Interaction between somatostatin analogues and targeted therapies in neuroendocrine tumor cells

Abstract

Somatostatin analogues (SSA) represent the standard of care for symptom control in patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In addition, SSA exert significant anti-proliferative effects in mid-gut and pancreatic NET (PanNET). In parallel, molecularly targeted therapies (MTT) have been shown to improve progression free survival (PFS) in patients with PanNET. However, due to either primary or acquired resistance to MTT, their impact on overall survival (OS) remains unclear. To date, various hypotheses exist to explain differences in patient responsiveness to SSA and MTT. However, data addressing one of the most pivotal questions, whether combining SSA with novel MTT will result in synergistic or additive efficacy compared to monotherapy, are lacking. The aim of this study is to characterize the interaction, optimal sequence and dosing of SSA-based and molecularly targeted therapies in PanNET. Somatostatin receptor subtypes 1–5 (SSTR) were evaluated in the neuroendocrine cell lines Bon1, QGP1 and Ins-1 via immunoblot and qRT-PCR. The impact of the SSA-analogue lanreotide alone or in combination with the MTT sunitinib, everolimus and regorafenib on intracellular signalling, hormone secretion and cell proliferation was determined in cell lysates and supernatants. In addition, synergistic effects of SSA and MTT in various sequential therapeutic approaches were investigated. SSTR were differently expressed in the examined neuroendocrine tumor cell lines. SSTR modulation via lanreotide moderately influenced proliferation, mainly via modulating AKT and ERK signalling, which was paralleled by decreased chromogranin A (CgA) expression and secretion. Interestingly, MTT treatment with regorafenib upregulated the expression of SSTR-2 and -5, while sunitinib and everolimus did not significantly alter SSTR expression. Cell viability was significantly reduced by all MTT, with regorafenib exerting the most significant effects. However, compared to the marked effects of MTT alone, synergistic effects of combined MTT and lanreotide treatment were only modest and time- and dose-dependent. SSTR are differentially expressed in various NEN cell lines. Their expression is influenced by MTT treatment. Various sequential or simultaneous combinations of lanreotide and MTT did not lead to significant synergistic effects.

PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

“…Vitale and colleagues showed a synergy between everolimus and demethylating agent 5-aza-2 0 -deoxycytidine (AZA) in chemoradiotherapy resistant medullary thyroid cancer cells (23). We did not observe any synergy with everolimus and somatostatin analogs which is in agreement with the findings of Krug and colleagues (24), however, a study has demonstrated that lanreotide inhibited the cell growth syngergistically in everolimus-resistant BON1 cells (25). In contrast, Hue-Fontaine and colleagues did not observed synergy between everolimus and metformin in the diabetic patients (26) maybe because of the targeting of same pathway.…”

Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma

“…SSTR2 are not only expressed by neuroendocrine neoplastic cells, but also by some tumor-infiltrating B-cells. Hence, direct anti-proliferative effects of octreotide on both neoplastic and immune cells of the tumor microenvironment are possible [ 34 ]. On the other hand, it is tempting to speculate that, by targeting neoplastic lymphocytes, PRRT may have coincidently improved the immunocompetence status of our CLL patients, as the peripheral lymphocyte counts of both patients substantially decreased during treatment, and neither patient showed CLL exacerbation.…”

Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs)

“… 18 Expression of somatostatin receptors 2 and 5 is common in NETs, and these receptors modulate hormone and growth-factor release, angiogenesis, and other functions. 19 SSAs are first-line therapy for well-differentiated G1 or G2 tumors with somatostatin receptor expression and are approved as treatment for the hormonal-induced syndromes, including carcinoid syndrome, associated with functional NETs. The PROMID and CLARINET studies demonstrated the antiproliferative effects of SSAs in patients with well-differentiated NETs.…”