Targeting tumour angiogenesis with VEGF receptor tyrosine kinase inhibitors

1



Drugs for combining with radiotherapy Drug
targets, the pipeline and evaluation
Ian Stratford School of Pharmacy and
Pharmaceutical Science, Manchester Cancer
Research Centre University of Manchester
Manchester Cancer Research Centre - Creating a
world leader in the fight against cancer
2
Hallmarks of Cancer
Hanahan and Weinberg 2000, Cell, 100, 57-70
3
Drug targets and the drug pipeline

• Drug discovery programmes are NOT based on
  radiotherapy

• The prevailing culture is to demonstrate single
  agent activity

• Drug/Drug combinations

(Such combinations often fit conveniently into
standard Phase I models in end-stage disease
where treatment is palliative and toxicity
end-points are reached during the first one or
two 3-week cycles)
4
Considerations for combining radiation with
targeted chemotherapy

• Does radiation effect the expression and/or
  function of the drug target?
• Does the targeted chemotherapy effect any of
  those processes (the Rs) that can effect outcome
  of radiotherapy?

5
Mechanisms underlying response to radiotherapy

• Repair
• Repopulation
• Redistribution
• Reoxygenation
• Radiosensitivity

6
Exploitable Mechanisms when combining drugs with
radiation

• Cytotoxic enhancement
• Temporal modulation
• Biological cooperation
• Spacial cooperation
• Normal tissue protection

Bentzen, Harari and Bernier (2007) Nature
Clinical Practice Oncology, 4, 172-180
7
Protection of normal tissues

• Modification of oxygen/haemoglobin association
• Activation / Inhibition of p53
• Stem cell transplantation

8
Protection of normal tissues

• Modification of oxygen/haemoglobin association
• Activation / Inhibition of p53
• Stem cell transplantation

9
Changing 2,3 DPG levels in haemoglobin alters p50
Siemann and Macler (1986) Int. J. Radiat. Oncol.
Biol. Phys
10
Oxygen dissociation curves of peripheral blood
from pigs before and after the infusion of either
20 or 100 mg/kg of BW12C. Blood samples were
taken 35-40 min after the infusion of BW12C
Partial Pressure of Oxygen (mm Hg)
11
Time-related changes of the P50, obtained from
oxygen dissociation curves, after the infusion of
100mg/kg of BW12C.
12
Protective effect of 50mg/kg BW12C on epidermal
skin reaction in pigs treated with Strontium-90
plaques
13
Dose dependent reduction in P50 in blood from
pigs treated 30 mins previously with BW12C
14
Protective effect of 70mg/kg BW12C on acute
radiation-mortality of CBA/H mice irradiated with
single doses of 250kV X rays.
15
Effect of BW589C on Hb function in mice
8 hrs
24hrs
46 hrs
control
16
Effect of BW589C on Hb function in C57 mice
17
Protection of normal tissues

• Modification of oxygen/haemoglobin association
• Activation / Inhibition of p53
• Stem cell transplantation

18
Activation / Inhibition of p53

• In the hematopoietic system, radiation-induced
  death of both differentiating and stem cells
  strongly depends on p53, suggesting that p53
  suppression would decrease damage and promote
  faster recovery of hematopoiesis after
  anti-cancer therapy. However, p53 does not effect
  the recovery of radiosensitive epithelia since
  their stem cells, in contrast to differentiating
  cells, die in a p53-independent manner.

Komarova and Gudkov (1998) Semin.Cancer Biol. 8,
389-400
19
Activation / Inhibition of p53

• Bone marrow toxicity
• Pharmacological intervention with pifithrin-?
  protects mice from doses of radiation that cause
  lethal heamatopoietic syndrome (Strom et al 2006
  Nature Chem. Biol, 2, 474-479)
• Ex-Rad protects against radiation damage (Ghosh
  SP et al (2009) Rad. Res. 171, 173-179)

20
Effect of pifithrin on radiation induced
lethality in mice
Strom et al (2006) Nature Chem.Biol. 2, 474-479
21
Radiation protection by Ex-Rad
22
Activation / Inhibition of p53

• Bone marrow toxicity
• Short term knock-down of p53 (using tet-regulated
  shRNA) protects heamopoietic cells from radiation
  damage (Lee and Kirsch unpublished)

23
Activation/Inhibition of p53

• GI toxicity
• Selective deletion of p53 from the gut epithelium
  but not the endothelial cells sensitized mice to
  GI damage.
• Whereas over expression of p53 in all tissues
  protected mice against radiation-induced GI
  toxicity
• (Kirsch DG (2009) Science, published online
  December 17)

24
Protection of normal tissues

• Modification of oxygen/haemoglobin association
• Activation / Inhibition of p53
• Stem cell transplantation

25
Protection of normal tissues

• Thiols
• Antioxidant enzymes and mimetics
• Antioxidant nutrients
• Phytochemicals
• Physiological and receptor-mediated protectors.

Weiss and Landauer (2009) Int.J.Radiat.Biol. 85,
539-573
26
Pre-clinical evaluation Novel drugs/novel
targets

• In vitro studies

- Does over-expression of target effect
radiosensitivity? - Does genetic knock-out effect
radiosensitivity?

• conditional (e.g. tet-inducible) knock-out
• clonogenic assay

- Sensitivity in hypoxia
- Sub-lethal damage repair
- Potentially lethal damage repair
27
Pre-clinical evaluation Novel drugs/novel
targets

• In vitro studies
• - Dose response curves
• - Scheduling
• - Radiosensitization, Additivity, Synergy

28
Pre-clinical evaluation Novel drugs/novel
targets

• In vivo studies
• - The model(s) ?
• - Xenografts (sc, im, orthotopic)
• - Syngeneic tumours
• - Genetically engineered mouse models
• - Genetic background of the
  model

29
Pre-clinical evaluation Novel drugs/novel
targets

• In vivo studies
• - Single radiation doses
• - Fractionated treatment
• - Scheduling
• - The end-point

30
Combining radiation with targeted drugs

• The number of possible targets and the
  availability of more than one drug for each
  target dictates the need for consensus guidelines
  that can be used to aid target selection and
  prioritisation, preliminary in vitro and in vivo
  testing and subsequent early phase clinical
  trials.

31
Drugs for combining with radiotherapy Drug
targets, the pipeline and evaluation
What is the UK position?
32
NCRI Review 2008

• Establish a new multi-workstream group to drive
  area Clinical and Translational Radiotherapy
  Research Working Group (CTRRWG)
• CTRRWG Executive Chair (Tim Maughan), Deputy
  (Tim Illidge), Director ROB (Gillies McKenna),
  workstream co-chairs.
• 4 work streams each led by 2 co-chairs
• 1. Science base
• 2. Phase I / II trials
• 3. Phase III trials
• 4. New technology, physics and QA

• Aim To achieve changes in clinical practice

33
Workstream 1 Science base

• Overall aims
• Progress new targeted drugs into clinical
  evaluation in combination with radiotherapy.
• Identify those patients most likely to respond to
  treatment with radiotherapy ? chemotherapy ?
  targeted drugs.
• Be able to monitor response to therapy during and
  after treatment.
• Co-Chairs Ian Stratford, Thomas Brunner

34
Workstream 2 Phase I/II trials

• Overall aim
• Develop a series of innovative phase I and II
  trials integrating current and novel systemic (or
  locoregional) therapies with either palliative or
  radical radiotherapy, supported with novel
  imaging and biomarker studies.
• Co-Chairs Kevin Harrington, Ruth Plummer

35
(No Transcript)