SUMMARY
The project is concerned, on the one hand, with creating “live” models, using avatar mice, which will act as mirrors of the tumours found in the patients and, on the other, with using genomic techniques to analyse the genetic changes which give rise to the tumour in each patient. These data will be used to look for inhibitors of the altered pathways, which will be tested on the avatar mice in order to see if they work as possible patient treatments. In this project, the CRIS foundation is financing the genome sequencing of the patients’ tumours.
SOCIAL RELEVANCE OF THE PROJECT
With a high mortality rate and slow progress in research, pancreatic cancer tumours currently pose one of the greatest scientific challenges, highlighting the importance of research into new treatments.
Pancreatic cancer in Spain:
– Is the only malignant tumour whose mortality rate has increased for both sexes, 160% in recent decades
– Each year, between 5,000 and 6,000 new cases of this type of cancer are diagnosed
– Seven in every 100,000 Spanish residents die of this tumour each year, that is, 3,000 per year, the same figure as for breast cancer
– It has a very low survival rate, the one-year rate is 30% and the five-year survival rate 6%
– Diagnosis is usually late, in 80% of cases the cancer is advanced, with metastasis in other organs, which can imply a life expectancy of three months
– Only two out of ten patients can undergo surgery and, in 90% of cases, cancer recurs
– Pancreatic ductal adenocarcinoma is the most common (PDAC)
THE AIM OF THE STUDY
The aim of this three-year project is to improve the survival rate of patients with advanced pancreatic cancer, from the current 20% to over 40% in patients who have been treated with chemotherapy, but who still have the disease.
To do this, it is necessary to carry out a study comprising a large number of patients and a long-term follow-up.
SCIENTIFIC EVIDENCE TO SUPPORT THE PROJECT
Research into this cancer in recent decades has shown that it is a genetic disease and that the accumulation of mutations in oncogenes and tumour suppressor genes leads to expression of phenotype and to tumour development.
On the other hand, evidence exists that personalised medication strategies focused on individual patients’ genetic alterations are successful. Research indicates that pancreatic cancer is a particularly complex and heterogeneous type of cancer, with serious variations in each patient. Also, studies of pancreatic ductal adenocarcinoma, the most common type, have shown that it is an unstable tumour and that the tumours acquire new mutations during the process of metastasis.
In a previous study, our group demonstrated an improvement in the survival rate of patients in which the PALB2 gene suffered a mutation that made it sensitive to alkylating agents We have also established a live model with avatar mice that support this response to alkylating agents in 25 patients with solid tumours, discovering alterations in the following pathways: CHEK1, FGFR2, IGF1R, MET, BRCA1, XPC, NOTCH, CREB3LB, GNA11, and EGFR.
To date, 13 patients have been treated and in 6 of them, the disease has recurred.
DEVELOPMENT OF THE PROJECT
We propose to use live models with immuno-compromised mice in order to reproduce patient’s tumours and sequence these tumours
in order to observe the implicated mutations, and design appropriate treatments for these tumours, first in the avatar and then, depending on results, by applying them to the patient.
Steps of this process will be:
– To determine if the integration of the model with mice avatars improves patient survival.
– To identify existing PDAC mutations and those which are acquired during the process of metastasis, comparing them with initial values.
– To reproduce possible PDAC variations in 80 – 100 avatar mice models in order to be able to use them as metastatic models, separate from those which are created using primary tumours.
– To develop a system to monitor the disease through extra-cellular DNA circulating in the blood which can be used to predict the development of the disease.