Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly solid tumours. This is due to a generally late-stage diagnosis of a primarily treatment-refractory disease. Several large-scale sequencing and mass spectrometry approaches have identified key drivers of this disease and in doing so highlighted the vast heterogeneity of lower frequency mutations that make clinical trials of targeted agents in unselected patients increasingly futile. There is a clear need for improved biomarkers to guide effective targeted therapies, with biomarker-driven clinical trials for personalised medicine becoming increasingly common in several cancers. Interestingly, many of the aberrant signalling pathways in PDAC rely on downstream signal transduction through the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which has led to the development of several approaches to target these key regulators, primarily as combination therapies. The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway.

Keywords: cell biology; clinical trials; pancreatic cancer.

Figure 1

Schematic representation of PDAC progression from the primary tumour to a locally invasive disease and eventually metastasis. (1) Pancreatic cancer cells proliferate in the primary tumour, metabolising nutrients delivered by the blood vasculature and surrounding stroma. (2) Cancer cells invade through the extracellular matrix (ECM), including cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs), among other cancer-associated cell types, eventually intravasating or invading into the lymph and travelling to distant sites. (3) Circulating tumour cells (CTCs) must develop resistance to anoikis, as well as shear stress, in order to survive in the circulation with red blood cells (RBCs) and leucocytes. (4) After travelling through the circulation, CTCs extravasate at secondary sites, commonly the liver, establishing a new niche. ECM, extracellular matrix; PDAC, pancreatic ductal adenocarcinoma.

Figure 2

Adaptable drug development pipeline, demonstrating the progression of lead compounds through target validation, lead compound identification and optimisation, then preclinical validation. The necessary addition to this process is the identification of biomarkers to guide both lead compound development and later stratification in phase II/III clinical trials. These processes may be iterated to improve on-target efficacy, solubility and biomarkers. After safety and tolerability is confirmed in phase I clinical trials, biomarker-driven phase II/III may reduce the high attrition rates of lead compounds if appropriate patient stratification can demonstrate beneficial response in the assessed subsets of patients. These biomarkers may also provide opportunities for retrospective analysis and later iteration into clinical trials. PI3K, phosphoinositide 3-kinase.

Figure 3

Simplified schematic of the PI3K pathway, which highlights the common targets for small molecule inhibitors. Briefly, signalling from growth factors activates RTKs and recruits PI3K and other scaffold proteins to the cell membrane, where PIP₂ is converted to PIP₃. This recruits phosphoinositide-dependent kinase-1 (PDK1) and Akt to the membrane and leads to downstream signalling through the kinase activities of Akt. (1) Single-strand break repair is regulated primarily by PARP and inhibition of PARP can lead to genomic instability. (2) Double-stranded break repair is primarily regulated by a complex with BRCA2, which is lost in familial pancreatic cancer and some PDAC cases and can lead to genomic instability. Genomically unstable tumours require the PI3K pathway to maintain survival pathways and PI3K pathway inhibition may be an emerging option for patients with BRCA2 mutations or in combination with PARP inhibitors. More exhaustive pathway maps can be found in refs . P13K, phosphoinositide 3-kinase; RTKs, receptor tyrosine kinases.

Figure 4

Schematic of the formation of a hypoxic environment and the potential targeting of this microenvironment with HAPs. RBCs transport oxygen through the blood vasculature, and hypoxia forms when this diffusion-limited process delivers insufficient oxygen to cells distant to the vasculature (blue cells). The extreme case of anoxia (grey cells) regularly results in necrotic cell death. HAPs take advantage of the hypoxic environment of tumours to deliver cytotoxic compounds to these tumour regions, where the prodrug is either enzymatically cleaved by the cells metabolic machinery or undergoes a conformational change in response to the low oxygen partial pressure. HAPs, hypoxia-activated prodrugs; RBCs, red blood cells.