This document discusses epigenetic therapies for cancer treatment. It introduces DNA methylation and histone modifications as two main types of epigenetic modifications. It then reviews four FDA-approved epigenetic drugs - azacytidine, decitabine, vorinostat, and romidepsin - and their efficacy in treating various cancers like myelodysplastic syndromes and cutaneous T-cell lymphoma. The document finds that combination epigenetic therapies may have synergistic effects in solid tumors and help reduce side effects. Overall, the future of epigenetic cancer treatment likely involves effective combination approaches and more targeted epigenetic inhibitors.
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 Methylation
2. Histone Tail Modifications
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. 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. 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. Introduction: Overview of DNA
Methylation and Histone Tail Modifcation
•Genes silenced if DNA is methylated
•Genes expressed if histone is acetylated
7. Genetic/Epigenetic Basis of
Cancer
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. 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. 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. DNMT Inhibitor Treatments
1. Azacytidine: “Vidaza” Subcutaneous
2. 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. 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. 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. 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. HDAC Inhibitor Treatments
1. Vorinostat: “Zolinza,” pill form
2. 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. 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
17. Efficacy of Single Epigenetic
Therapy 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. Efficacy of Combined Therapies on
Solid 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. Future Potential Of Combination
Therapy
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. 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
