Investigating Personalised Therapy in Mouse Models of Pancreatic Cancer
Lead Research Organisation:
University of Glasgow
Department Name: Institute of Cancer Studies
Abstract
Pancreatic cancer is the 5th commonest cause of cancer-related death in the UK killing over 7,000 people each year. Long-term survival has not improved for the last 20 years, with only 2-3% of patients still alive 5 years after diagnosis, despite the significant improvements made in the treatment of other cancers. At the time of diagnosis most patients have advanced disease not suitable to curative surgery and the chemotherapies used presently offer only very marginal benefits with average survival times in this group of only 2-11 months on average.
Recently, studies in the Sansom laboratory on human pancreatic cancer tissue have shown that cancers with high levels of a protein called LKB1 appeared less aggressive and patients lived longer than those whose cancers had a low level. LKB1 is known to inhibit an important growth signalling molecule called mammalian target of rapamycin (mTOR) and so we suspect that excessive mTOR signalling may be the reason for the poorer survival in those cancers which lack LKB1. We propose to test other inhibitors of mTOR in pancreatic cancers to see if this can improve survival for those tumours which initially would appear aggressive and so develop new treatments for humans.
Recently, studies in the Sansom laboratory on human pancreatic cancer tissue have shown that cancers with high levels of a protein called LKB1 appeared less aggressive and patients lived longer than those whose cancers had a low level. LKB1 is known to inhibit an important growth signalling molecule called mammalian target of rapamycin (mTOR) and so we suspect that excessive mTOR signalling may be the reason for the poorer survival in those cancers which lack LKB1. We propose to test other inhibitors of mTOR in pancreatic cancers to see if this can improve survival for those tumours which initially would appear aggressive and so develop new treatments for humans.
Technical Summary
Aims: Pancreatic cancer kills 7,000 people each year. The disease is usually too advanced for surgery at diagnosis and current chemotherapies are of negligible survival benefit with current 5 year survival of only 2-3% which has been unchanged for 20 years. We aim to use a murine model of pancreatic cancer to determine if there is a subset of tumours which have particular dependency on mTOR signalling and consequently if inhibition of mTOR signalling can improve survival in this group. If successful this could lead to new personalised therapies for patients with pancreatic cancer.
Objectives:
1. Generate cell-lines from the pancreatic ductal adenocarcinoma (PDAC) in each of three mouse genotypes and assess sensitivity to growth inhibition by a variety of compounds such as rapamycin, metformin, AICAR, and novel inhibitors of mTORC1/2.
2. Generate cohorts of mice for each genotype and perform chemoprevention and chemotherapeutic studies using rapamycin.
3. If chemoprevention/therapeutic studies are effective, we will mimic a human trial and perform surgical resection of the tumour once clinically evident and use rapamycin in an adjuvant role post-operatively.
4. Histoscore tissue micro-arrays of human PDAC which have been stained for mTOR, AKT and PTEN and correlate with previous histoscores of LKB1 and known clinical outcome.
Design/Methodology: The Sansom lab has refined three models of pancreatic cancer with targeted expression of constitutively activated KrasG12D to the mouse pancreas using Cre-lox technology. Cre-recombinase is expressed under control of the Pdx1 promoter resulting in mosaic expression of Cre in the mouse pancreas. The models bear Lox-STOP-Lox (LSL) KrasG12D which results in excision of the STOP region in tissue expressing Cre-recombinase and constitutive expression of activated Kras in the pancreas. In isolation this leads to the development multiple of pancreatic intra-epithelial neoplasia but not invasive cancer. By incorporating mutant Trp535172H/+, LKB1flox/+ and PTENflox/+ into three separate models (Pdx1-Cre LSL-KrasG12D, Trp535172H/+ ; Pdx1-Cre LSL-KrasG12D, LKB1flox/+ ; Pdx1-Cre LSL-KrasG12D, PTENflox/+) there is marked increase in frequency of progression to invasive and metastatic pancreatic cancer with patterns of disease mimicking human pancreatic cancer becoming evident by 10 weeks.
Scientific/Medical Opportunities: The models used in this project closely mimic human pancreatic cancer and the known interaction of the knocked-out gene products via mTOR suggests this molecule may play a role in human pancreatic cancer. We can test this hypothesis using in vivo mTOR inhibitors aiming to discover additional treatments for human pancreatic cancer.
Objectives:
1. Generate cell-lines from the pancreatic ductal adenocarcinoma (PDAC) in each of three mouse genotypes and assess sensitivity to growth inhibition by a variety of compounds such as rapamycin, metformin, AICAR, and novel inhibitors of mTORC1/2.
2. Generate cohorts of mice for each genotype and perform chemoprevention and chemotherapeutic studies using rapamycin.
3. If chemoprevention/therapeutic studies are effective, we will mimic a human trial and perform surgical resection of the tumour once clinically evident and use rapamycin in an adjuvant role post-operatively.
4. Histoscore tissue micro-arrays of human PDAC which have been stained for mTOR, AKT and PTEN and correlate with previous histoscores of LKB1 and known clinical outcome.
Design/Methodology: The Sansom lab has refined three models of pancreatic cancer with targeted expression of constitutively activated KrasG12D to the mouse pancreas using Cre-lox technology. Cre-recombinase is expressed under control of the Pdx1 promoter resulting in mosaic expression of Cre in the mouse pancreas. The models bear Lox-STOP-Lox (LSL) KrasG12D which results in excision of the STOP region in tissue expressing Cre-recombinase and constitutive expression of activated Kras in the pancreas. In isolation this leads to the development multiple of pancreatic intra-epithelial neoplasia but not invasive cancer. By incorporating mutant Trp535172H/+, LKB1flox/+ and PTENflox/+ into three separate models (Pdx1-Cre LSL-KrasG12D, Trp535172H/+ ; Pdx1-Cre LSL-KrasG12D, LKB1flox/+ ; Pdx1-Cre LSL-KrasG12D, PTENflox/+) there is marked increase in frequency of progression to invasive and metastatic pancreatic cancer with patterns of disease mimicking human pancreatic cancer becoming evident by 10 weeks.
Scientific/Medical Opportunities: The models used in this project closely mimic human pancreatic cancer and the known interaction of the knocked-out gene products via mTOR suggests this molecule may play a role in human pancreatic cancer. We can test this hypothesis using in vivo mTOR inhibitors aiming to discover additional treatments for human pancreatic cancer.
