Transcript Bases of Medical Cancer Therapy

Basis of Medical Cancer Therapy
Rebecca Roylance
Senior Lecturer in Medical Oncology
Background
• Chemotherapy
• Radiotherapy
• Endocrine Therapy
• Biological Therapy
‘Ideal’ Cancer Treatment
• Highly efficacious
• Highly tumour specific
• Minimal toxicity
Chemotherapy
• Efficacious
90% cure occurs in only 10% of cancers
• Completely non-specific
• Marked toxicity
Historical Background
• 1940s alkylating agents were identified as byproduct of secret gas production
marrow & lymphoid hypoplasia
• Used leukaemia/lymphomas - pub 1946
• Folic acid lead to proliferation of leukaemic
cells
antifolates e.g. methotrexate
Mechanism
• Principle of treatment - tumour growth fraction
– Malignant cells do not divide more quickly
than normal cells
– Bigger population of cells dividing
Number of cells surviving
C
10
10
C
C
C
C
12
10
M
T
10
10
8
6
Fractional Cell Kill Hypothesis
10
10
4
2
Time
Classes of Drug
•
•
•
•
•
•
Alkylating agents
Platinum compounds
Anthracyclines
Antimicrotubule agents
Antimetabolites
Topoisomerase II inhibitors
PHASE NON-SPECIFIC
Alkylating agents
Cisplatin
Nitrosoureas
Antibiotics
VINCA
ALKALOIDS
TAXANES
M
G0
G2
G1
S
METHOTREXATE
HYDOXYUREA
CYTOSINE ARABINOSIDE
ANTHRACYCLINES
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
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
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
Mitotic block
Anaphase
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Metaphase
Vinca alkaloids
prevent microtubule
assembly
Taxanes prevent
microtubule
disassembly
Dihydrofolate
reductase
METHOTREXATE
Blocks here
Dihydrofolate
(FH2)
Tetrahydrofolate
(FH4)
Folinic acid
Bypasses block
Thymidine
monophosphate
Deoxyuridine
monophosphate
Combination Chemotherapy
•
•
•
•
•
Only use if effective alone
Non-overlapping toxicity
Each drug used at optimal dose and schedule
Synergistic action
Different effects cell cycle
Uses of chemotherapy
• Cure
– Induction
– Adjuvant
– Primary (neoadjuvant)
• Palliation
Neoadjuvant chemotherapy
Taken from Biology of Cancer
Clinical Trials
• Phase I - determine optimal dosage
• Phase II - assess tumour response
• Phase III - large randomised studies assess
improvement in survival
Endocrine therapy
• Efficacious
– Breast
– Prostate
• Fairly specific
• Minimal toxicity
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
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
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
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Taken from BJC 2004 90(1) S2-6
Biological Therapy
• Efficacious
– But less than expected, mechanisms not
fully understood
• Specific
• Minimal toxicity
• cf trastuzumab (herceptin)
Biological Therapy
• Monoclonal antibodies
• Small molecule inhibitors
HER2/ERBB2
• 1987 - amplified and overexpressed in 2530% breast cancers
• Associated with poor prognosis
• No natural ligand
• Activation results in heterodimerisation
• Many downstream substrates
FISH amplification
of HER2
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
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)
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
Other targeted monoclonal antibody
therapies
Target
VEFR
EGFR
CD20
CD52
Drug
Bevacizumab
Cetuximab
Retuximab
Alemtuzumab
Use
colorectal
colorectal
B cell NHL
CLL
HER2
Pertuzumab
clinical trials
Small molecule therapy
Receptor
KIT
EGFR
HER1,2
RTK
Drug
Imatinib (Gleevec)
Erlotinib (Tarceva)
Gefitinib (Iressa)
Lapatinib
Sunitinib (Sutent)
Use
GIST
NSCLC
NSCLC
Breast
RCC
Imatinib (Gleevec)
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GIST
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Pre
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Post
Can understanding the basic biology of cancer
improve the treatment…..?
Sorlie, Therese et al. (2001) Proc. Natl. Acad. Sci. USA 98, 10869-10874
Copyright ©2001 by the National Academy of Sciences
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