Pancreatic cancer is the result of the progressive accumulation of genetic mutations that cause tumor development, or of the occurrence of somatic mutations that affect signaling pathways and proteins, some of which are considered to be potential therapeutic targets.
The mutation of the KRAS oncogene is very frequent in pancreatic cancer (50-90%) and this pathway is a target of choice in this tumor. Different strategies have been proposed such as inhibition of the enzyme farnesyltransferase that regulates RAS post-translational modifications (tipifarnib), allosteric inhibitors of RAS isoforms, or blocking the transport of the RAS protein to the membrane (deltarasin). The inhibition of proteins involved in RAS downstream signaling, such as MEK1/2, has given deceiving results in the clinic. Similarly, the use of inhibitors of the PI3K-mTOR pathway was not convincing. This signaling pathway is activated in 59% of pancreatic cancers and plays a key role in the survival and development of cancer cells through mTOR and NFκB. It could also be involved in pancreatic cancer resistance to gemcitabine. However, inhibitors of mTOR, such as temsirolimus, everolimus or sirolimus, did not show any clinical effect in patients with advanced pancreatic cancer. Only curcumin, a natural product extracted from the curcuma longa plant and capable of inhibiting NFκB, displayed an encouraging effect in two phase II clinical trials, alone or in combination with gemcitabine.
Inhibition of the JAK-STAT and Notch signaling pathways also has been much studied and seems to be a promising approach for the treatment of pancreatic cancer. Interesting results were obtained in a phase II clinical trial where capecitabine was associated with ruxolinib (JAK1-JAK2 inhibitor) in patients whose disease progressed during treatment with gemcitabine. Currently, two ongoing phase III clinical trials evaluate capecitabine with or without ruxolinib as second-line treatment (JANUS1 and JANUS2). Early phase clinical trials are assessing the association of this inhibitor or of a JAK1 inhibitor with nab-paclitaxel plus gemcitabine (NCT01822756, NCT 01858883).
The Notch cascade also has been targeted with a specific antibody against the Notch ligand DDL4 that showed anti-tumoral activity in association with gemcitabine in mouse models. These results were strengthened by a phase Ib study that reported disease stabilization in patients treated with this antibody associated with gemcitabine or gemcitabine+nab-paclitaxel. Pre-clinical studies demonstrated that the combination of JAK and Notch signaling pathway inhibitors has anti-tumor activity, but this finding must be confirmed in the clinic.
Another approach consists in modifying the metabolism of cancer cells by using modulators of autophagy (a type of cell death), such as hydroxychloroquine combined with gemcitabine or nab-paclitaxel, as neo-adjuvant treatment, or in patients with advanced disease (NCT 015006973).
Many research works have highlighted the involvement of tyrosine kinase receptors (e.g., EGFR, VEGFR, IGFR, cMET) in the progression of various cancers, including pancreatic cancer. These receptors are overexpressed in tumors, but also in stromal cells. Targeting the receptors of the EGFR family with antibodies (cetuximab for EGFR, or trastuzumab for HER2) or small chemical molecules (erlotinib or lapatinib) did not lead to a significant anti-tumor effect in patients with pancreatic cancer, despite some positive responses, particularly with erlotinib. Nevertheless, the benefit-cost ratio remains very low and the selection of responder patients is non-existing. This explains why this treatment is not recommended. Currently, early clinical trials are studying the therapeutic effect of antibodies against HER3, another member of the EGFR family that is also strongly involved in tumor growth (NCT01447225).
Anti-angiogenic agents, such as bevacizumab or sorafenib, did not show promising results in association with gemcitabine for the treatment of this disease.
The physical characteristics and particularly the presence of a pronounced desmoplastic reaction and hypoxic environment could explain this tumor aggressiveness and resistance to therapies. To overcome the difficulty of delivery, new formulations of classical chemotherapy drugs have been developed, such as MM-398 (nanoliposomal irinotecan) that increases irinotecan half-life and concentration in the tumor. Encouraging results have been obtained in a phase III clinical trial (NAPOLI-1) in patients resistant to gemcitabine in combination with 5-FU and folinic acid. The chlorethazine derivative evofosfamide (TH-302), a pro-drug that is active only in hypoxic conditions, has shown positive results in association with gemcitabine in a randomized phase II trial in patients with advanced pancreatic cancer.
