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Basis of Medical Cancer Therapy Rebecca Roylance Senior Lecturer in Medical Oncology
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Background Chemotherapy Radiotherapy Endocrine Therapy Biological Therapy
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‘Ideal’ Cancer Treatment Highly efficacious Highly tumour specific Minimal toxicity
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Chemotherapy Efficacious 90% cure occurs in only 10% of cancers Completely non-specific Marked toxicity
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Historical Background 1940s alkylating agents were identified as by- product of secret gas production marrow & lymphoid hypoplasia Used leukaemia/lymphomas - pub 1946 Folic acid lead to proliferation of leukaemic cells antifolates e.g. methotrexate
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Mechanism Principle of treatment - tumour growth fraction –Malignant cells do not divide more quickly than normal cells –Bigger population of cells dividing
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10 12 10 10 8 10 6 10 4 10 2 Time Number of cells surviving M T Fractional Cell Kill Hypothesis CCCCC
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Classes of Drug Alkylating agents Platinum compounds Anthracyclines Antimicrotubule agents Antimetabolites Topoisomerase II inhibitors
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G0G0 M G2G2 G1G1 S METHOTREXATE HYDOXYUREA CYTOSINE ARABINOSIDE ANTHRACYCLINES VINCA ALKALOIDS TAXANES PHASE NON-SPECIFIC Alkylating agents Cisplatin Nitrosoureas Antibiotics
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Alkylating agents e.g. Cyclophosphamide Covalently link to structures in nuclei acids inter- or intra-DNA strand cross-linking impairs DNA replication More lethal if occurs during S-phase
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Platinum Drugs e.g. Cisplatin, carboplatin, oxaliplatin Platinum drugs bind to DNA intra-strand cross-linking predominantly Conformational change in DNA - making repair of the damage difficult
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Anthracyclines e.g. Doxorubicin, epirubicin, mitoxantrone Bind tightly to DNA and deform its structure Intercalate DNA causing single-stranded and double stranded breaks Produce intracellular free radicals - contribute to toxicity
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Metaphase Anaphase Vinca alkaloids prevent microtubule assembly Taxanes prevent microtubule disassembly Mitotic block
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Dihydrofolate reductase Dihydrofolate (FH 2 ) Tetrahydrofolate (FH 4 ) Thymidine monophosphate Deoxyuridine monophosphate METHOTREXATE Blocks here Folinic acid Bypasses block
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Combination Chemotherapy Only use if effective alone Non-overlapping toxicity Each drug used at optimal dose and schedule Synergistic action Different effects cell cycle
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Uses of chemotherapy Cure –Induction –Adjuvant –Primary (neoadjuvant) Palliation
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Neoadjuvant chemotherapy Taken from Biology of Cancer
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Clinical Trials Phase I - determine optimal dosage Phase II - assess tumour response Phase III - large randomised studies assess improvement in survival
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Endocrine therapy Efficacious –Breast –Prostate Fairly specific Minimal toxicity
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Historical Background 1896 case report of oophorectomy in breast cancer by Beatson Postulated a link between ovaries and proliferation of breast cells 33 yr old women lump L breast 12cm at presentation - breast removed but cancer advanced oophorectomy pt survived for further 4 years
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Taken from BJC 2004 90(1) S2-6
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Tamoxifen 1969 development of tamoxifen as a contraceptive SERM - selective oestrogen receptor modulator 1973 licenced for use in breast cancer 1980s clinical trials demonstrated a benefit in overall survival
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Further Oestrogen modulation Aromatase inhibitors –Steroidal e.g. exemestane –Non-steroidal e.g. arimidex Anti-oestrogen e.g. fulvestant
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Mechanism of action of fulvestrant Taken from BJC 2004 90(1) S2-6
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Biological Therapy Efficacious –But less than expected, mechanisms not fully understood Specific Minimal toxicity cf trastuzumab (herceptin)
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Biological Therapy Monoclonal antibodies Small molecule inhibitors
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HER2/ERBB2 1987 - amplified and overexpressed in 25- 30% breast cancers Associated with poor prognosis No natural ligand Activation results in heterodimerisation Many downstream substrates
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FISH amplification of HER2
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HER2 IHC
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Trastuzumab (Herceptin®) Humanised monoclonal antibody to HER2 receptor Infusion related reaction - chills, fever, rash - rarely repeated Cardiac toxicity - especially if given in association with anthracyclines ?why - cross reactivity with cardiac muscle
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Clinical trials - metastatic 2001 Phase III clinical trial showed in combination with chemotherapy in metastatic setting: Improved response rate 50% vs 32% (p<0.001) Decreased one year mortality 22 vs 33% (p=0.008)
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Clinical trials - adjuvant 2006 - 4 trials >10000 women Interim analysis resulted in stopping trials early Decreased risk of relapse - 50% Survival advantage of 2.5% NEJM 2005 353 1659-72 & 1673-84
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Other targeted monoclonal antibody therapies TargetDrugUse VEFRBevacizumabcolorectal EGFRCetuximab colorectal CD20 RetuximabB cell NHL CD52AlemtuzumabCLL HER2 Pertuzumab clinical trials
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Small molecule therapy ReceptorDrugUse KITImatinib (Gleevec)GIST EGFRErlotinib (Tarceva)NSCLC Gefitinib (Iressa) NSCLC HER1,2LapatinibBreast RTKSunitinib (Sutent)RCC
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Imatinib (Gleevec)
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GIST Pre Post
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Can understanding the basic biology of cancer improve the treatment…..?
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Copyright ©2001 by the National Academy of Sciences Sorlie, Therese et al. (2001) Proc. Natl. Acad. Sci. USA 98, 10869-10874
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The future Understanding the genetic pathways of cancer development Treatment will be tailored to individual patients Aim of making it much more effective and less toxic
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