New medical technology for advanced-stage pancreatic ductal adenocarcinoma
The pancreas is richly supplied with nerves, frequently closely adherent to pancreatic arteries and ducts, even more so in pancratic cancer than normal pancreas. Pancreatic cancer usually lies directly against the perineurium, and grows internally and externally along the nerve. Thus, the research hypothesis in this project was that combination of local denervation and chemotherapy will suppress the advanced pancreatic cancer. The aim of this project was to develop a new and better therapy for advanced pancreatic cancer. Main results: • Mass spectrometry-based proteomic analysis of mouse model of pancreatic cancer: During the past 2 years, we have obtained a mouse pancreatic cancer cell line originating from a genetically engineered mouse model with KRAS mutation and created the tumor model by orthotopically implantation in C57BL/6 mice. We have performed proteomic analysis and found 1521 of 3927 proteins were significantly expressed (q<0.05). Accordingly, we have made a protein tree of pancreatic cancer especially highlighting the branch of neuro proteins. This was included in an MSc thesis by Therese Stork Høiem and to be defended in January 27th, 2017, and will be included as part of PhD thesis by Hanne-Line Rabben. • Preclinical trial of pancreatic cancer treatment in mice: 221 mice have been used for 8 experimental groups including untreated controls, single therapy with local denervation, IP compound, gemcitabine, double and triple combination therapies. Preliminary results showed the novel combination therapy markedly suppressed the pancreatic cancer progression, leading to a significantly-improved survival rate. Further experiments and data analyses • Surrogate endpoints for cancer (SECs): All blood and tissue samples have been collected from the experiments. We are performing pathological evaluation. We will perform in situ hybridization and immunohistochemistry with a panel of 26 probes and/or antibodies. • Proteomic analysis: We have completed the protein profiling of the mouse model of pancreatic cancer. We will further perform bioinformatics and advanced data analysis to obtain the protein profiling in mice that have been treated with the triple combination therapy in order to identify potential therapeutic biomarkers and explore the underlying mechanisms. • Transcriptomic analysis: We have processed the extraction of RNA from the tissues samples collected for RNA-Seq analysis. Additional grant application (søknad på forsknings- or innovasjonsmidler fra St. Olavs Hospitl 2017) has been submitted for this analysis. • Clinical trial preparation: A cohort of 10 pancreatic cancer patients will be selected at St. Olavs Hospital. Key inclusion criteria are patients with histologically confirmed pancreatic ductal adenocarcinoma and non-resectable or inoperable according to evaluation by multidisciplinary team at St. Olavs Hospital. The primary endpoint will be 6-month overall survival (OS), and the secondary endpoints will be response rate (by Response Evaluation Criteria In Solid Tumors, RECIST) (CT evaluation after 8 and 20 weeks), progression-free survival, safety, and toxicity profile. Pancreatic cancer is the 4th leading cause of cancer death in Norway and the only cancer which has not seen an improvement for both men and women. More than 8 out of 10 exocrine pancreatic cancers are adenocarcinomas. Nearly all of these (90%) are pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most aggressive cancers with 5-year survival rate of <5%. Only a minority (10-15%) of patients can undergo potentially curative surgical resection. The majority of patients are diagnosed with advanced-stage PDAC, either metastatic (50%) with a median survival of 3-5 months or locally advanced cancer (30%)(6-10 months survival). Unlike other cancer entities such as breast cancer and colon cancer, the targeted therapies in PDAC have, so far, largely failed to positively impact patient survival after a decade of effort. Results we have obtained in this project, for the first time, showed that a new triple combination therapy markedly suppressed the tumor progression and increased survival rate nearly 100% in a mouse model of PDAC. Thus, we expect that the outcomes of this project will provide strong evidence to design a clinical trial for patients with advanced-stage pancreatic cancer.
The new concept of "nerve-cancer cell cross-talk" has been developed. Nerve in the tumour may contribute to its growth. We have successfully established an animal model of pancreatic cancer which mimics the cancer behaviour in humans. The initial results are promising. Pancreatic cancer is the 4th leading cause of cancer death in Norway as well as in Europe and the only cancer which has not seen an improvement in European mortality figures for both men and women. More than 8 out of 10 exocrine pancreatic cancers are adenocarcinomas. Nearly all of these (90%) are pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most aggressive cancers with a 5-year survival rate of <5%. Only a minority (10-15%) of patients can undergo potentially curative surgical resection. The majority of patients are diagnosed with advanced-stage PDAC, either metastatic (50%) with a median survival of 3-5 months or locally advanced cancer (30%)(6-10 months survival). Although palliative chemotherapy is the standard of care for patients with metastatic disease, management of locally advanced PDAC is controversial. Several treatment options, including extended surgical resections, neoadjuvant therapy with subsequent resections, as well as palliative radiotherapy and/or chemotherapy, are currently used. However, there is little evidence available to support treatment options for locally advanced PDAC. In 2000, the U.S. National Cancer Institute initiated a planning for pancreatic cancer research, aiming to develop targeted molecular therapeutics. Unlike other cancer entities such as breast cancer and colon cancer, the targeted therapies in PDAC have largely failed to positively impact patient survival after a decade of effort. Very recently, we and others have found strong evidence that nerve plays an important role in cancer initiation and progression. The pancreas is richly supplied with nerves, and even more so in PDAC than normal pancreas. In this project, we are aiming to develop a new and better therapy for locally advanced PDAC cancer. During the past year, we have tested different treatment methods in pancreatic cancer cell lines and have established an excellent mouse model of pancreatic cancer. The preliminary results showed that the tumour growth in mice was suppressed by 43% within 2 weeks of the treatment. A clinical trial at St. Olav’s hospital is under preparation. This proposal has been evaluated by NTNU Technology Transfer AS (TTO) and found to have patentability of the invention.