Biography:
Clara Montagut graduated from the Autonomous University of Barcelona with a degree in Medicine and Surgery and trained in medical oncology at the Hospital Clínic. She specialized in translational cancer research, specifically in biomarkers and mechanisms of resistance to biological drugs at the Hospital Clínic itself and at the Massachusetts General Hospital Cancer Center (Harvard Medical School, USA). In 2008, she joined the Medical Oncology Department of the Hospital del Mar. She is currently director of the Gastrointestinal Cancer Unit of the Medical Oncology department of Hospital del Mar and leads the clinical and translational research group on new therapies and biomarkers in colorectal cancer at the Hospital del Mar Research Institute (IMIM). Her team has identified a mechanism of resistance to anti-EGFR drugs in patients with colorectal cancer, which has been awarded a patent and can be applied in daily clinical practice. The objective is to monitor resistance and choose appropriate treatment strategies for patients. At present, Dr Montagut chairs the Cancer Evaluation Commission (FIS) of the ISCiii, as well as the Agency of Health Quality and Assessment of Catalonia (AGAUR).
Introduction:
Bowel or colorectal cancer is currently a major public health concern. There are around 42,300 new bowel cancer cases in the UK every year, that’s more than 110 every day. Bowel cancer is the 4th most common cancer in the UK, accounting for 11% of all new cancer cases. Of the patients diagnosed with this type of cancer, those with metastases have a much poorer prognosis.
A large group of patients with metastatic disease have tumours that rely on a protein called Epidermal Growth Factor Receptor, or EGFR. This protein, which is found on the surface of a large number of cells, allows tumour cells to maintain their growth and multiplication rate. For this reason, one of the most effective treatments for metastatic colon tumours is a class of drug that attacks EGFR, such as cetuximab. However, not all patients respond to these treatments and, those who do, go on to develop resistance.
This project therefore focuses on these mechanisms of resistance in order to improve EGFR treatments. In order to do this, analysis of tumour cells at different stages in patient tumours will be carried out, the role of the immune system in these processes will be explored and new therapeutic strategies will be developed to combat these resistances.
The project:
The aim of this project is to better understand the mechanisms of resistance to anti-EGFR treatments in metastatic colorectal tumours. In order to achieve this, the following points will be addressed:
- Study of circulating tumour DNA (ct-DNA) in patients treated with cetuximab:
One of the most fascinating discoveries of the past decade is the ability to detect remnants of tumour DNA in patient blood (circulating tumour DNA or ctDNA). This discovery has huge applications in patient diagnosis and follow-up since, through analyzing blood samples, it is possible to get a fairly good idea of what is happening in patient tumours. It also enables a better understanding of the different populations of tumour cells present in the tumour compared with a biopsy.
Consequently, the integration of ct-DNA analyses could provide significant clues as to whether the patient is developing resistance to anti-EGFR treatments and whether the treatments are still effective. These analyses could be vital in guiding decisions on whether to continue treatment or seek alternatives that may be more effective against each patient’s disease. Dr Montagut’s group will work with samples from three clinical trials (PLATFORM-B, SEQUENCE and CITRIC) in which patients are treated with anti-EGFR therapy and periodic ct-DNA analysis will be performed.
- Analysis of NK cell populations in patients treated with anti-EGFR.
Natural Killer (NK) cells are the first line of response to tumours as their specialism lies in detecting and eliminating any cell with abnormal characteristics. It has been determined that the presence of different types and states of Natural Killer cells may be associated with the patient’s prognosis. For example, the presence of NK in the tumour area is often associated with a better prognosis. However, the detection of senescent (aged or inactive) NK cells in the blood may be associated with a poorer prognosis.
The second objective of this project is to study the populations of NK cells in the blood of patients from various clinical trials (such as CITRIC) and patient cohorts, before and after treatment with EGFR therapies.
- New strategies to combat resistance to anti-EGFR treatments.
To address the problem of resistance to treatment with cetuximab, this project will pre-clinically (in the laboratory) study three strategies that are currently being developed. One of them is to use other EGFR treatments (such as Pan004), which attack EGFR differently to cetuximab. Another strategy is to use 6 different antibodies simultaneously to attack EGFR so that even if the tumour changes its EGFR slightly, there is always an antibody that can attack it. Lastly, another strategy is based on withdrawing the anti-EGFR treatment for a period of time, enabling other cells to grow in addition to the resistant cells and, all being well, the resistant cells will be displaced; after a period of time, anti-EGFR treatment will be administered once again and it should be more effective in this second round.
Results Update:
The COVID-19 pandemic has had massive implications for the development of numerous groups’ projects. Firstly, many research centres have had to partially close or limit their activities. Secondly, the number of patients diagnosed has plummeted because people take longer to decide whether go to hospital or because primary care itself is at capacity. Nonetheless, despite these difficulties, Dr Montagut’s group has reached several significant milestones within the project objectives.
Firstly, the CITRIC clinical trial has been launched. 10 centres from across Spain are participating in this trial, which is currently recruiting patients. This study focuses on patients who have received anti-EGFR therapy, become resistant and subsequently received a different therapy, which has also been ineffective for them. An analysis of the circulating tumour DNA (ct-DNA) of these patients will be undertaken and, based on the populations, mutations and characteristics of the remnants of tumour DNA, a decision will be made on whether to administer anti-EGFR treatment or seek alternatives. The relevance of this study is huge: firstly, it may be key to validating the analysis of ct-DNA in making clinical decisions on the treatment of metastatic colon cancer. Secondly, it may provide significant outcomes for validating the anti-EGFR re-treatment strategy in patients who have received other therapies after initial anti-EGFR therapy.
The preparation and analysis of samples from the PLATFORM-B trial has also begun, in which the relevance of ct-DNA analysis is studied during the periodic follow-up of patients while receiving EGFR treatment, as well as making therapeutic decisions.
Resources:
In the first few months of the project, the budget has been used for the following items, which correspond to what was anticipated:
- Contracting of a Laboratory Technician
- Specialisation of Dr Clara Montagut in order to free up her patient-facing time and enable her to dedicate of her working day to research.
- Specialisation of Dr Carmen García in order to free up her patient-facing time and enable her to dedicate of her working day to research.
- Rental of space within the institution’s nitrogen tanks. Freezing samples and cells in liquid nitrogen guarantees their optimal state and preservation in optimal conditions over long periods of time. However, these systems are expensive to maintain and space in these tanks must be rented.
- Acquisition of an ultra-low temperature freezer at -80 °C, which enables proper preservation of samples and cells. Unlike nitrogen tanks, this enables quicker and easier access to the samples.
- Other consumable laboratory materials.