Tumour ReviewNew therapeutic targets in pancreatic cancer
Introduction
Pancreatic adenocarcinoma (PDAC) is the most common type of pancreatic cancer (PC) [1], [2], [3]. PDAC incidence is rising; it is expected to become the second cause of cancer-related death by 2030 and has a very poor prognosis [4]. More than 80% of patients have an advanced disease at diagnosis, and the 5-year overall survival rate is approximately 7% [5]. Poor survival is attributed to high aggressiveness, intrinsic chemotherapeutics resistance and lack of effectively targetable oncogenic drivers. Systemic chemotherapy is the mainstay of locally advanced (LAPC) and metastatic (MPC) patients treatment and single-agent gemcitabine had been the standard for more than two decades until first-line FOLFIRINOX and nab-paclitaxel/gemcitabine demonstrated better efficacy [6], [7], [8], [9]. Targeted therapies play a limited role in PDAC management [10], [11]. Therefore, new therapeutic approaches with meaningful impact on patients survival are urgently needed.
Recently, substantial progress was made in the understanding of PDAC genetic background and molecular biology. Up to 4 molecular subgroups have been identified, each with distinct molecular signatures and potential specific therapeutic targets [12]. These valuable research efforts, however, have not yet been matched either by the successful development of novel agents or by the identification of predictive biomarkers that could increase the effectiveness of existing therapies. As a result, PDAC remains refractory to most currently available treatments [13]. Furthermore, the peculiar tumour microenvironment with the excessive desmoplastic stroma represents an important biological barrier for drug delivery and activity [11], [13]. In this regard, however, targeting components of the tumour stroma that contribute to desmoplasia emerged as a potentially valid therapeutic approach [14].
This article aims to review the complex and heterogeneous molecular characteristics of PDAC and to discuss novel promising molecular targets and therapeutic agents.
Section snippets
Molecular subtypes of pancreatic cancer
Several studies of genetic/epigenetic sequencing revealed significant molecular heterogeneity among PDAC. Collison et al. considered three molecular subtypes: classical, quasi-mesenchimal, endocrine-like; then, Moffit et al. identified four different molecular entities: classical, basal-like, normal stromal and activated stromal [12], [15]. Recently, Bailey et al. suggested the existence of four molecular subtypes with different biological features and prognostic relevance: squamous, pancreatic
Potential targets in pancreatic cancer
PDAC is a genetically and biologically heterogeneous tumour. Recently, emerging evidences demonstrated that a number of cancer genes and signalling pathways are critically involved in the processes of PDAC tumourigenesis and progression and, as such, they may be potentially useful therapeutic targets [21].
Clinical trials and future perspectives
Several trials have been conducted and many others are on going to investigate the role of various innovative drugs in PDAC either as monotherapy or in combination with chemotherapy (Fig. 1, Table 1, Table 2)
Conclusion
Despite the recent increased number of treatment options, PC still shows modest response to conventional cytotoxic drugs and a dismal prognosis. This is partly due to the unique characteristics of the tumour microenvironment which is poorly immunogenic and largely composed of a highly desmoplastic stroma. Also, activation of oncogenic signalling pathways and frequent EMT dysregulation likely contribute to PDAC biological aggressiveness. While sophisticated studies allowed dissecting the genomic
Acknowledgements- Contributors
All Authors have materially participated in research and/or article preparation and made substantial contribution to the conception and design of the article or the acquisition of data or analysis and interpretation of data. E.L., M.S., M.P. and P.Z. conceived the manuscript; E.L. and M.S. wrote the manuscript. M.P., P.Z, A. Pretta and F.S. provided writing assistance and language help. All Authors did the literature search. A. Pretta conceived the figure, E.L. and S.M. conceived the tables.
Declaration of Competing Interest
None. All Authors have approved the final article.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References (99)
- et al.
Addressing the challenges of pancreatic cancer: future directions for improving outcomes
Pancreatology
(2015) - et al.
Pancreatic cancer: progress in cancer therapy
Crit Rev Oncol Hematol
(2008) - et al.
Trp53R172H and KRASG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Cancer Cell
(2005) - et al.
Mist1 regulates pancreatic acinar cell proliferation through p21 CIP1/WAF1
Gastroenterology
(2008) - et al.
Activation of WNT/β-catenin signaling enhances pancreatic cancer development and the malignant potential Via Up-regulation of Cyr61
Neoplasia
(2016) - et al.
A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas
Eur J Cancer
(2014) - et al.
A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer
Ann Oncol
(2012 Nov) - et al.
A phase 3 randomized, double-blind, placebo controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial
Ann Oncol
(2015) - et al.
Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma
Eur J Cancer
(2018) - et al.
A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer
Ann Oncol
(2014)
Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-Centre, open-label, dose-finding, nonrandomised, phase 1b trial
Lancet Oncol
Genetics and biology of pancreatic ductal adenocarcinoma
Genes Dev
The italian rare pancreatic exocrine cancer initiative
Tumori
Systemic chemotherapy for advanced rare pancreatic histotype tumors: a retrospective multicenter analysis
Pancreas
Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States
Cancer Res
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial
J Clin Oncol
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer
N Engl J Med
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine
N Engl J Med
Second-line chemotherapy for advanced pancreatic cancer: Which is the best option?
Crit Rev Oncol Hematol
Targeted therapies for pancreatic cancer and hurdles ahead
Anticancer Res
Molecular subtypes of pancreatic cancer
Nat Rev Gastroenterol Hepatol
Pancreatic cancer
Nat Rev Dis Primers
Stromal depletion goes on trial in pancreatic cancer
J Natl Cancer Inst
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
Nat Genet
Genomic analyses identify molecular subtypes of pancreatic cancer
Nature
Integrated genomic characterization of pancreatic ductal adenocarcinoma
Cancer Cell
TP63-Mediated enhancer reprogramming drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma
Cell Rep
Deciphering role of FGFR signalling pathway in pancreatic cancer
Cell Prolif
Targeting the Akt/PI3K signaling pathway as a potential therapeutic strategy for the treatment of pancreatic cancer
Curr Med Chem
Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine
Recent advances in basic science 5 November
Cancer of the pancreas: molecular pathways and current advancement in treatment
J Cancer
Efficacy of larotrectinib in TRK fusion– positive cancers in adults and children
N Engl J Med
Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior
Int J Cancer
Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy
Expert Opin Ther Targets
Robo signalling controls pancreatic progenitor identity by regulating Tead transcription factors
Nat Commun
ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signaling
Nat Commun
Clinical trials targeting the stroma in pancreatic cancer: a systematic review and meta-analysis
Cancers (Basel)
Sonic hedgehog protein is frequently up-regulated in pancreatic cancer compared to colorectal cancer
Pathol Oncol Res
Inhibition of pancreatic cancer stem cell characteristics by α-Mangostin: Molecular mechanisms involving Sonic hedgehog and Nanog
J Cell Mol Med
NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer
Cancer Discov
Germline mutations in pancreatic cancer and potential new therapeutic options
Oncotarget
Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations
Cancer Res
The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers
Br J Cancer
Emerging role of immune checkpoint blockade in pancreatic cancer
Int J Mol Sci
The Next wave of stroma-targeting therapy in pancreatic cancer
Cancer Res
Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis
Biochem Soc Trans
Cancer-associated fibroblasts' functional heterogeneity in pancreatic ductal adenocarcinoma
Cancers (Basel)
Targeting the tumor stroma: the biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20)
Curr Oncol Rep
Low CD8+ T Cell Infiltration and High PD-L1 Expression Are Associated with Level of CD44+/CD133+ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer
Cancers (Basel)
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Postal Address: Gastrointestinal Unit, Jules Bordet Institute, Boulevard de Waterloo, 125 – B-1000 Brussels, Belgium.