Efficacy of epigenetic therapy as cancer treatment


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Efficacy of epigenetic therapy as cancer treatment

  2. 2. Introduction: Epigentic modification Central dogma of molecular biology:  DNA RNA Translation Transcription Protein Epigenetic modifications – molecular changes to the structure of the genome that affect gene expression with out altering the DNA. Two main types:1. DNA Methylation2. Histone Tail Modifications
  3. 3. Introduction: DNA Methylation •CH3 inhibits transcription factors from attaching to DNA •Gene(s) silenced/inactivated, esp. if promoter region is methylated •Hypermethylation -> inactivated genes; •Hypomethylation -> genomic instability •Catalyzed by presence of DNA Methyltransferase (DNMT) enzymes
  4. 4. Introduction: Histone Tail Modifications Histone – basic protein around which a DNA strand is wound to form chromatin Molecular modifications to the histone “tail” (sticks out from the chromatin) determine how tightly the DNA is wound Tightly wound DNA ->genes inactivated, silenced Loosely wound DNA -> genes activated, expressed
  5. 5. Introduction: Histone Acetlyation/Deacetylation•Acetylation: Addition of COCH3 groups; •DNA more loosely wound -> genes expressed•Deacetylation: Removal of COCH3 groups ; •DNA more tightly wound -> genes silenced•Deacetylation catalyzed by presence of Histone Deacetylase (HDAC)enzymes
  6. 6. Introduction: Overview of DNAMethylation and Histone Tail Modifcation •Genes silenced if DNA is methylated •Genes expressed if histone is acetylated
  7. 7. Genetic/Epigenetic Basis ofCancer Cancer – unregulated growth of abnormal cells; abnormal cell cycle Often caused by inactivation of tumor suppressing gene  Inactivation caused by loss of function mutation in DNA  OR caused by epigenetic gene silencing *genetic changes are irreversible, but epigenetic changes are not!*
  8. 8. Current Cancer treatments Supportive treatment – care, not cure Radiation therapy – non- selectively damages DNA of cells near tumor  Fatigue, skin irritation Tumor removal surgery – often not plausable Traditional chemotherapy – non - selectively targets all rapidly dividing cells  nausea, loss of appetite, hair loss, brittle skin and nails, fatigue, ect.
  9. 9. Epigenetic Cancer Treatments Attempt to inhibit and reverse the epigenetic modifications that cause cancer Reactivate tumor suppressor genes  Apoptotic genes, cell cycle regulators Inhibit the enzymes that catalyze epigenetic modifications  HDACs, DNMTs Currently 4 FDA approved epigenetic treatments for cancer Treatments for cancers of the blood, bone marrow, and lymph nodes  Hematologic malignancies
  10. 10. DNMT Inhibitor Treatments1. Azacytidine: “Vidaza” Subcutaneous2. Decitabine: “Dacogen” IV Both used to treat Myelodysplastic Syndromes (MDS)  Bone marrow cancers; “prelukemia” -> 1/3 transform to Acute Myelgenous Leukemia (AML) Only used when conventional treatments have failed  Supportive care, stem cell transplant, chemotherapy
  11. 11. Efficacy of Azacytidine and Decitabine In comparison to supportive care, both hypomethylating agents:  Had significantly higher rates of response, partial response, improvement, and remission  Had higher survival rate  Delayed transformation to ALS  Delayed death  Increased overall wellbeing
  12. 12. Efficacy of Azacytidine and Decitibine Azacytidine  60% response  7% complete remission  16% partial response  37% improved  2 yr survival rate twice that of conventional treatments Decitibine  17-49% response  Large variance  Effect on chronic myelomoncyctic leukemia:  25% response  14% complete remission  11% partial response  11% improved  39% stable disease
  13. 13. Draw Backs of Azacytidine and Decitabine Abnormal methylation patterns can return Side effects:  Nausea, vommiting, anorexia, myelosuppression (decrease in blood cell production)  Thrombocytopenia – low platelet count  Neutropenia – low white blood cell count Thrombocytopenia and neutropenia caused by cytotoxicity of specific mechanisms which are not related to the hypomethylating effect
  14. 14. HDAC Inhibitor Treatments1. Vorinostat: “Zolinza,” pill form2. Romidepsin: “Istodax,” IV Both treat cutaneous T-cell lymphoma (CTCL)  Cancers of the immune system; non-Hodgkin’s lymphoma Both prove effective, with response rate around 30% Both only prescribed when convetional treatments have failed (Refractory CTCL)
  15. 15. Efficacy of Vorinostat and Romidepsin for CTCL Treatment Vorinostat  29.7% response  Continued treatment 2yrs: (small n)  16.7% complete remission  66.7% partial remission  16.7% stable disease Romidepsin  34-35% response
  16. 16. Draw backs of Vorinostat andRomidepsin side effects: Romidepsin  86% nausea  77% fatigue  52% vomiting  54% anorexia  *cardiotoxicity Vorinostat  26% thrombocytopenia  14% anemia  54% fatigue  61% nausea  31% Diarrhea
  17. 17. Efficacy of Single EpigeneticTherapy on Solid Tumor cancers Azacytidine – no effect published Decitadine – no effect published Vorinostat – small effect on:  Colorectal, breast, head and neck, and prostate cancer  Small sample size, small effect size (5-8%)  Very severe side effects; some results were jeopardized Romidepsin – shown small effect on:  refactory AML/MDS, CLL, lung cancer, hormone refractory cancer  Small sample sizes, small effect size (4-9%)
  18. 18. Efficacy of Combined Therapies onSolid Tumor cancers  Addition of Azacytidine to conventional chemotherapeutic agents(docetaxel & cisplatin) increased response of refractive prostate cancer 13%  Addition of Vorinostat to conventional chemotherapeutic agents (carboplatin & paditaxel) increased response rate of non-small cell lung carcinoma 22%  Combination of Decitabine and two HDAC inhibitors (LBH589 or MGCD0103) had synergistic effect on small cell lung cancer cells; reduced proliferation of 56% or strains  Addition of Decitabine to radiation therapy of breast cancer cells increased response rate 33%
  19. 19. Future Potential Of CombinationTherapy Apparent synergistic effects of epigenetic therapies Epigenetic therapy is not a cure; combination with chemotherapy/radiation could be Negative side effects were muted when paired with other chemotherapeutic drugs  Esp. Vorinostat
  20. 20. Conclusions Epigenetic therapies improvement on past treatments, especially when combination approach Seems future is in finding effective combinations Also, efforts should be made to make the inhibitors more selective in order to lessen the side effects