The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10–20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies.

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…This therapeutic combination could also be beneficial in PDAC, as an alternative approach for inhibiting oncogenic Kras, which is located upstream of MEK/ERK and PI3K. Thus far, attempts at targeting the most frequently mutated protein in PDAC, KRAS, have been unsuccessful [14,219]. Whilst the combination of MEK inhibitors with alternative pathway inhibitors such as PI3K or Src has shown early promise [218,220,221], the combinations, including addition of chemotherapies, may require an alternative, intermittent dosing regimen design due to issues with chronic administration [222][223][224], and are yet to be systematically examined in PDAC.…”

“…PDAC has a high molecular heterogeneity despite being morphologically indistinguishable [11,12]. Characterisation of this complex molecular landscape has revealed key insights into the biology of tumours [11,13,14], enabling us to build upon the traditional anatomical definition of cancer and further includes molecular subtyping or 'omic' stratification as a foundation for developing approaches for early detection and improved treatment options [11,15,16], as well as identification of mechanisms of therapeutic resistance [11,12,17]. With new advances in sequencing and analytical methodologies, PDAC has been genomically and transcriptomically characterised to an incredible depth, as reviewed recently [14].…”

“…Characterisation of this complex molecular landscape has revealed key insights into the biology of tumours [11,13,14], enabling us to build upon the traditional anatomical definition of cancer and further includes molecular subtyping or 'omic' stratification as a foundation for developing approaches for early detection and improved treatment options [11,15,16], as well as identification of mechanisms of therapeutic resistance [11,12,17]. With new advances in sequencing and analytical methodologies, PDAC has been genomically and transcriptomically characterised to an incredible depth, as reviewed recently [14]. Building on early studies which have identified the 12 key pathways and oncogenes genetically altered in most pancreatic cancers [18], this disease has since been stratified into distinct molecular subtypes using gene expression profiling [17], and comprehensive whole genome sequencing (WGS) approaches [11,12,19].…”

Super-enhancers modulate interleukin-6 expression and function in cancers

“…Pancreatic cancer is almost resistant to all current therapeutic regimens and this is likely due to broad heterogeneity of genetic mutations and dense stromal environment ( 3 ). So far, no molecular-targeted therapies have given satisfactory results and gemcitabine which approved at 1997, was still the first-line drug for pancreatic cancer patients at a good performance status ( 4 , 5 ). Inflammatory conditions such as pancreatitis not only represent a well-known risk for pancreatic cancer development but also as a consequence for pancreatic cancer ( 6 ).…”

Qingyihuaji formula reverses gemcitabine resistant human pancreatic cancer through regulate lncRNA AB209630/miR-373/EphB2-NANOG signals

“…Pancreatic cancer has become a major diagnostic and therapeutic problem faced by the medical community at home and abroad. Any single treatment method is difficult to achieve satisfactory results [4,10]. At the same time, adjuvant chemotherapy is used in order to improve the quality of life and prolong the survival time.…”