How do mutations cause cancer?
Transcript of How do mutations cause cancer?
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How do mutations cause cancer?
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Cell Signaling Pathways
• Take information from outside of the cell and transmit the signal to create an output
• Examples: Cell division, cell death, responses to stress, etc.
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Ras pathway – cell growth
B-Raf
Cell growth and proliferation
Ras
Growth signal
Activated
growth genes
Mek
Normal Cell
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Ras pathway – cell growth
B-Raf
Abnormal cell growth and division
Ras
Growth signal
Activated
growth genes
Mek
Cancer Cell
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There are many diverse types of cancer
• Depending on mutation, different signaling pathways are affected
Signaling Pathway A
Signaling Pathway B
Signaling Pathway C
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Summary
• Properties of cancer cells– Abnormal growth and migration through the
body
• Mutations in DNA and signaling pathways can cause cancer– Example: mutation in the Ras pathway that
controls cell growth
• Cancer is not one disease!
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Part 2: Cancer Therapies, Present and Future
Adrianna San RomanLeah Liu
Clare Malone
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Objectives• Learn about cancer therapies that attack general
features common to all cancers
• Learn about cancer therapies that attack specific features or mutations found in individual cancers
• The therapeutic window is the medicine dosage range that is both effective AND safe
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Properties of Normal Cells vs. Cancer Cells
Normal Cells Cancer Cells
Controlled growth Uncontrolled growth
Stay within their home tissue
Can move to other tissues in the body
Maintain normal tissue structure
Disrupt tissue structure and cause blood vessel growth
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DNA replication during cell division
Dividing cell
DNA
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General and Specific Features of Cancer Cells
DNA mutation
AGCGTATGTGTCAC
AGCGTATCTGTCAC
Uncontrolled cell division and DNA replication
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Chemotherapy consists of chemicals that kill cells that divide
rapidly
Chemotherapy agents bind toDNA
Cell division is blocked
Leads to cell death and tumor shrinkage
Most cells in the body do not divide frequently
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Therapeutic Window:• Medicine dosages that are both safe and effective
Dose
Benefit
100 500
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Therapeutic Window:
Dose
Benefit
100 200
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Chemotherapy causes side effects
Inflammation of the digestive tract, nausea, diarrhea
http://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm
Fewer blood cells, suppressed immune system (bone marrow)
Hair loss
Chemotherapy has a small therapeutic window
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Why are the bone marrow, hair, and digestive tract
affected?• Chemotherapy attacks ANY fast-
dividing cells, including but not limited to cancer cells
Blood cells in bone marrow
Hair follicle Intestinal cells
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How effective is chemotherapy?
• The 5 year survival rate for all cancers is 63%
• 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 attributed to chemotherapy
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Each type of cancer responds very differently to chemotherapy
Adapted from Morgan, G., et al. Clinical Oncology (2004) 16: 549-560
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Radiation therapy damages DNA
Cell death, tumor shrinkage
http://www.cancer.gov/cancertopics/factsheet/Therapy/radiation
Radiation is targeted to a specific body part DNA
Damage
Cancer cells are bad at repairing DNA
Normal cells can also be affected
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Radiation Therapy causes side effects
http://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm
Radiation therapy has a small therapeutic window
Skin irritation, scar tissue
Fatigue, memory loss
Chronic bowel effects
Very rare secondary tumors
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http://www.gpnotebook.co.uk/simplepage.cfm?ID=2060451853
Different cancers respond very differently to radiation therapy
Responsive Cancers Resistant Cancers
Lymphoma Melanoma
Medulloblastoma Glioma
Neuroblastoma Large bowel cancer
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Summary: Current Cancer Therapies
• Chemotherapy attacks cells that divide rapidly such as cancer cells but other tissues too
• Radiation therapy damages DNA in cancer cells such that it cannot be repaired
• Both chemotherapy and radiation therapy have small therapeutic windows
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General and Specific Features of Cancer Cells
DNA mutation
AGCGTATGTGTCAC
AGCGTATCTGTCAC
Uncontrolled cell division and DNA replication
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There are many diverse types of cancer
• Depending on mutation, different signaling pathways are affected
Signaling Pathway A
Signaling Pathway B
Signaling Pathway C
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“Targeted therapies” are medicines that interfere with specific mutated proteins necessary for tumor growth
AGCGTATGTGTCACNormal sequence
AGCGTATCTGTCACMutated sequence
Functional protein
Oncogenic protein
Targeted Therapy
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AGCGTATGTGTCACNormal sequence
AGCGTATCTGTCACMutated sequence
Functional protein
Oncogenic protein blocked
“Targeted therapies” are medicines that interfere with specific mutated proteins necessary for tumor growth
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Targeted therapies only work for patients with the correct
mutation
Targeted Therapy A
• Patients must be tested for the targeted mutation before treatment
Targeted Therapy B
Targeted Therapy C
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Targeted Therapies have fewer side effects
Targeted therapies specifically target cancer cells which have the mutations and not normal cells and have a wider therapeutic window
Joint pain, fatigue, skin lesions, for PLX4032
“minimal” side effects: nausea, muscle pain, diarrhea with Gleevec
http://www.nejm.org/doi/pdf/10.1056/NEJMoa1002011 http://www.nejm.org/doi/pdf/10.1056/NEJM200104053441401
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http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted
Uncontrolled cell division
Oncogenic BCR-ABLTurns on cell division proteins in signaling pathway
Chronic myelogenous leukemia (CML) is a cancer of white blood
cells
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Chronic myelogenous leukemia is a cancer of white blood cells
Druker, et al. NEJM (2006) 355:2408-2417, http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted
Oncogenic BCR-ABLSignaling pathways blocked
•CML currently 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/imatinib
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BRAF inhibitors for melanoma
• Melanoma, a type of skin cancer, is resistant to chemotherapy and radiation
• 68,000 new cases and 8,700 deaths/year in U.S.
• 40-60% of melanomas have a driver oncogene called BRAF
http://www.nlm.nih.gov/medlineplus/news/fullstory_109152.html, http://www.nejm.org/doi/full/10.1056/NEJMoa1002011
B-Raf
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BRAF inhibitors for melanoma
• Melanoma, a type of skin cancer, is resistant to chemotherapy and radiation
• 68,000 new cases and 8,700 deaths/year in U.S.
• 40-60% of melanomas have a driver oncogene called BRAF
http://www.nlm.nih.gov/medlineplus/news/fullstory_109152.html, http://www.nejm.org/doi/full/10.1056/NEJMoa1002011
Over-activate signaling pathways for cell division
B-Raf
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PLX4032/vemurafenib inhibits oncogenic BRAF
B-Raf
PLX4032
Oncogenic B-Raf
Prevention of overactive cell division
Tumors shrink
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Examples of PLX4032 effectiveness during
clinical trials
Bollag, et al. Nature (2010) 467: 596-599.
Before
Before
After After
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PLX4032 randomized clinical trial
Chapman, et al. NEJM 2011
336 patients with BRAF oncogene on PLX4032
336 patients with BRAF oncogene on chemotherapy
6 months
63% less risk of death
Chemotherapy group given opportunity to try PLX4032
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Summary: Cancer Therapies• Chemotherapy and radiation therapy attack general
features of cancer cells
– effective treatment for many, but not all types of cancer, and lead to side effects due to small therapeutic window
• Targeted therapies attack specific features (mutations) of cancer cells
– Cancers with those mutations respond very well with fewer side effects
• Understanding the genetics of cancer is important for developing therapies