Anticancer targets and drugs

Austin Duffy, Consultant Medical Oncologist, The Mater

Hospital
Associate Professor of Translational Oncology, UCD
What is cancer?
• Abnormal growth of cells
What is cancer?
• Abnormal growth of cells

Dysregulated
- Not responsive to extracellular
signals…
- insensitive to local environment..
- Typically driven by some
malwiring (stuck accelerator)
 Dysregulated growth

Cancer
Normal
cell
cell

Ordered, organized,
coordinated growth,
maturation Dysregulated growth tumour
 Dysregulated growth

Cancer
Normal
cell
cell

Anti-cancer
Treatment!
Ordered, organized,
coordinated growth,
maturation Dysregulated growth tumour
(The way I think of) anti-cancer treatment
• Specific (‘targeted’)

• Non-specific
• Chemotherapy
• Radiation
• Surgery

• Immune-based (tune in Monday..)

(The way I think of) anti-cancer treatment
• Specific (‘targeted’)

• Non-specific
• Chemotherapy
• Radiation
• Surgery

• Immune-based (tune in Monday..)

Non-specific anti-cancer treatment
 Categories of Chemotherapeutics
• Alkylating agents…..
• Antimetabolites……
• Platinums……
• Microtuble inhibitors…..
• Topoisomerase
inhibitors…
• Antibiotics…..

You don’t need to know this

(I don’t even need to know this..)
 Categories of Chemotherapeutics
Type of DNA damage

• Alkylating agents….. Cross-linking DNA strands

• Antimetabolites……
• Platinums……
• Microtuble inhibitors…..
• Topoisomerase
inhibitors…
• Antibiotics…..
RNA/DNA synthesis (false metabolites)
DNA adducts leading to strand breaks
Interfere with mitosis
Stop DNA replication, RNA transcription
Inhibits DNA synthesis

You don’t need to know this

(I don’t even need to know this..)
+
 (non specific) Efficacy
‘Anti-mitotic’

+ ‘Cell killing’
‘Tumor growth inhibition’
 (non specific) Efficacy
‘Anti-mitotic’

+ ‘Cell killing’
‘Tumor growth inhibition’

(non specific) Toxicity

Alopecia
neutropenia
 1960’s-70’s: Heyday of chemotherapy
- from fringe to cure
• “In the 1960s, medical oncology did not exist as a clinical specialty. Those who
were given the task of administering chemotherapy at most medical centers were
regarded as underachievers at best.”
Vincent DeVita ‘A History of Cancer Chemotherapy’
• Cures:
- ALL (1964)
- Hodgkin’s lymphoma (1965)
- Testicular cancer (1976)

• Adjuvant therapy  high dose adjuvant therapy with stem cell support
 1960’s-70’s: Heyday of chemotherapy
- from fringe to cure
• “In the 1960s, medical oncology did not exist as a clinical specialty. Those who
were given the task of administering chemotherapy at most medical centers were
regarded as underachievers at best.”
Vincent DeVita ‘A History of Cancer Chemotherapy’
• Cures:
- ALL (1964)
- Hodgkin’s lymphoma (1965)
- Testicular cancer (1976)

• Adjuvant therapy  high dose adjuvant therapy with stem cell support

Central Dogma: cure of cancer really just a question of getting the right combination
of chemotherapy drugs at high enough doses
Discovery of oncogenes
Anti-cancer treatment
• Specific (‘targeted’)

• Non-specific
• Chemotherapy
• Radiation
• Surgery

• Immune-based
Anti-cancer treatment
• Specific (‘targeted’)

• Non-specific
• Chemotherapy Identifying the
• Radiation
dominant driver of
• Surgery
the cancer cell and
inhibiting that
• Immune-based
Let’s take for example the ‘EGFR’ pathway…
Epidermal
Growth
Factor
Receptor
Receptor receiving signal
Epidermal
Growth
Factor
Receptor
Receptor receiving signal

…the nucleus (engine room)

where instructions to grow,
divide, metastasize etc are
acted on by gene expression
Epidermal
Growth
Factor
Receptor
Receptor receiving signal

Very complicated and

interconnected pathways
for transducing signal to…

…the nucleus (engine room)

where instructions to grow,
divide, metastasize etc are
acted on by gene expression
 Normal cell

EGFR

Ligand-dependent
firing

Signal to nucleus Signal to nucleus

 Normal cell

Some ways to describe how this

cell is going to behave with regard
EGFR to other cells…
Physiologic
Sensitive to environment
Responsive
Well-regulated
Ligand-dependent Conducive to good behaviour
firing
A good civic-minded nextdoor
neighbour and fine upstanding
member of community…
Signal to nucleus Signal to nucleus
 Normal cell Cancer cell

Activating
mutation
(stuck
accelerator)

Ligand-dependent firing Ligand-independent firing

(foot on accelerator) (no foot on accelerator, car still goes!)

Signal to nucleus Signal to nucleus

 Normal cell Cancer cell

Ligand-dependent Receptor overexpression

firing

Signal to nucleus Signal to nucleus


(inappropriate or excessive)
Signal to nucleus
Some ways to describe
how this cell behaves…
insensitive to environment
Non-responsive
dysregulated
Conducive to bad,
aggressive
behaviour
An unruly and disruptive
neighbour
eg Erlotinib
(small molecule,
tyrosine kinase inhibitor)

Signal to nucleus
Baseline 8 weeks post erlotinib
Small molecule,
(internal/intracellular)
tyrosine kinase inhibitor

Signal to nucleus
Small molecule, Blocking receptor by monoclonal antibody
(internal/intracellular)
tyrosine kinase inhibitor

Signal to nucleus Signal to nucleus

Small molecule, Blocking receptor by monoclonal antibody
(internal/intracellular)
tyrosine kinase inhibitor

Signal to nucleus Signal to nucleus

However….
(before you start to
think this is easy)
 Conclusions
• Simply put, anti-cancer treatments aim to stop cell division

• Specific or non-specific…(though this is admittedly a little arbitrary)

• I suppose by specific what I really mean is the following:

Understanding what is driving the cancer (ie The Science) can lead to rational drug development
(and the more specific that is the less toxicity should be)…

Thank you for your attention!