War on cancer stroma: a novel pathway to treat pancreatic cancer
By Laureano Simon, CEO at Oncomatryx
Pancreatic cancer is the fourth most fatal cancer in men and women. Most patients with pancreatic cancer progress to either metastatic or locally advanced disease in the asymptomatic phase. Its prognosis has not improved over the past 20 years; life expectancy is lower than 5% at 5 years of diagnosis and mortality is increasing worldwide; 82.300 deaths in Europe in 2014 is a devastating example.
While the NCNN and ESMO clinical practice guidelines agree on surgical resection as the only definitive treatment, it is only possible in 15%–20% of the patients. Major improvements in the chemotherapy of pancreactic cancer have rendered not longer than 3-5 months extended OS survival, for a median OS shorter than 12 months. Recent clinical trials have shown a median OS of 11.1 months in patients treated with FOLFIRINOX, a highly aggressive combination of 5-FU/leucovorin plus oxaliplatin plus irinotecan; 8.5 months was the median OS in patients treated with a combination of nab-paclitaxel with gemcitabine, compared with 6.7 months in gemcitabine –treated patients.
Clinical practice guidelines recommend that investigational options must be considered to manage pancreatic cancer patients at all stages of the disease. But very few novel approaches are in clinical trials or even in earlier stages of preclinical development.
Novel biomarkers for patient and treatment selection must be validated. ESMO guidelines state that the G-protein coupled receptor smoothened inhibitor Saridegib, which failed to provide any benefit in tests on non-selected pancreatic cancer, might be of particular interest among patients with hedgehog signalling activation. Mutations in PTCH (receptor for hedgehog) are also known to activate hedgehog signalling in experimental models, and are detected in 2% of patients with pancreatic cancer.
Novel molecular pathways must be also targeted, to complement classic approaches that target epithelial cells. The most common pancreatic tumors are adenocarcinomas, which account for ∼95% of all pancreatic cancers. Pancreatic adenocarcinomas elicit a vast desmoplastic reaction that comprises up to 90% of the tumor mass. This tumor-associated stroma, the tumor microenvironment, is a complex network of extracellular matrix proteins, endothelial cells, immune cells and fibroblasts, which play a very significant, but ignored, role in tumor invasion, drug resistance and immune suppression.
A paneuropean consortium of academic labs and small biotech companies, led by Oncomatryx Biopharma, is following a novel route to treat pancreatic cancer: target the cancer stroma.
Novel therapeutic antibodies and antibody-drug conjugates targeting the tumor microenvironment have already been developed. They have shown higher efficacy and a better safety profile than gemcitabine and nab-paclitaxel in several pancreatic cancer patient-derived xenograft mice models, and biomarkers have already been identified to select the patients to be treated in the clinical trials to come. This european team of scientists and entrepeneurs have declared war on cancer stroma, ready to deploy all their resources to follow this route and help beat pancreatic cancer.
M.Ducreux, et al. On behalf of the ESMO Guidelines Committee. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2015. Annals of Oncology 26 (Supp 5): v56–v68
M.A. Tempero et al. NCCN Clinical Practice Guidelines in Oncology Version 2.2015. Pancreatic Adenocarcinoma.