Genetics · MU Sofia

26. Treatment of genetic disorders: conventional treatment, orphan drugs, targeted therapy, gene therapy principles and applications.

Inside: 56 sections · 39 labelled pictures · 2 tables · 59 flashcards · 20 min

Topic 26 of 79 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 56 sections, about 2,435 words (20 min of reading), with 59 flashcards.

In this note

  1. Targeted therapy - general characteristics. Targeted therapy for breast and ovarian cancer.
  2. I. MOLECULAR BASIS OF BREAST AND OVARIAN CANCER
  3. II. TARGETED THERAPY IN BREAST CANCER
  4. C. PARP INHIBITORS IN BREAST CANCER
  5. IV. TARGETED THERAPY IN OVARIAN CANCER
  6. C. ANTI-ANGIOGENIC TARGETED THERAPY
  7. V. COMPARISON: TARGETED THERAPY IN BREAST VS OVARIAN CANCER
  8. VI. RESISTANCE TO TARGETED THERAPY
  9. VII. ROLE OF MOLECULAR TESTING
  10. Targeted therapy - general characteristics. Targeted therapy in chronic myeloid leukemia (CML).
  11. I. MOLECULAR BASIS OF CML
  12. II. PATHOGENESIS OF CML
  13. III. TARGETED THERAPY STRATEGY IN CML
  14. IV. TYROSINE KINASE INHIBITORS (TKIs)
  15. V. FIRST-GENERATION TKI
  16. VI. SECOND- AND THIRD-GENERATION TKIs
  17. VII. MONITORING OF TARGETED THERAPY IN CML
  18. VIII. TARGETED THERAPY ACROSS CML PHASES
  19. IX. LIMITATIONS OF TARGETED THERAPY IN CML
  20. X. ROLE OF TARGETED THERAPY IN MODERN HEMATOLOGY
  21. Conventional therapy of genetic diseases. Orphan drugs.
  22. I. GENERAL CONCEPT OF THERAPY IN GENETIC DISEASES
  23. II. PRINCIPLES OF CONVENTIONAL THERAPY OF GENETIC DISEASES
  24. III. DIETARY AND METABOLIC THERAPY
  25. IV. ENZYME AND PROTEIN REPLACEMENT THERAPY
  26. V. HORMONE AND FACTOR REPLACEMENT
  27. VI. PHARMACOLOGICAL MODULATION OF PATHWAYS
  28. VII. SYMPTOMATIC AND SUPPORTIVE THERAPY
  29. VIII. PREVENTIVE THERAPY AND EARLY INTERVENTION
  30. IX. ORPHAN DRUGS
  31. X. TYPES OF ORPHAN DRUGS USED IN GENETIC DISEASES
  32. XI. CHALLENGES OF ORPHAN DRUG THERAPY
  33. XII. ROLE OF GENETIC COUNSELING IN THERAPY
  34. Targeted therapy - general characteristics. Targeted therapy for colorectal carcinomas and gastrointestinal stromal tumors (GIST).
  35. I. GENERAL CHARACTERISTICS OF TARGETED THERAPY
  36. II. MOLECULAR BASIS OF TARGETED THERAPY
  37. Main Classes of Targeted Drugs
  38. III. TARGETED THERAPY IN COLORECTAL CARCINOMA (CRC)
  39. IV. TARGETED THERAPY IN GASTROINTESTINAL STROMAL TUMORS (GIST)
  40. V. TYROSINE KINASE INHIBITORS IN GIST
  41. VI. COMPARISON: CRC vs GIST TARGETED THERAPY
  42. VII. LIMITATIONS OF TARGETED THERAPY
  43. VIII. ROLE OF MOLECULAR DIAGNOSTICS
  44. Gene therapy - principles, possibilities, applications.
  45. I. DEFINITION AND GENERAL CONCEPT
  46. II. BASIC PRINCIPLES OF GENE THERAPY
  47. III. TYPES OF GENE THERAPY
  48. IV. GENE DELIVERY SYSTEMS (VECTORS)
  49. V. METHODS OF GENE THERAPY APPLICATION
  50. VI. GENE EDITING TECHNOLOGIES
  51. VII. APPLICATIONS OF GENE THERAPY
  52. B. CANCER GENE THERAPY
  53. C. GENE THERAPY FOR INFECTIOUS AND ACQUIRED DISEASES
  54. VIII. LIMITATIONS AND RISKS OF GENE THERAPY
  55. IX. ETHICAL AND SOCIAL CONSIDERATIONS
  56. X. FUTURE POSSIBILITIES OF GENE THERAPY

I. MOLECULAR BASIS OF BREAST AND OVARIAN CANCER

Key Oncogenic Pathways

  • HER2 signaling pathway
  • Estrogen receptor (ER) signaling
  • PI3K–AKT–mTOR pathway
  • DNA damage repair (BRCA-dependent homologous recombination)
  • Angiogenesis (VEGF pathway)

Targeted therapy exploits abnormalities in these pathways.

II. TARGETED THERAPY IN BREAST CANCER

A. HER2-POSITIVE BREAST CANCER

HER2 (ERBB2) is a transmembrane receptor tyrosine kinase. HER2 amplification or overexpression leads to:

  • constitutive signaling,
  • increased proliferation,
  • aggressive tumor behavior.

HER2 positivity occurs in ~15–20% of breast cancers.

Pathogenesis

  1. HER2 gene amplification.
  2. Overexpression of HER2 receptor.
  3. Persistent activation of growth signaling pathways.
  4. Increased tumor aggressiveness and recurrence risk.

HER2-Targeted Therapy

Monoclonal antibodies

  • Bind extracellular HER2 domain
  • Block receptor activation
  • Promote immune-mediated tumor cell destruction

Tyrosine kinase inhibitors

  • Inhibit intracellular kinase activity
  • Block downstream signaling

Clinical Impact

  • Dramatically improves survival
  • Converts aggressive tumors into treatable disease
  • Used in adjuvant and metastatic settings

B. HORMONE RECEPTOR–POSITIVE BREAST CANCER (Targeted Aspect)

Estrogen Receptor Signaling

ER-positive tumors depend on estrogen-mediated proliferation.

Targeted Pathway Modulation

Targeted agents are used to:

  • block estrogen signaling,
  • inhibit resistance pathways.

PI3K–AKT–mTOR Pathway

Pathogenesis

  1. PI3K pathway activation via mutations.
  2. Increased cell survival and proliferation.
  3. Resistance to endocrine therapy.

Targeted Strategy

  • Inhibition of pathway restores hormone sensitivity.

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