Manchester Cancer Research Centre - Creating a world leader in the fight against cancer 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

Hallmarks of Cancer Hanahan and Weinberg 2000, Cell, 100, 57-70

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)

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?

Mechanisms underlying response to radiotherapy Repair Repopulation Redistribution Reoxygenation Radiosensitivity

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,

Protection of normal tissues Modification of oxygen/haemoglobin association Activation / Inhibition of p53 Stem cell transplantation

Protection of normal tissues Modification of oxygen/haemoglobin association Activation / Inhibition of p53 Stem cell transplantation

Changing 2,3 DPG levels in haemoglobin alters p50 Siemann and Macler (1986) Int. J. Radiat. Oncol. Biol. Phys

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 min after the infusion of BW12C Partial Pressure of Oxygen (mm Hg)

Time-related changes of the P 50, obtained from oxygen dissociation curves, after the infusion of 100mg/kg of BW12C.

Protective effect of 50mg/kg BW12C on epidermal skin reaction in pigs treated with Strontium-90 plaques

Dose dependent reduction in P 50 in blood from pigs treated 30 mins previously with BW12C

Protective effect of 70mg/kg BW12C on acute radiation- mortality of CBA/H mice irradiated with single doses of 250kV X rays.

Effect of BW589C on Hb function in mice 8 hrs 24hrs 46 hrs control

Effect of BW589C on Hb function in C57 mice

Protection of normal tissues Modification of oxygen/haemoglobin association Activation / Inhibition of p53 Stem cell transplantation

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,

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, ) – Ex-Rad protects against radiation damage (Ghosh SP et al (2009) Rad. Res. 171, )

Effect of pifithrin on radiation induced lethality in mice Strom et al (2006) Nature Chem.Biol. 2,

Radiation protection by Ex- Rad

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)

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)

Protection of normal tissues Modification of oxygen/haemoglobin association Activation / Inhibition of p53 Stem cell transplantation

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,

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

Pre-clinical evaluation : Novel drugs/novel targets In vitro studies : - Dose response curves - Scheduling - Radiosensitization, Additivity, Synergy

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

Pre-clinical evaluation : Novel drugs/novel targets In vivo studies : - Single radiation doses - Fractionated treatment - Scheduling - The end-point

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.

Drugs for combining with radiotherapy: Drug targets, the pipeline and evaluation What is the UK position?

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”

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

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