Elsevier

Cancer Treatment Reviews

Volume 41, Issue 9, November 2015, Pages 754-760
Cancer Treatment Reviews

Laboratory-Clinic Interface
Dual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: From bench to bedside

https://doi.org/10.1016/j.ctrv.2015.06.008Get rights and content

Highlights

  • Clinical trials reported a potential synergistic effect of sunitinib in combination to rapalogs in some advanced cancers.

  • Several VEGF pathway inhibitors have shown clinical activity in NENs.

  • Sunitinib exhibits a weak cytotoxic activity due to its inhibitory effect on VEGFR2 signalling.

  • Inhibition of Akt/mTOR signalling sensitises resistant cancer cells to treatment with sunitinib.

  • We discuss the role of dual blockade of VEGF and mTOR pathway, focusing on current studies and future perspectives.

Abstract

After years of limited progress in the treatment of neuroendocrine neoplasms (NENs), an increasing number of therapeutic targets have recently emerged as potential tools to improve disease outcome. The mammalian target of rapamycin (mTOR) pathway and vascular endothelial growth factor (VEGF) signalling are implicated in the regulation of cell growth, proliferation, neo-angiogenesis and tumour cell spread. Their combined blockade, in a simultaneous or sequential strategy, represents an intriguing biological rationale to overcome the onset of resistance mechanisms. However, is becoming increasingly imperative to find the optimal sequential strategy according to the best toxicity profile, and also to identify predictive biomarkers. We will provide an overview of the pre-clinical and clinical data relating to mTOR pathway/VEGF signalling as a potential targets of treatment in NENs.

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.

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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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      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.

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