Effect of Tumour Biology on Therapeutic Response
Group Leader: Professor Barbara Pedley
The group develops, tests and optimises selective cancer treatments in vitro and in vivo, using novel antibody and vascular targeted therapies as either single or combined strategies (Fig 1). We have increasingly concentrated on the impact of the tumour microenvironment on therapy and vice versa, and a major part of our research concerns the development of systems for overcoming or exploiting tumour heterogeneity, in order to optimise future clinical trials. The most intensively studied tumour is colorectal carcinoma, but many of the other common tumours are also under investigation.
A detailed study of the tumour microenvironment has shown extensive regional heterogeneity in many parameters, including antigen expression, blood vessel distribution and perfusion, and hypoxia. These factors in turn influence the delivery and efficacy of therapeutic agents. We are using a wide range of biomarkers and digital, multiparametric imaging systems to define these characteristics in tumours and inform the rational design of therapy. Hypoxia is one of the major tumour parameters being investigated (Fig. 2), as this can increase radio- and chemo-resistance by approximately 3-fold compared to well oxygenated tumour regions.
Therapeutic strategies against tumour cells
Much of our pre-clinical research involves the use of antibodies to selectively target therapeutic agents, such as radioactivity, to tumour cells while protecting normal tissues. Antibody distribution is quantified over time in relation to tumour biology, using radio- or fluorescently-labeled antibodies (Fig 3). Regional tumour damage and repair following therapy is also studied using further functional biomarkers, eg. TUNEL, caspase 3, H2AX, angiogenesis, apoptosis etc.
Therapeutic strategies against vasculature
We are employing a range of techniques to study tumour vasculature (Fig 4). This is highly abnormal compared with the vasculature of normal tissues, but it provides a useful target for therapy. There are several advantages to targeting the tumour vasculature instead of the tumour cells themselves. These include ease of access for the therapeutic, reduced likelihood of developing resistance, applicability to all solid tumours, and the fact that killing 1 capillary will destroy many more dependent tumour cells. We are approaching this in two ways: targeting the vasculature with therapeutic antibodies (Fig 5), or using vascular disrupting agents (VDAs). These agents rapidly reduce blood flow within the tumour, leading to destruction of existing blood vessels within the tumour and large areas of necrosis (Fig. 6).
Most cancer treatment will require a combination of different therapeutic agents in order to overcome the problem of heterogeneity and destroy the whole tumour. Using our advanced microscopy systems we have shown that VDAs destroy the majority of the tumour, but leave a viable outer rim which will continue to grow. However, this area is effectively targeted by antibody therapies (Fig 6), leading to a synergistic combined therapy which has entered clinical trial. Other novel, combined treatments using antibody-targeted and antivascular agents are constantly under investigation.
We have also developed a systems biology approach to tumour pathophysiology and therapeutics. This facilitates the discovery of new targets and prognostic biomarkers by linking data on DNA damage response and molecular mechanisms of repair, from both in vitro data and microscopy of pre-clinical and clinical samples, to bioinformatics analysis of repair pathways. This substantially improves the translation of pre-clinical data into novel clinical trials, and the prediction of therapeutic performance in the clinic.
• Dr Vin Rajkumar PhD (Postdoc)
• Peter Johnson (PhD student)
• Dr Geoff Boxer FIBMS (Lab Manager)
• Mathew Robson (Technician)
Dearling JLJ, Flynn AA, Qureshi U, Whiting S, Boxer GM, Begent RHJB, Pedley RB. Localization of radiolabeled anti-CEA antibody in subcutaneous and intrahepatic colorectal xenografts: Influence of tumor size and location within host organ on antibody uptake. Nucl Med Biol 36: 883-894, 2009. Pubmed
Panasyuk G, Nemazanyy I, Zhyvoloup A, Filonenko V, Davies D, Robson M, Pedley RB, Waterfield M, Gout I. The mTORbeta splicing isoform promotes cell proliferation and tumorigenesis. J Biol Chem. 284(45):30807-14, 2009. Pubmed
Fidarova EF, El-Emir E, Boxer GM, Qureshi U, Robson MP, Dearling JLJ, Trott KR, Begent RHJ, Pedley RB. Microdistribution of targeted, fluorescently-labeled anti-carcinoembryonic antigen antibody in metastatic colorectal cancer: implications for radioimmunotherapy. Clin Cancer Res 14:2639-2646, 2008 Pubmed
Violet JA, Dearling JLJ, Green AJ, Begent RHJ, Pedley RB. Fractionated 131I anti-CEA Radioimmunotherapy- Effects on xenograft tumour growth and haematological toxicity in mice. Br J Cancer 99: 632 – 638, 2008 Pubmed
El-Emir E, Qureshi U, Dearling JLJ, Boxer GM, Clatworthy I, Folarin AA, Robson MP, Konerding MA, Nagl S, Pedley RB. Predicting response to radioimmunotherapy from the tumor microenvironment of colorectal carcinomas. Cancer Res 67: 11896-11905, 2007 Pubmed
Lankester KJ, Maxwell RJ, Pedley RB, Dearling JL, Qureshi UA, El-Emir E, Hill SA, Tozer GM. Combretastatin A-4-Phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down. Int J. Oncol. 30: 453-460, 2007. Pubmed
El Emir, E., Dearling, J.L, Huhalov, A., Robson, M., Boxer, Neri, D., I. A., van Dongen, GAMS, Begent, R.H..J. and Pedley, R.B. Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models. Br J Cancer 96: 1862-1870, 2007. Pubmed