Page 59 - Read Online

neoplasms. [79-80] IGF-1 receptors (IGF-1R), binding Kulke et al. [116] conducted a phase II trial evaluating
IGF-1, activate signals inside normal neuroendocrine the efficacy of sunitinib in GEP-NETs. They showed a
cell, through components of the PI3K/Akt/mTOR significant antitumor activity in P-NETs vs. carcinoid
and the Ras/Raf/MEK/ERK pathways, [82-86] inducing tumors and good tolerance. In addition, in a phase III trial
cellular proliferation and over-regulating antiapoptotic involving low- and intermediate-grade advanced P-NETs,
activity. [81] [Figure 1] IGF-1 receptors, then, are usually Raymond et al. [117] demonstrated a better PFS in the arm
overexpressed in NETs, [87-90] especially in symptomatic of sunitinib compared to placebo. The improved PFS did
and functioning ones. This represents a possible role not depend on previous treatments or concomitant SSAs.
in tumorigenesis of GEP and bronchial NETs and a Therefore, sunitinib is approved for the treatment of
potential target for therapy. [91-93] The rationale for the P-NETs after disease progression.
use of IGF1R inhibitors depends on their theoretical
capability to reduce AKT phosphorylation induced by Considering the importance of VEGF in the pathogenesis
mTOR inhibitors. [94-96] of NENs, bevacizumab, an anti-VEGF antibody, has
been used either alone or in combination with other drugs
In this regard, cixutumumab, a fully human with favorable results. A phase II trial, in particular,
immunoglobulin G1 monoclonal antibody competitively enrolled patients with advanced carcinoid tumors with
binding IGF-1R, is in the early phases of clinical stable doses of octreotide to receive either bevacizumab
progress. [97] Cixutumumab is still studied in association or pegylated Interferon α2b. Bevacizumab showed
with octreotide LAR in an ongoing phase II study superiority in objective responses, reduction of tumor
enrolling patients with progressing metastatic P-NETs blood flow, and PFS. [118,119] Bevacizumab in association
and midgut carcinoid tumors. [98] Also, the combination with temozolomide in patients with metastatic NETs also
of cixutumumab, everolimus, and octreotide is being showed a major response rate, PFS, and OS in P-NETs. [120]
evaluated in a phase I trial conducted in patients with
advanced low- or intermediate-grade neuroendocrine In another recently completed phase II study, everolimus
tumors for which standard curative measures do not exist and bevacizumab were shown to be associated with an
(Clinical Trial: NCT01204476). Another similar phase overall tumor response rate of 26% and good tolerance in
I trial was performed in advanced cancer patients, with advanced P-NETs. [121] Therefore, a further phase II trial
candidates receiving temsirolimus with cixutumumab. The will compare everolimus alone with the combination of
[99]
preliminary results showed good tolerance. [Table 3] everolimus and bevacizumab in patients with P-NETs, in
order to find supplementary function of antiangiogenetic
Similarly, ganitumumab, another fully human monoclonal agents in this setting of patients (ClinicalTrials. Gov
antibody against IGF-1R, is undergoing evaluation Identifier: NCT01229943). Randomized studies of anti-
in clinical trials. Rothenberg et al. [100] demonstrated VEGF TKI should also be evaluated in patients with
encouraging activity and good tolerance in a phase I trial
including previously treated metastatic NET patients advanced carcinoid tumors.
[Table 3]. Strosberg et al. [101] performed a phase II study Pazopanib is an oral bioavailable, multitargeted tirosine
of ganitumumab in patients with metastatic progressive
low- and intermediate-grade carcinoids or P-NETs. kinase inhibitor (VEGF receptors 1, 2, and 3), involved
[122]
This trial showed a good tolerance of ganitumumab, in reducing neoplastic growth and dissemination.
[123]
but no objective responders [Table 3]. Further studies Ahn et al. demonstrated, in a non-randomized, open-
are necessary to deepen the role of cixutumumab and labeled, single-center phase II trial, that pazopanib in
ganitumumab and to identify other IGF-1R targets. monotherapy was as effective as the other available
targeted therapies, not only in P-NETs, but also in GI
VEGF AND ITS RECEPTOR INHIBITORS NETs [Table 4]. Phan et al. [124,125] found that pazopanib
in combination with octreotide LAR depot was more
Neuroendocrine neoplasms, especially for midgut and effective in advanced G1-G2 P-NETs than in advanced
P-NETs and bronchial carcinoids, are highly vascularized carcinoid tumors [Table 4].
and overexpress vascular endothelial growth factor
(VEGF) and its receptors. [102,103] Four VEGF forms are Other trials with pazopanib, and with other multitarget
individuated and examined: VEGF-A, VEGF-B, VEGF-C, agents such as famitinib (c-kit, platelet-derived growth
and VEGF-D, [104-108] with a different affinity to their three factor receptor (PDGFR), VEGFR2, VEGFR3, Flt1 and
own receptors. [109-113] [Figure 1] For these reasons, the Flt3 inhibitor), regorafenib (c-Raf; BRAF, VEGFR-1,2,3;
interest of angiogenesis inhibition was encouraged. PDGFRα, Fibroblast Growth Factor Receptor (FGFR)-
1; c-kit; RET; Flt-3 inhibitor), and nintedanib (VEGFR,
The small molecule tyrosine kinase inhibitor (TKI) FGFR, PDGFR inhibitor) are ongoing. Some of them
sunitinib has been studied as a targeted therapy option are also enrolling patients with bronchopulmonary
in NENs. Based on these results in term of response rate NETs (Clinical Trial: NCT01280201; NCT01994213;
that were observed in phase I trial with sunitinib, [114,115] NCT02259725; NCT02399215). [126-128]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦ 335