Exploring c-Met and HER3 crosstalk by nano-proximity imaging for understanding its clinical significance in lung adenocarcinoma.

Lung cancer has a long-standing reputation of being difficult to treat, particularly since it is often identified after spread to other organs. However, doctors and lung cancer scientists have become very excited about a new type of targeted therapy known as a "cancer growth blocker", that blocks the interaction between natural chemicals in the body controlling growth ("growth factors") with the part of the cell that receives the signal of these growth factors. Such growth signals are produced uncontrollably by cancer cells so that drugs blocking the signal could be a highly effective way to block cancer growth. In fact, these drugs are now commonly used in a several types of cancer including a form of lung cancer called "Non-small cell lung cancer". One particularly important example are drugs that block one of the main signal receivers or "receptors" - known as the "epidermal growth factor receptor" - e.g. Gefitinb or Erlotinib, which have considerably improved the life expectancy of lung cancer sufferers.

Unfortunately the cancer often becomes resistant to these drugs by finding other ways to communicate the message from the growth factors via different receptors i.e. if one receptor is blocked by drug, with time, another receptor can start receiving the same signal, which means the treatments stop working i.e. "treatment resistance". I will use a special type of microscope that uses "FLIM" (Fluorescence Lifetime Imaging Microscopy) that allows us to see how these receptors are located in the cell and how active they are in response to treatment. I will then use cells from tumours of different patients (that have or have not developed resistance) to test a new "inhibitor" against a different type of receptor "c-Met" because there is some good evidence to suggest its importance in lung cancer signalling, particularly if the cancer is resistant to other treatments. These cells can then be injected into a small number of mice that can be treated with the drugs to see how the cancer behaves in a living organism. I will then use this special microscope to examine the tumours formed and the effect of this drug in mice, and later on in biopsy specimens from patients, to predict response to the drug. One of the most important findings will be understanding treatment resistance in more detail. This will also allow us to identify patients that will benefit from the use of new drugs that may beat resistance, without subjecting others to the side effects if they are not suited to their type of cancer.

In the future, such information would be useful to other scientists developing ways of predicting lung cancer responsiveness to treatment to focus the patients who will benefit most from them. This could make drug trials more affordable and potentially more accessible for patients, thus avoiding waste in a time when resources are scarce.

This research will be conducted by a research doctor training at a higher level in respiratory medicine who has a particular interest in caring for patients with lung cancer. The research team will also include a senior chest physician with expertise in lung cancer research and a professor of oncology.

This research will be largely based in the laboratory, studying cells and mice using very specialised microscopes. In addition, an important part of the study will be on samples that patients have donated to research including lung tumours that have been operated on but also materials coming from glands that will give us unique information about why cancer spreads.

This is an exciting area in lung cancer research which has the opportunity to help patients in a disease which can be extremely difficult to treat and can leave patients with life expectancies of less than six months at diagnosis. In patients in whom the treatment has stopped working where life expectancy can be be extremely poor, this kind of approach could offer a new lease of life to those with weeks or months to live.

The study aims to explore the interaction between two receptors, c-Met and HER3 in lung cancer, in order to understand their role in the development of EGFR-tyrosine kinase inhibitor resistant adenocarcinoma. This will be achieved by using a lung cancer cell model developed in the sponsoring laboratory. This model represents common clinical phenotypes of EGFR (TKI Resistant/sensitive and wildtype). We will image the interaction between c-Met and HER3 in vitro, using this cell model, under basal conditions or with c-Met inhibition. The sponsoring laboratory has proof-of-principle data demonstrating quantification of hetero-dimerisation/oligomerisation of HER family receptors using Förster (Fluorescence) resonance energy transfer (FRET). In addition we will use these cells to develop xenograft tumours in mice, to compare c-Met inhibitor exposed or naive animals. These groups will be assessed for tumour cell proliferation and other tumoral properties, and very importantly, to explore how the c-Met and HER3 interaction is modulated in vivo. The study will finally use archival NSCLC adenocarcinoma sub-type patient specimens (resected primary tumours and regional lymph nodes) to explore the putative interaction between c-Met and HER3 in metastasis and its potential role as a clinical tool in the context of a prognostic model that could predict responsiveness to c-Met inhibitors.

The main purpose of this application is to develop a better understanding of the role of c-Met and HER3 heterodimerisation in lung cancer, with particular reference to EGFR-TKI resistance. The potential beneficiaries of this understanding are plentiful incorporating patients, physicians, academics (locally and overseas), in particular those within oncology and respiratory research and also industry representatives working in the development and commercialisation of EGFR TKI's. Another major target of this project is to develop the knowledge required (and potentially a clinically applicable assay) to predict patients that will benefit from c-Met inhibition. The evidence is growing that a subset of patients will benefit from c-Met inhibition - our work would seek to prove the underlying mechanism that would make a clinically useful assay plausible. If successful, such an approach could be extended to other HER family members and different tumour types with overlapping receptor profiles.

The outcomes of this project will be of particular interest to the pharmaceutical industry. Increasing recognition of the importance of microscopy-based assays to analyse cell function would fuel interest in our work that could contribute to the development of novel therapies and better patient selection for such treatments. Certainly, although there is thus the potential to attract commercial interest in this field, such assays can often be readily exploited within public sector facilities run by the NHS. Such opportunities would be capitalised upon in accordance with the host institution's clear code of practice for commercial exploitation of intellectual property.

With the evolution of commissioning, in current times of economic strain, the selection of novel and expensive targeted therapies will need to be more carefully managed. The time is ripe for better understanding of mechanisms that allow correct translation of such agents to clinical medicine and for allocation of resources to patients in whom it can be proven will benefit from them. Such knowledge would be of huge benefit to the health economy given the expense of targeted agents that could then be focused on only those with achievable benefit. Policymakers and in particular the National Institute for Clinical Excellence would have potential gain from this information if it could be successfully applied to the clinical environment.

In addition to wider societal benefits, the proposed research will equip me with valuable practical skills including comprehensive microscope experience and will place me in a strong position to compete for further academic training such as an NIHR Academic Clinical Lectureship and to ultimately establish my own research group.