UCL Cancer Institute

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.

Tumour Heterogeneity

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).

Combination therapies

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.

Systems biology

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.