Part2:%Cancer%Therapies,%%...
Transcript of Part2:%Cancer%Therapies,%%...
Part 2: Cancer Therapies, Present and Future
Adrianna San Roman Leah Liu
Clare Malone
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
Unlimited and Uncontrolled Replica?on
Normal Cell
Cancer Cell
Tumor
General vs. Specific Features of Cancer Cells
Uncontrolled cell division and DNA replica?on
Specific DNA muta?on
DNA replica?on occurs during each cell division
DNA replica?on occurs during each cell division
Ac?vely dividing cell
DNA
Cell division
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
Therapeu?c Window: • Medicine dosages that are both safe and effec?ve
Increasing Dose
Benefit
Smaller Therapeu?c Window: effec?ve dose is close to toxic dose
Increasing Dose
Benefit
Nausea
Drowsiness
Blood clots
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
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
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%
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
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
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
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
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
General vs. Specific Features of Cancer Cells
Uncontrolled cell division and DNA replica?on Specific DNA muta?on
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
Targeted therapies aBack specific mutated proteins
Normal protein Oncogenic protein
Targeted Therapy
Targeted therapies aBack specific mutated proteins
Normal protein
Targeted Therapy
Oncogenic protein blocked
Targeted therapies only work for pa?ents with the correct muta?on
Targeted Therapy A Targeted Therapy B Targeted Therapy C
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
• 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
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
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
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
PLX4032 inhibits oncogenic B-‐raf
B-‐raf
PLX4032
Oncogenic B-‐Raf Prevent overac?ve cell division
Tumors shrink
PLX4032 effec?veness during clinical trials
Bollag, et al. Nature (2010) 467: 596-‐599.
Before Aner
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
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