Website for lectures and course book:

http://www.homepages.ucl.ac.uk/~regobto/

Cure

Death

DNA repairLimitation of exposureAnti-carcinogens

Large tumour masses

Generation of tumour vasculature

Genetic instability

Immortalisation

Inheritance, Environment,Viruses, Age

Invasion

Loss of homeostasis

Loss of tumour suppressor gene functionGain of oncogene function

Metastasis

Multistep gene damage

Resistance to apoptosis

Single cancer cell

Treatment

Uncontrolled proliferation

Elements of Cancer

DNA repair, limitation of exposure, anti-carcinogens

Inheritance, Environment,Viruses, Age

Multistep gene damage

Single cancer cell

A Model of Cancer

DNA repair, limitation of exposure, anti-carcinogens

Immortalisation

Inheritance, Environment,Viruses, Age

Loss of tumour suppressor,gain of oncogene function

Multistep gene damage

Single cancer cell

Uncontrolled proliferation

A Model of Cancer

Resistance to apoptosis

Gen

etic

inst

abili

ty

Death

DNA repair, limitation of exposure, anti-carcinogens

Large tumour masses

Immortalisation

Inheritance, Environment,Viruses, Age

tumour vasculatureInvasion

Loss of homeostasis

Loss of tumour suppressor,gain of oncogene function

Metastasis

Multistep gene damage

Single cancer cell

Uncontrolled proliferation

A Model of Cancer

Resistance to apoptosis

Gen

etic

inst

abili

ty

Aberrant protein production

Paraneoplastic syndromes

Does this help to design therapy?

Cur

e an

d co

ntro

l

Death

DNA repair, limitation of exposure, anti-carcinogens

Large tumour masses

Immortalisation

Inheritance, Environment,Viruses, Age

tumour vasculatureInvasion

Loss of homeostasis

Loss of tumour suppressor,gain of oncogene function

Metastasis

Multistep gene damage

Single cancer cell

Tre

atm

ent

Uncontrolled proliferation

A Model of Cancer

Resistance to apoptosis

Gen

etic

inst

abili

ty

Pre

ven

tion

Aberrant protein production

Paraneoplastic syndromes

Proliferation

• Cytotoxic chemotherapy• Selective delivery of cytotoxic therapy

– antibodies delivering a toxin– antibody-targeted enzymes activating a prodrug

• Radiation– radioimmunotherapy

• Hormones• Cytokines• Signalling inhibiton

– Small molecules eg glivec, iressa– Antibodies eg herceptin

Resistance to apoptosis

Induction of apoptosis– Rituximab– Geldanamycin– Antisense to BCL2– Restoration of wild type p53 function

Aberrant protein expression

Antibody targeting to tumour protein

• Stimulation of natural effector mechanisms– antibody dependent cell mediated cytotoxicity

(ADCC) eg rituxumab, herceptin– complement activation eg rituximab

Developments in therapeutic antibodies

Murine monoclonal antibodyderived entirely from mice

Chimeric antibodymouse V-regions and human C-regions

Humanized antibody only antigen binding regions (CDRs) from mouse

Human antibodies from phage libraries

Human antibodies from micemade in mice which have human antibody genes

Imm

unog

enic

ity

But - human CDRs can be immunogenic

Vascular

• Vascular endothelial proliferation inhibitors– anti-VEGF neutralising antibody– thalidomide

• Vascular endothelial poisons– Combretastatin– DMXAA

Invasion

• Inhibitors of matrix metalloproteases

• Inhibitors of integrins

Metastasis

• Antibodies to chemokine receptors

Large tumour masses

• Surgery

• Radiation

• Laser

• Radiofrequency ablation

Paraneoplastic syndromes

• Cachexia

• Neurological syndromes

• Connective tissue syndromes

• Hormonal syndromes

Treat the cause + symptomatic measures

Loss of Homeostasis

• General medicine– Tissue– Organ– System

Colon cancer survival 1971-2001

1 year 5 year 1 year 5 year

’71-5 ’76-80 ’96-9 2001-5’81-5 ’86-90 ’91-5

males females

% s

urvi

val

Understanding cancer and its therapy

Patient

Treatment Tumour - target - delivery - therapeutic mechanism - effect of

therapy on germline & somatic events

New & improved: ●treatments ●diagnosis ●prognostics

Information Shared & Integrated

Clinical features Environment Psychosocial Germline - genetic variation - epigenetics - gene expression -proteins, - pathways, cells, - tissues, - whole person

Clinical features Somatic - genetic variation - epigenetics - gene

expression - proteins, - pathways,