Part2:%Cancer%Therapies,%%...
Transcript of Part2:%Cancer%Therapies,%%...
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Part 2: Cancer Therapies, Present and Future
Adrianna San Roman Leah Liu
Clare Malone
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Objec?ves
• Most cancer therapies aBack general features common to all cancers
• New cancer therapies aBack specific features or muta?ons found in individual cancers
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Unlimited and Uncontrolled Replica?on
Normal Cell
Cancer Cell
Tumor
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General vs. Specific Features of Cancer Cells
Uncontrolled cell division and DNA replica?on
Specific DNA muta?on
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DNA replica?on occurs during each cell division
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DNA replica?on occurs during each cell division
Ac?vely dividing cell
DNA
Cell division
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Chemotherapy: chemicals that kill fast-‐dividing cells
Chemotherapy agents cover DNA
Cell division is blocked
cell death and tumor shrinkage
Most cells in the body do not divide frequently
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Therapeu?c Window: • Medicine dosages that are both safe and effec?ve
Increasing Dose
Benefit
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Smaller Therapeu?c Window: effec?ve dose is close to toxic dose
Increasing Dose
Benefit
Nausea
Drowsiness
Blood clots
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Chemotherapy causes side effects
Inflamma?on of the diges?ve tract, nausea, diarrhea
hBp://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm
Hair loss
Fewer blood cells, suppressed immune system (bone marrow)
Chemotherapy has a small therapeu?c window
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Why are the bone marrow, hair, and diges?ve tract affected?
• Chemotherapy aBacks ANY fast-‐dividing cells
Blood cells in bone marrow Hair follicle Intes?nal cells
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How effec?ve is chemotherapy?
• What would be the 5 year survival rate without chemotherapy?
A. 2% B. 33% C. 61%
Morgan, G., et al. Clinical Oncology (2004) 16: 549-‐560
63% -‐ 61% = 2% of survival rate can be aBributed to chemotherapy
The 5 year survival rate for all cancers is 63%
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Each type of cancer responds differently to chemotherapy
Adapted from Morgan, G., et al. Clinical Oncology (2004) 16: 549-‐560
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Increase in 5-‐yr survivors a;
er che
mo
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Radia?on therapy damages DNA
hBp://www.cancer.gov/cancertopics/factsheet/Therapy/radia?on
Radia?on is targeted to a specific body part
Cell death, tumor shrinkage
Cancer cells are bad at repairing DNA
Normal cells can also be affected
DNA Damage
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Radia?on Therapy causes side effects
hBp://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm
Radia?on therapy has a small therapeu?c window
Skin irrita?on, scar ?ssue
Fa?gue, memory loss
Very rare secondary tumors
Chronic bowel effects
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hBp://www.gpnotebook.co.uk/simplepage.cfm?ID=2060451853
Different cancers respond very differently to radia?on therapy
Responsive Cancers Resistant Cancers
Lymphoma Melanoma
Medulloblastoma Glioma
Neuroblastoma Large bowel cancer
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Summary: Current Cancer Therapies
• Chemotherapy aBacks cells that divide rapidly
• Radia?on therapy damages DNA in cancer cells
• Both chemotherapy and radia?on therapy have small therapeu?c windows
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General vs. Specific Features of Cancer Cells
Uncontrolled cell division and DNA replica?on Specific DNA muta?on
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There are many diverse types of cancer
Muta?on A Signaling Pathway A
Muta?on B Signaling Pathway B
Muta?on C Signaling Pathway C
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Targeted therapies aBack specific mutated proteins
Normal protein Oncogenic protein
Targeted Therapy
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Targeted therapies aBack specific mutated proteins
Normal protein
Targeted Therapy
Oncogenic protein blocked
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Targeted therapies only work for pa?ents with the correct muta?on
Targeted Therapy A Targeted Therapy B Targeted Therapy C
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Targeted Therapies have fewer side effects
Targeted therapies have a wider therapeu?c window
Joint pain, fa?gue, skin lesions
nausea, muscle pain, diarrhea
hBp://www.nejm.org/doi/pdf/10.1056/NEJMoa1002011 hBp://www.nejm.org/doi/pdf/10.1056/NEJM200104053441401
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• In 95% of CML cases, the oncogene is BCR-‐ABL, which increase cell division
hBp://www.cancer.gov/cancertopics/factsheet/Therapy/targeted
Uncontrolled cell division
Chronic myelogenous leukemia (CML) is a cancer of white blood cells
Oncogenic BCR-‐ABL Turns on cell division proteins in signaling pathway
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Gleevec/Ima?nib blocks the responsible oncogene
Druker, et al. NEJM (2006) 355:2408-‐2417, hBp://www.cancer.gov/cancertopics/factsheet/Therapy/targeted
Oncogenic BCR-‐ABL Signaling pathways blocked
• CML has 89% 5-‐year survival rate compared to 23% in 1975
• Gleevec can be used for other cancers that have BCR-‐ABL
Uncontrolled cell division is stabilized
Gleevec/ima?nib
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B-‐raf oncogene in melanoma
• Melanoma is resistant to chemotherapy and radia?on
• 40-‐60% of melanomas have a oncogene called B-‐raf
B-‐raf
Abnormal cell
growth and
division
Ras
Growth signal
Mek
Cancer Cell
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B-‐raf oncogene in melanoma
hBp://www.nlm.nih.gov/medlineplus/news/fullstory_109152.html, hBp://www.nejm.org/doi/full/10.1056/NEJMoa1002011
Over-‐ac?vate signaling pathways for cell division
B-‐raf
Tumor forma?on
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PLX4032 inhibits oncogenic B-‐raf
B-‐raf
PLX4032
Oncogenic B-‐Raf Prevent overac?ve cell division
Tumors shrink
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PLX4032 effec?veness during clinical trials
Bollag, et al. Nature (2010) 467: 596-‐599.
Before Aner
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PLX4032 clinical trial
• How effec?ve is PLX4032 long-‐term? Chapman, et al. NEJM 2011
Half of pa?ents given PLX4032
Half of pa?ents given chemotherapy
6 months
63% less risk of death
Chemotherapy group given opportunity to try PLX4032
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Summary: Cancer Therapies
• Chemotherapy and radia?on therapy aBack general features of cancer cells
• Targeted therapies aBack specific features (muta?ons) of cancer cells
• Understanding the gene?cs of cancer is important for developing therapies