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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 DNA Cell division Ac?vely dividing cell Chemotherapy: chemicals that kill fast-­‐
dividing cells Chemotherapy agents cover DNA cell death and tumor shrinkage Cell division is blocked Most cells in the body do not divide frequently Therapeu?c Window: Benefit •  Medicine dosages that are both safe and effec?ve Increasing Dose Smaller Therapeu?c Window: effec?ve dose is close to toxic dose Nausea Benefit Drowsiness Blood clots Increasing Dose Chemotherapy causes side effects Hair loss Fewer blood cells, suppressed immune system (bone marrow) hBp://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm Chemotherapy has a small therapeu?c window Inflamma?on of the diges?ve tract, nausea, diarrhea Why are the bone marrow, hair, and diges?ve tract affected? Blood cells in bone marrow Hair follicle Intes?nal cells •  Chemotherapy aBacks ANY fast-­‐dividing cells How effec?ve 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% 63% -­‐ 61% = 2% of survival rate can be aBributed to chemotherapy Morgan, G., et al. Clinical Oncology (2004) 16: 549-­‐560 Each type of cancer responds differently to chemotherapy Increase in 5-­‐yr survivors a;er chemo 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Adapted from Morgan, G., et al. Clinical Oncology (2004) 16: 549-­‐560 Radia?on therapy damages DNA Radia?on is targeted to a specific body part DNA Damage Cancer cells are bad at repairing DNA Cell death, tumor shrinkage Normal cells can also be affected hBp://www.cancer.gov/cancertopics/factsheet/Therapy/radia?on Radia?on Therapy causes side effects Fa?gue, memory loss Skin irrita?on, scar ?ssue hBp://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm Radia?on therapy has a small therapeu?c window Very rare secondary tumors Chronic bowel effects Different cancers respond very differently to radia?on therapy Responsive Cancers Resistant Cancers Lymphoma Melanoma Medulloblastoma Glioma Neuroblastoma Large bowel cancer hBp://www.gpnotebook.co.uk/simplepage.cfm?ID=2060451853 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 Targeted Therapy Normal protein Oncogenic protein Targeted therapies aBack specific mutated proteins Targeted Therapy Normal protein 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 Joint pain, fa?gue, skin lesions Targeted therapies have a wider therapeu?c window nausea, muscle pain, diarrhea hBp://www.nejm.org/doi/pdf/10.1056/NEJMoa1002011 hBp://www.nejm.org/doi/pdf/10.1056/NEJM200104053441401 Chronic myelogenous leukemia (CML) is a cancer of white blood cells •  In 95% of CML cases, the oncogene is BCR-­‐ABL, which increase cell division Oncogenic BCR-­‐ABL Turns on cell division proteins in signaling pathway hBp://www.cancer.gov/cancertopics/factsheet/Therapy/targeted Uncontrolled cell division Gleevec/Ima?nib blocks the responsible oncogene Gleevec/ima?nib Oncogenic BCR-­‐ABL Signaling pathways blocked Uncontrolled cell division is stabilized • CML has 89% 5-­‐year survival rate compared to 23% in 1975 • Gleevec can be used for other cancers that have BCR-­‐ABL Druker, et al. NEJM (2006) 355:2408-­‐2417, hBp://www.cancer.gov/cancertopics/factsheet/Therapy/targeted B-­‐raf oncogene in melanoma •  Melanoma is resistant to chemotherapy and radia?on •  40-­‐60% of melanomas have a oncogene called B-­‐raf Cancer Cell Growth signal Ras B-­‐raf Mek Abnormal cell growth and division B-­‐raf oncogene in melanoma B-­‐raf Over-­‐ac?vate signaling pathways for cell division Tumor forma?on hBp://www.nlm.nih.gov/medlineplus/news/fullstory_109152.html, hBp://www.nejm.org/doi/full/10.1056/NEJMoa1002011 PLX4032 inhibits oncogenic B-­‐raf PLX4032 Tumors shrink B-­‐raf Oncogenic B-­‐Raf Prevent overac?ve cell division PLX4032 effec?veness during clinical trials Before Bollag, et al. Nature (2010) 467: 596-­‐599. Aner PLX4032 clinical trial Half of pa?ents given PLX4032 63% less risk of death 6 months Half of pa?ents given chemotherapy Chemotherapy group given opportunity to try PLX4032 •  How effec?ve is PLX4032 long-­‐term? Chapman, et al. NEJM 2011 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