Download Study title : CYTOKINES AS PREDICTIVE FACTORS OF

STUDY TITLE : CYTOKINES AS PREDICTIVE FACTORS OF RESPONSE TO SSA
TREATMENT IN NEUROENDOCRINE TUMOUR PATIENTS
SCIENTIFIC LEADER (NAME, LOCATION): Prof. Michele Caraglia Department of
Biochemistry, Biophysics and General Pathology II University of Naples.
STUDY DESIGN :
The aim is to analyze significant differences in cytokine levels and before and after SSA treatment
in NET. A ROC (Receiver-Operator Curve) will be created to determine the predictive value of the
cytokines levels.
Background: Neuroendocrine tumors (NETs) are rare, usually slow growing, neoplasms
characterized by the ability to store and secrete different peptides and neuroamines. Some of these
substances cause a specific clinical syndrome. It is important to be able to recognize from the
clinical presentation the most useful markers to reduce time and costs and that way facilitate the
diagnosis and make wise use of resources.
It was observed that tumor cells could synthesize CKs (1). As a consequence, CKs are not only
central mediators of lymphoid cell interactions, but they may also act as tumor growth factors (e.g.,
IL-8) (2); alternately, through their immune regulatory properties, they may allow tumor evasion
from immune surveillance (3).
Previous studies documented a number of growth factor responsive genes in human NE GI tumour
cells, shedding new light into the molecular mechanisms involved in growth control of these cells
(4)
Therefore, cytokine panels could serve as cancer biomarkers for early diagnosis and assessment of
response to therapy.
Several recent studies with prostate cancer cells have demonstrated that IL-6 can promote NE
differentiation through different intracellular signal transduction pathways, including the
phosphatidylinositol 3-kinase/epithelial and endothelial tyrosine kinase (PI 3-kinase/Etk) pathway
(5), signal transducers and activators of transcription 3 (STAT3) pathway (6), and mitogenactivated protein kinase (MAPK) pathway (7, 8). The protein of erbB2 gene, one member of the
erbB gene family, is shown to be a critical component of IL-6 signaling through the MAPK
pathway (8). Data suggest that IL-6 acts as an autocrine and paracrine growth factor in hormone
refractory human prostate cancer cell lines, and, in contrast, as a paracrine growth inhibitor in
hormone-dependent cell lines (5).
IL-2 is a potent proinflammatory cytokine and a key regulatory cytokine in T cell-dependent
immunity. According to Quian et al. (9), IL-2-deficient mice have lower values of gastrointestinal
neuroendocrine peptides, and Garrelds et al. (10) found that IL-2-deficient mice are more
susceptible to gastrointestinal inflammation. SST analogues inhibit the secretion of
autocrine/paracrine effectors of tumour cell survival such as the IGF-1 and -2, EGF, interleukin-6
and the transforming growth factor family. The attenuation of secretion of such survival factors in
the tumour microenvironment accordingly establishes an
autocrine/paracrine anti-proliferative effect (11).
Considering Somatostatin analogs treatment, octreotide has been demonstrated to inhibit early TNFα production and localization in experimental chronic colitis (12); furthermore, somatostatin
suppresses TNF-α secretion in activated human monocytes (13). Moreover the increase of IL10
production seems to characterize the antiproliferative effect of octreotide (14) and the expression on
T cells of SST3 is well documented (15). Lattuada et al demonstrated that octreotide and pasireotide
inhibit γ-interferon production and the lattest also IL2 release (16).
A study demonstrate that a lanreotide significantly suppresses smooth muscle cell replication in
allograft arteriosclerosis (chronic rejection) and delays the generation of arteriosclerotic changes in
nonimmuno-suppressed recipients concomitantly reducing growth factors in the vascular wall as
they were the effector molecules of smooth muscle cell replication (17).
Study Design:
Aim of the present study is to investigate the presence of the following different cytokines: IL-1β,
IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, tumour necrosis factor (TNF)-α,
granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor
(GM-CSF), IFN-γ, macrophage inflammatory protein (MIP)-1β, monocyte chemotactic protein
(MCP), MMP-2 and MMP-9.
Cytokines evaluation as predictive factors of tumoral response to SSAs in NETs will be analyse test
stored blood samples of patients diagnosed to be affected by NET and previously treated with
Lanreotide.
Inclusion criteria:
- Locally inoperable advanced disease or metastatic disease, both with carcinoid syndrome or
functionally inactive;
- Patients naïve to SSA treatment;
- Patients at least a month of suspension from any other specific cancer treatment.
Methods:
Peripheral blood serum from NET patients have been periodically collected and stored at -80 °C.
Samples have been collected before treatment started, about once a month, for one year, according
to clinical practice.
Before starting data collection patients have been asked to sign an informed consent for blood
samples analysis.
STATISTICAL EVALUATION:
To analyze significant differences in cytokine levels before and after treatment a t-student test will
be performed. Statistical significance will be defined with α = 0.05. Receiver-operator curves
(ROC) will be created to determine the predictive value of the cytokines.
STUDY POPULATION : The tests will be performed on 30 WDNET patients.
STUDY ENDPOINTS :
PRIMARY EFFICACY ENDPOINT : Prognostic significance evaluation of cytokine panel for
the prediction of response to SSA treatment in individual patients.
SAFETY END POINTS AND EVALUATIONS : N.A.
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