in the UK.

  • Significant risk of metastases in bone and lymph nodes.

4. Androgen Synthesis Inhibitors

  • Abiraterone Acetate (2012):

  • Competitive inhibitor of CYP17A1.

  • Reduces testosterone to undetectable levels.

  • Used in castration-resistant metastatic prostate cancer after docetaxel.

  • Finasteride (1992):

  • Competitive inhibitor of 5-alpha reductase.

  • Prescribed for benign prostatic hypertrophy (improves urine flow).

5. Treatment of Urinary Retention

  • Tamsulosin:
  • α1-adrenoceptor antagonist selective for α1A subtype.
  • Effects include relaxation of the bladder neck and prostate muscle.
  • Used for benign prostatic hypertrophy and kidney stones.

6. GnRH Receptor Modulators

  • GnRH Agonists:
  • Enhance initial FSH/LH release (e.g., Goserelin) leading to eventual androgen depletion.
  • GnRH Antagonist (Degarelix):
  • Provides immediate testosterone reduction, avoiding ‘tumor flare’ effects.

7. Androgen Receptor Antagonists

  • Flutamide (1st generation) and Bicalutamide (2nd generation):
  • Oral medications for metastatic prostate cancer resistant to GnRH therapy.

8. Breast Cancer Overview

  • Estrogen Receptor Positive Cases:
  • 70% of breast cancers in women influenced by estrogen.
  • Estrogen stimulates cell growth by binding to ER and modifying gene activity.

9. Aromatase Inhibitors

  • Function:
  • Block conversion of androgens to estrogens in postmenopausal women.
  • Types include:
    • Type I: Steroid (Exemestane).
    • Type II: Non-steroid (Anastrozole, Letrozole).
  • Adverse Effects: Hot flushes, joint pain, osteoporosis.
  • Contraindication: Ineffective in premenopausal women.

10. Pre-Menopausal Breast Cancer Treatment

  • GnRH agonists and aromatase inhibitors can be implemented, but effectiveness varies based on receptor status.

11. Estrogen Receptor Antagonist (Fulvestrant)

  • Effective second-line therapy in advanced breast cancer but lacks significant cost-effectiveness over aromatase inhibitors.

12. Tamoxifen Overview

  • SERM (Selective Estrogen Receptor Modulator):
  • Acts as both an estrogen antagonist in breast tissue but as an agonist in bone.
  • Therapeutic Effects: In ER+ breast cancer improve survival, reduce recurrence rates.
  • Risks: Increased thromboembolism, restricted typically for 5-year use.

13. Mifepristone (Progesterone Receptor Antagonist)

  • Affects PR signaling, can be beneficial in combination therapy.

14. Prescription Items for Breast Cancer Treatments

  • Aromatase Inhibitors: Anastrozole, Letrozole, Exemestane.
  • Fulvestrant (0.02%) and Tamoxifen (33%) as key therapies.

15. Tamoxifen Resistance Factors

  • CYP2D6 Polymorphism: A known factor for intrinsic resistance.
  • Responsiveness Rates: Only 70% ER positive cancers respond fully.

16. Survival Rates Overview (SEER Data)

  • Local Stage: 99%
  • Regional Stage: 86%
  • Distant Stage: 31%

17. Growth Factor Inhibitors in Cancer Therapy

  • HER2-related Therapies:

  • Trastuzumab (Herceptin):

  • Monoclonal antibody targeting HER2, reducing cell proliferation.

  • Adverse effects include flu-like symptoms and potential heart failure.

  • Pertuzumab:

  • Works in combination with trastuzumab targeting different segments of HER2 receptors.

18. Angiogenesis in Tumor Growth

  • Involves balance between growth factors like VEGF and inhibitors.

19. Bevacizumab (Avastin)

  • Humanized VEGF-A antibody aiming at inhibiting angiogenesis.
  • Adverse Effects: Include bleeding, high blood pressure, and gastrointestinal issues.

20. VEGF Fusion Protein (Aflibercept)

  • Used in metastatic colorectal cancer, binds to VEGF-A and VEGF-B.

21. VEGF Receptor Antagonist (Ramicirumab)

  • Targets VEGF-2 receptor involved in angiogenesis signaling for treatment of gastric and lung cancers.

22. Tyrosine Kinase Inhibitors Overview

  • Mechanism of Action: Block activation of tyrosine kinases which are involved in signaling pathways for cell proliferation.

23. Imatinib (Gleevec)

  • Targeting BCR-ABL fusion gene leading to inhibition in chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL).

24. Protein Kinase Inhibitors

  • Include various targeted therapies for different mutated kinases involved in cancer such as KRAS and BRAF.

25. Malignant Melanoma and BRAF Inhibitors

  • Vemurafenib: Targets mutated BRAF V600E protein, improves survival rates but requires careful monitoring for adverse effects.

26. CAR-T Cell Therapy Overview

  • Tisagenlecleucel (Kymriah): One-time treatment for relapsed/refractory B cell malignancies, demonstrating a high success rate in children with acute lymphoblastic leukemia (ALL) despite costly considerations and potential side effects.