Laboratory-Clinic InterfaceDual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: From bench to bedside
Graphical abstract
In neuroendocrine tumours, mTOR pathway plays a central role with VEGF signalling pathway and Met upregulation, stimulating cell proliferation, survival and angiogenesis: under hypoxia conditions, the HIF upregulation induces mTOR activation by TSC1/2, VEGF production and Met upregulation through CRCX4.
Introduction
Over the last decades, accumulating knowledge of the pivotal molecular mechanisms in NENs has led to several studies exploring targeted therapies against VEGF and phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathways. The recent approval of sunitinib and everolimus in this setting has yielded promising therapeutic options for patients with pancreatic NENs (PNENs). Moreover, recent pre-clinical studies have reported a potential synergistic effect of a combination of sunitinib and rapalogs in some types of advanced cancers, thereby providing a rationale for initiating clinical trials to assess the potential therapeutic advantages of the combination in patients. However, the design of clinical studies is challenged by the lack of clear criteria for an optimal protocol regarding whether to administer the combination, simultaneously or sequentially, and if the latter, in what order. Furthermore, although these two agents have clearly shown statistically-significant clinical benefit in terms of progression-free survival (PFS) in PNENs, a number of tumours show intrinsic or acquired resistance. Both de novo and acquired resistance share similar molecular and cellular mechanisms. Therefore there is a strong need to investigate treatments which could overcome the possible mechanisms of resistance targeting the two pathways. This review focuses on the role of mTOR and VEGF in the development of NENs, the possible mechanisms of resistance to mTOR inhibitors (mTOR-I) and anti-VEGF agents, the state of the art of co-targeting these two pathways and possible future scenarios.
Section snippets
The mTOR pathway in cancer
mTOR is a serine-threonine kinase that plays a critical role in regulating cell growth, proliferation and protein synthesis [1], [2]. All the members of PI3K/Akt/mTOR pathway, from the upstream receptor tyrosine kinases (RTK) inducers to the final effectors, have been associated with cancer development and progression: PI3K amplification, AKT overexpression as well as loss of phosphatase and tensin homolog (PTEN) function can be molecularly altered in cancer cells [3], [4]. Altered activity of
Alterations of mTOR pathway in NENs
Deregulated activity of the mTOR pathway has been described in NENs [9]. Mutations in PI3KCA, at the p110alfa subunit, were identified in 1.4% of PNENs, whereas, to date, no data relative to PI3K amplification or data regarding Akt amplification are available in NENs [10]. A recent expression profiling of PNENs has shown that the activation of mTOR pathway in those tumours is mainly attributed to alterations of tuberous sclerosis complex-2 (TSC2) and PTEN protein expression (in 16% of cases)
VEGF signalling in cancer
Angiogenesis is a hallmark for tumour growth as well as for development of metastases [19]. The VEGF family consists of 5 structurally related factors: VEGF-A, -B, -C, -D and placenta growth factor (PlGF). VEGF-A is considered to be the key player in tumour angiogenesis. VEGF-B is an inefficient factor for induction of angiogenesis. VEGF-C and D induce venous and lymphatic angiogenesis [20]. The complexity is increased further by alternative splicing and processing, that induce changing in
Dual inhibition of mTOR pathway and VEGF signalling in NENs/Rationale for clinical dual inhibition of VEGF signalling-mTOR pathway
Accumulating knowledge of the molecular mechanisms that are pivotal in pNEN pathogenesis, such as the role of the PI3K/Akt/mTOR as well as the angiogenic pathways, have led to the development of new target-specific drugs with demonstrable efficacy in the clinic. More recent studies support the rationale for combination treatment and dual/multitargeted agents, with the aim of targeting different components of the above reported pathways. This strategy has the potential to both overcome
Conclusion
After years of limited progress in the treatment of patients with advanced-stage GEP NENs, strategies using targeted agents have been developed on the basis of increased knowledge of the biology of these tumours. Particularly, targeted therapies against VEGF signalling and mTOR pathways have altered the management of metastatic disease both in NENs and other solid tumours. Outward randomized clinical trials, the reiterating use of several single agents in clinical practice, has induced a
Conflict of interest
None.
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Targeting angiogenesis in hepatocellular carcinoma
2022, Theranostics and Precision Medicine for the Management of Hepatocellular Carcinoma, Volume 2: Diagnosis, Therapeutic Targets, and Molecular MechanismsEffects of islet neogenesis associated protein depend on vascular endothelial growth factor gene expression modulated by hypoxia-inducible factor 1-alpha
2019, PeptidesCitation Excerpt :VEGF-A is also expressed in islet β-cells, and its presence is necessary for correct pancreatic growth and development of islet-specific capillary fenestrations [27–30]. VEGF-A exerts its effects through a tyrosine kinase receptor that activates PI3K [31] and mTOR pathways [32–34]. Also, we recently demonstrated that INGAP-PP effects on β-cell mass and function are significantly associated with islet angiogenesis and VEGF-A production/release.
INGAP-PP effects on β-cell mass and function are related to its positive effect on islet angiogenesis and VEGFA production
2018, Molecular and Cellular EndocrinologyCitation Excerpt :Concurrently, we recently demonstrated that PI3K/AKT pathway participates in the mechanism by which INGAP-PP increases islet glucokinase activity, glucose metabolism and tyrosine phosphorylation of insulin receptor and also insulin receptor substrates (IRS1 and IRS2) (Chang et al., 2011). Downstream effectors of PI3K cascade also modulate mTORC pathway, which in turn up-regulates multiple processes including angiogenesis (Dibble and Manning, 2013; Cella et al., 2015; Ersahin et al., 2015). The fact that Rapamycin significantly decreased insulin and VEGFA secretion in the presence or absence of INGAP-PP strongly suggests that mTORC pathway could actively participate in the mechanism by which INGAP-PP enhances VEGF-A secretion.
TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors
2016, Molecular and Cellular EndocrinologyCitation Excerpt :However, a large proportion of patients either presents with metastatic spread at initial work-up or with recurrence during follow-up examination. While for NETs in recent years accumulating insights into molecular mechanisms led to the development of promising therapeutic strategies blocking VEGF and mTOR signaling (Cella et al., 2015), clinical studies with targeted therapies for patients with ACC were unfortunately mainly disappointing so far (Fassnacht et al., 2015; Else et al., 2014). Thus, more insights into mechanisms of drug resistance are urgently needed.