Current Scientific Rationale for the Use of Somatostatin Analogs and mTOR Inhibitors in Neuroendocrine Tumor Therapy
ABSTRACT Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR).
The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy.
The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which preferentially target subtype 2) and thus has a broader spectrum of activity. Everolimus is a rapamycin analog that inhibits mTOR, but it is more soluble than rapamycin and can be administered orally. mTOR is a protein kinase involved in many signaling pathways, primarily those initiated by tyrosine kinase receptors. Sustained mTOR activity leads to the induction of cell growth, proliferation, and cell survival. Everolimus therefore has obvious potential in cancer therapy.
The combination of somatostatin analogs and everolimus in therapeutic trials offers a promising treatment option for neuroendocrine tumors.
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ABSTRACT: Androgen deprivation therapy has become the fist-line treatment of metastatic prostate cancer; however, progression to castrate resistance disease occurs in the majority of patients. Thus, there is an urgent need for improvements in therapy for castration-resistant prostate cancer. The aims of the present study were to determine the efficacy somatostatin analogue octreotide (OCT) combined with a low dose of docetaxel (DTX) using castration resistant prostate cancer cells and to investigate the involved molecular mechanisms in vitro. The anti-proliferative and synergism potential effects were determined by MTT assay. Induction of apoptosis was analyzed employing annexing V and propidium iodide staining and flow cytometry. VEGFA, CASP9, CASP3 and ABCB1 gene expression was evaluated by RT-PCR and Q-RT-PCR analysis. OCT in combination with DTX treatments on DU145 cell migration was also evaluated. Investigation revealed that combined administration of DTX and OCT had significant, synergistically greater cytotoxicity than DTX or OCT treatment alone. The combination of the two drugs caused a more marked increase in apoptosis and resulted in greater suppression of invasive potential than either individual agent. There was obvious increase in caspase 3 expression in the OCT alone and two-drug combined treatment groups, however, VEGFA expression was markedly suppressed in them. These results support the conclusion that somatostatin analogues combined with docetaxel may enhance the chemotherapy efficacies through multiple mechanisms in castration-resistant PCa cell line. This work provides a preclinical rationale for the therapeutic strategies to improve the treatment in castrate resistance disease.PLoS ONE 03/2014; 9(3):e91817. DOI:10.1371/journal.pone.0091817 · 3.53 Impact Factor
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ABSTRACT: Purpose To characterize the heterogeneity of metastatic neuroendocrine tumor (NET) lesions, we compared the [18F]-fluorodeoxyglucose (FDG) uptake and the 111In-pentetreotide (SRS) uptake for somatostatin receptor scintigraphy using the CT-based fusion imaging techniques of PET/CT and SPECT/CT. Methods Fifteen consecutive patients with NET lesions were examined using both FDG-PET/CT and SRS SPECT/CT prospectively. A total of 45 metastatic NET lesions were evaluated for FDG uptake according to the standardized uptake value (SUV) and for SRS uptake according to the tumor-to-muscle count ratio (T/M ratio); these values were then compared according to the grade of NET (G), also compared to the tumor volume. Results Both the SRS uptake and FDG uptake showed no significant correlation to the tumor volume, and suggested no significant artifacts in these data. The T/M ratio for the SRS uptake ranged from 192.7 to 1.9 and exhibited very wide range of distribution. The SUV for the FDG uptake ranged from 13.8 to 0.77 and exhibited narrow range of distribution. The uptake of the two tracers in individual lesions showed an inverse correlation. The G1 + 2 lesions had a higher SRS uptake than the G3 lesions, but the difference was not significant because of the large variation (40.65 ± 48.03, n = 39 vs. 8.66 ± 13.13, n = 6). However, the G1 + 2 lesions had a significantly lower FDG uptake than the G3 lesions (3.52 ± 1.84, n = 39 vs. 10.82 ± 4.50, n = 6). The tracer uptakes varied largely not only in an inter-subject manner, but also in an intra-subject manner. Conclusion An inverse correlation between SRS uptake and FDG uptake in the metastatic NET lesions observed in this study may be consistent with the opposing ideas of differentiation and proliferation in oncology. The large variations in SRS and FDG uptake by metastatic NET lesions suggest the biological heterogeneity of advanced NET. These results support the idea that combination therapy targeting both receptor-positive cells and proliferating cells may be beneficial from a functional imaging perspective.Annals of Nuclear Medicine 09/2014; 28(10). DOI:10.1007/s12149-014-0900-3 · 1.51 Impact Factor
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ABSTRACT: Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Well-differentiated NETs can be broadly classified as either carcinoid or pancreatic NET. Although they have similar characteristics on routine histologic evaluation, the 2 tumor subtypes have different biology and respond differently to treatment, with most therapeutic agents demonstrating higher response rates in pancreatic NETs compared with carcinoid. Until recently, systemic treatment options for patients with advanced NETs were limited. However, improvements in our understanding of signaling pathways involved in the pathogenesis, growth, and spread of NETs have translated into an expansion of treatment options. Aberrant signaling through the mechanistic pathway of rapamycin (mTOR) pathway has been implicated in neuroendocrine tumorigenesis. Additionally, altered expression of mTOR pathway components has been observed in NETs and has been associated with clinical outcomes. Targeting the mTOR pathway has emerged as an effective treatment strategy in the management of advanced NETs. In a randomized, placebo-controlled study of patients with advanced pancreatic NET, treatment with the mTOR inhibitor everolimus was associated with improved progression-free survival (PFS). Largely based upon these data, everolimus has been approved in the United States and Europe for the treatment of patients with advanced pancreatic NET. The activity of everolimus remains under investigation in patients with carcinoid tumors. In a randomized study of patients with advanced carcinoid tumors associated with carcinoid syndrome, the addition of everolimus to octreotide was associated with improved PFS compared with octreotide. However, the results did not meet the prespecified level of statistical significance based on central review of radiographic imaging. Results from a randomized study examining the efficacy of everolimus in patients with nonfunctional gastrointestinal and lung NETs are awaited. In addition, further investigation is needed to determine whether primary tumor site or other clinical and molecular factors can impact response to mTOR inhibition. Although everolimus can slow tumor progression, significant tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with targeting a single pathway. Results of ongoing and future studies will provide important information regarding the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.Current Treatment Options in Oncology 08/2014; 15(3). DOI:10.1007/s11864-014-0294-4 · 3.24 Impact Factor