basis of medical cancer therapy rebecca roylance senior lecturer in medical oncology
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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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Classes of Drug
• Alkylating agents• Platinum compounds• Anthracyclines• Antimicrotubule agents• Antimetabolites• Topoisomerase II inhibitors
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SMETHOTREXATE
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 alkaloidsprevent microtubuleassembly
Taxanes prevent microtubule disassembly
Mitotic block
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Dihydrofolatereductase
Dihydrofolate(FH2)
Tetrahydrofolate(FH4)
Thymidinemonophosphate
Deoxyuridinemonophosphate
METHOTREXATEBlocks here
Folinic acidBypasses 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
Target Drug UseVEFR Bevacizumab colorectalEGFR Cetuximab colorectalCD20 Retuximab B cell NHLCD52 Alemtuzumab CLL
HER2 Pertuzumab clinical trials
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Small molecule therapy
Receptor Drug Use
KIT Imatinib (Gleevec) GIST
EGFR Erlotinib (Tarceva) NSCLC
Gefitinib (Iressa) NSCLC
HER1,2 Lapatinib Breast
RTK Sunitinib (Sutent) RCC
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Imatinib (Gleevec)
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GIST
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Pre Post
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Can understanding the basic biology of cancerimprove 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