Developments in radiobiology. Talk outline. Talk outline. Developments in radiobiology and clinical application

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Mayneord-Phillips Summer School 009 Oxford Developments in radiobiology and clinical application Catharine West The

uk Developments in radiobiology Developments in biology are increasing our understanding of the complex molecular pathways

years Radiobiology is exploiting these developments to find novel molecular targets for successful chemoradiotherapy

our as an example of a novel target The concepts of redundancy and synthetic lethality and The rationale behind and the

redundancy and synthetic lethality and Therapeutic ratio & rationale behind chemoradiotherapy 00% Molecularly targeted

is to improve the therapeutic ratio There is increasing use of concomitant chemotherapy with radiotherapy Normal tissue

1 Mayneord-Phillips Summer School 009 Oxford Developments in radiobiology and clinical application Catharine West The University of Manchester Christie Hospital Developments in radiobiology Developments in biology are increasing our understanding of the complex molecular pathways that control cellular processes Our understanding of radiation effects on cells has changed considerably over the past 0 years Radiobiology is exploiting these developments to find novel molecular targets for successful chemoradiotherapy approaches July 7 th 009 The rationale behind and the increasing use of The importance of cell signalling and changes in our as an example of a novel target The concepts of redundancy and synthetic lethality and The rationale behind and the increasing use of The importance of cell signalling and changes in our as an example of a novel target The concepts of redundancy and synthetic lethality and Therapeutic ratio & rationale behind chemoradiotherapy 00% Molecularly targeted chemotherapy to improve therapeutic ratio Probability 50% Tumour control TCP The rationale behind combined modality therapy is to improve the therapeutic ratio There is increasing use of concomitant chemotherapy with radiotherapy Normal tissue damage NTCP Randomised trials provide evidence of improvements in local control and survival Radiation dose (Gy) Developments in radiobiology are highlighting molecular targets for novel chemoradiotherapy approaches

Biological basis for Meta-analysis of head & neck cancer trials involving

or adjuvantly Used concurrently: Advantage: neither modality is delayed

radiotherapy targets local and chemotherapy distant disease Additive independent

normal cells (or protection of normal vs tumour cells) Michiels et al 009;

rationale behind and the increasing use of The importance of cell signalling and

synthetic lethality and Looking at cells in detail.

2 Biological basis for Meta-analysis of head & neck cancer trials involving concurrent chemotherapy Chemotherapy may be given neo-adjuvantly, concurrently or adjuvantly Used concurrently: Advantage: neither modality is delayed Disadvantage: risk of increased toxicity Biological basis Spatial co-operation: radiotherapy targets local and chemotherapy distant disease Additive independent cell kill with no overlapping toxicity Preferential sensitisation of tumour vs normal cells (or protection of normal vs tumour cells) Michiels et al 009; Lancet Oncol 0:34-50 We sometimes have a one dimensional view of a cell The rationale behind and the increasing use of The importance of cell signalling and changes in our as an example of a novel target The concepts of redundancy and synthetic lethality and Looking at cells in detail...highlights increasing complexity Aberrant cell signalling processes result in increased survival, proliferation and migration of cancer cells

$A network level view of signalling is emerging Changes in our understanding of how radiation interacts with cells Surviving fraction 0.$ paradigms: non-targeted effects occur extranuclear and extracellular effects are also involved S = e-αd-βd 0.0 0 4 6 8 0 Dose (Gy) Non-targeted effects Are low doses harmful?

paradigms: non-targeted effects occur extranuclear and extracellular effects are also involved S = e-αd-βd 0.0 0 4 6 8 0 Dose (Gy) Non-targeted effects Are low doses harmful?

3 A network level view of signalling is emerging Changes in our understanding of how radiation interacts with cells Surviving fraction 0. Old paradigm: DNA is the critical macromolecule in a cell; radiation interacts with DNA leading to multiple types of damage but it is unrepaired DNA double strand breaks that cause lethality New paradigms: non-targeted effects occur extranuclear and extracellular effects are also involved S = e-αd-βd Dose (Gy) Non-targeted effects Are low doses harmful? Inducible/adaptive responses A response to irradiation that is modified by a small dose of radiation given shortly before Gene activation following low doses of radiation Genes involved in proliferation, repair and cell kill Genomic instability Cells that survive radiation exposure have a persistently raised level of chromosomal aberrations Radiation can lead to long-lasting sub-lethal effects Bystander effects There is evidence that cell signalling processes are involved Each summer, hundreds of people come to the radon health mines to relax and soak up the therapeutic aura, swearing by the healing effects of the radon gases. epidermal growth factor receptor Radiation effects can be seen on adjacent unirradiated cells Nearly 0 people line the benches of the Merry Widow radon mine near Basin, Mont., June 0, 004, for a midday treatment. The rationale behind and the increasing use of The importance of cell signalling and changes in our Transmitting extracellular information is crucial for cell growth, movement and survival Extracellular dom ain as an example of a novel target Plasm a m em brane The concepts of redundancy and synthetic lethality and Intracellular dom ain Growth factor binding to cell surface receptors stimulates signalling networks / erbb- / Her is part of a receptor tyrosine kinase family, known as, erbb or Her is crucial for normal tissue development and homeostasis, null mice survive only a few days binding Tyrosine kinase activity 3

The (ErbB/Her) family and ligands EGF TGFα Amphiregulin, β-cellulin HB-EGF Epiregulin Heregulins NRG NRG3 Heregulins β-cellulin signal transduction Signal transduction

C-terminus HER erbb G FOS JUN Gene activation M S G cyclin D Cell cycle progression MAPK MEK RAF RAS GRB- SOS Activated receptor initiates a cascade of

Cell proliferation Input layer Hidden layers Output layer LPA, thrombin ET, etc.

PI3K Akt Bad S6K Shp β-cellulin () GAP HB-EGF (,4) Ras-GDP Ras-GTP Amphiregulin () RAF MEK MAPK Sos Grb NRG (3,4) α 4 4 3 Shc β PAK JNKK JNK NRG (4) Nck Jun Sp Myc Fos

enzymes Cascades Transcription factors Most cells have 0,000-00,000 s; on tumour cells the number can rise to several million Tumour expression is associated with a

4 The (ErbB/Her) family and ligands EGF TGFα Amphiregulin, β-cellulin HB-EGF Epiregulin Heregulins NRG NRG3 Heregulins β-cellulin signal transduction Signal transduction Tyrosine kinase domain Erb B- Her West et al 008 Br J Radiol 8: S36-S ErbB- Her neu ErbB-3 Her ErbB-4 Her4 Cysteine-rich domains C-terminus HER erbb G FOS JUN Gene activation M S G cyclin D Cell cycle progression MAPK MEK RAF RAS GRB- SOS Activated receptor initiates a cascade of phosphorylations Dedifferentiation Angiogenesis Cell migration and invasion activation Signalling cascade Gene activation Survival/protection from apoptosis G M S G Cell proliferation Input layer Hidden layers Output layer LPA, thrombin ET, etc. Src The HER signaling network TGFα () 3 Cbl EGF () PLCγ PKC Epiregulin (,4) Yarden and Sliwkowski Nat Rev Mol Cell Biol 00; : PI3K Akt Bad S6K Shp β-cellulin () GAP HB-EGF (,4) Ras-GDP Ras-GTP Amphiregulin () RAF MEK MAPK Sos Grb NRG (3,4) α Shc β PAK JNKK JNK NRG (4) Nck Jun Sp Myc Fos Elk Egr Stat β NRG3 (4) Vav Rac Abl NRG4 (4) Grb7 Cytokines Apoptosis Migration Growth Adhesion Differentiation α Crk s Receptor dimers Jak Adaptors and enzymes Cascades Transcription factors Most cells have 0,000-00,000 s; on tumour cells the number can rise to several million Tumour expression is associated with a poor outcome following radiotherapy NSCLC 40 80% Prostate 40 80% Gastric 33 74% Breast 4 9% Colorectal 5 77% Pancreatic 30 95% Ovarian 35 70% Head & neck 95 00% Renal Cell 50 90% Oesophageal 43 89% Cervix 80 90% Disease-free survival Low 49/0 0.4 High 0/5 0. p = Time (months) 4

In the CHART head & neck cancer trial, high tumour expression was associated with a benefit from accelerated radiotherapy and accelerated radiotherapy In the DAHANCA 6 and 7 trials, head and neck

5 In the CHART head & neck cancer trial, high tumour expression was associated with a benefit from accelerated radiotherapy and accelerated radiotherapy In the DAHANCA 6 and 7 trials, head and neck cancer patients with positive tumours responded better to moderately accelerated radiotherapy than those with low Eriksen et al 005; Radiother Oncol 74: antagonists are cytostatic and lead to G arrest, which could prevent accelerated repopulation Radiopotentiating effect of the anti- drug ZD839 was greater with fractionated than single dose irradiation suggesting it exerts an anti-proliferative effect and prevents accelerated repopulation Williams et al 00; Br J Cancer 86: 57-6 Bentzen, S. M. et al. J Clin Oncol; 3: Copyright American Society of Clinical Oncology Inverse relationship between expression and radiocurability Anti- strategies MAbs s Toxin conjugates Antisense K K K K K K K K The higher the value the more dose required to cure experimental tumours Akimoto, T. et al. Clin Cancer Res 999;5: MAbs= Signal monoclonal antibodies; Signal s=tyrosine kinase Cell inhibitors transduction transduction death Protein synthesis Copyright 999 American Association for Cancer Research Studies in experimental tumours show that anti- strategies enhance tumour response to radiation Post irradiation nuclear location of DNA 4 Gy 4 Gy Radiation stimulates signalling Anti- blocks import into the nucleus, radiation-induced activation of DNA-PK and DNA repair, and increases radiosensitivity Milas, L. et al. Clin Cancer Res 000;6: Copyright 000 American Association for Cancer Research Dittmann et al 005 J Biol Chem 80: 38 5

6 The anti- monoclonal antibody cetuximab (Erbitux, C5) improves locoregional control and overall survival in head & neck cancer patients Bonner et al 006 N Engl J Med : Gr 3-5 adverse event XRT XRT + cetux. P Acneiform rash % 7% <0.00 Infusion reaction 0% 3% 0.00 Anaemia 6% % Bonner et al 006 N Engl J Med : Signalling pathways are emerging as layered networks sharing structural and functional features with engineered information-processing systems The rationale behind and the increasing use of The importance of cell signalling and changes in our as an example of a novel target The concepts of redundancy and synthetic lethality and The rapidly expanding number of novel drugs targeting receptor tyrosine kinases Systems biology is a developing field Interaction maps are developing Molecular target Features of systems are modularity, buffering and functional redundancy, which aim to increase robustness Given the inherent complexity of and cross-talk between signalling pathways, there is considerable redundancy. This redundancy is an important part of tumour heterogeneity. Drug Description Cancer Approval status Cetuximab (Erbitux) Chimeric mab CRC, H&N Approved (004) Panitumumab (ABX-EGF) Human mab CRC Approved (006) Matuzumab (EMD 7000) Lung Gefitinib (Iressa) NSCLC Approved (005) Erlotinib (Tarceva) NSCLC, pancreas Approved (004) and HER Lapatinib (Tykerb) Breast Approved (007) HER Trastuzumab (Herceptin) Breast Approved (998) Pan-HER/ERBB The goal is to exploit knowledge of cell signalling pathways as system for novel drug to identify inhibitors of nodal proteins, HER, V The goal is also to identify biomarkers of response so that treatment is targeted towards tumours likely to respond Pertuzumab (Omnitarg) MDX0 Bispecific antibody Ovarian I CI-033 NSCLC AEE-788 Ovarian, breast Glioblastoma Phase I VEGFA Bevacizumab (Avastin) CRC, NSCLC Approved (004) V CDP79 Human F(ab) Lung V-3, KIT, RET, PDGFRα Sunitinib (Sutent) Renal, GIST Approved (006) V, KIT, PDGFRβ Sorafenib (Nexavar) Renal Approved (005) HGFR XL880 Solid tumors Phase I KIT, PDGFR, (ABL) Imatinib (Gleevec) GIST Approved (006) Amit et al 007 Mol Syst Biol 3:5. 6

Synthetic lethality Systems biology argues that evolvable systems are robust against common perturbations (single-agent therapy) but fragile to simultaneous perturbations (combination therapy) a rare

Synthetic lethality: two gene are synthetically lethal if a mutation in either is not lethal but mutations in both are Eg, there is evidence that the anti- monoclonal antibody cetuximab is more

synthesis and DNA repair New molecularly targeted drugs are emerging that inhibit signalling pathways crucial for cell growth Signalling pathways are being studied in the context of systems biology;

7 Synthetic lethality Systems biology argues that evolvable systems are robust against common perturbations (single-agent therapy) but fragile to simultaneous perturbations (combination therapy) a rare event for evolution-trained networks. Fragility derives from reliance on hubs. Synthetic lethality: two gene are synthetically lethal if a mutation in either is not lethal but mutations in both are Eg, there is evidence that the anti- monoclonal antibody cetuximab is more effective towards tumours with wildtype KRAS This is increasing personalised medicine Summary Use of concurrent chemoradiotheray is expanding Most traditional cancer drugs target mitosis, DNA synthesis and DNA repair New molecularly targeted drugs are emerging that inhibit signalling pathways crucial for cell growth Signalling pathways are being studied in the context of systems biology; they are emerging as important mediators in cellular responses to radiation There has been a rapid increase in the number of new agents being investigated with radiotherapy in early phase trials The challenge is to find which drug is appropriate for which tumour/patient involves parallel biomarker and drug Implications for radiotherapy The revigator Combined modality treatments will increase Treatment heterogeneity (personalisation) will increase In principle it is possible to use data from randomised trials to calculate the contribution of chemotherapy to overall tumour cell kill. The chemotherapy dose could be expressed in terms of the equivalent biologically effective dose (BED) of radiation. "More illness is caused by improper water than any other reason and largely because radioactivity is lost from our daily supply of drinking water." Moving towards construction of a complex tumour therapy computer programme? Jones & Hopkins 007; In: radiobiological Modelling in Radiation Oncolog; Eds: R Dale & B Jones 7

EGFR: fundamenteel en klinisch

EGFR: fundamenteel en klinisch Guido Lammering MAASTRO Clinic Maastricht, NL What is EGFR?? The EGFR some facts 1186 amino acids 170 kda Expressed by all cells of epithelial origin Increased activation