Summary of emerging personalized medicine in neuroendocrine tumors: are we on track?

Lee, Michael S.; O’Neil, Bert H.

doi:10.21037/jgo.2016.08.05

Cited by 9 publications

(6 citation statements)

References 111 publications

(117 reference statements)

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“…NETs can be categorized based on proliferative activity using the mitotic index and the Ki-67 index. G1 NETs have a low mitoses number and low Ki-67 index, G2 NETs have moderate proliferative activity, and G3 NETs are poorly differentiated with a high mitoses number or Ki-67 index [ 142 , 143 , 144 , 145 ]. NETs can be functional or non-functional depending on their ability to secrete specific hormones [ 80 , 83 ].…”

Section: Role Of Somatostatin Receptors In Neuroendocrine Tumorsmentioning

confidence: 99%

The Role of Receptor–Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

Milewska-Kranc,

Ćwikła,

Kolasinska-Ćwikła

2023

Cancers

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Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1–SSTR5). Understanding receptor–ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs’ significance as therapeutic targets is discussed. Additionally, somatostatin and analogues’ role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor–ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments.

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Section: Role Of Somatostatin Receptors In Neuroendocrine Tumorsmentioning

confidence: 99%

The Role of Receptor–Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

Milewska-Kranc,

Ćwikła,

Kolasinska-Ćwikła

2023

Cancers

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“…G1 NETs are classified by <2 mitoses/10 high-power fields and a Ki-67 index of <3%, G2 NETs are classified by 2-20 mitoses/10 high-power fields or a Ki-67 index of 3-20%. Well-differentiated G3 NETs are classified by >20 mitoses/10 high-power fields or a Ki-67 index of >20%, and poorly differentiated G3 NECs are classified by >20 mitoses/10 high-power fields or Ki-67 and expression alterations of p53 and Rb1 [1,[47][48][49]. Further classification depends on tumour location and functionality, and it is not uniform across different centres.…”

Section: Neuroendocrine Tumoursmentioning

confidence: 99%

Role of Somatostatin Signalling in Neuroendocrine Tumours

Rogoza

Megnis

Kudrjavceva

et al. 2022

IJMS

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Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.

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“…Mutations as well as aberrant activations in the PI3K-Akt-mTOR network were also observed in NENs ( 11 ). A series of clinical trials (RADIANT) resulted in the FDA-approval of everolimus for advanced pancreatic, non-functional gastrointestinal and lung NETs ( 12 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

mTOR Inhibitors as Radiosensitizers in Neuroendocrine Neoplasms

et al. 2021

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Peptide receptor radioligand therapy (PRRT) has evolved as an important second-line treatment option in the management of inoperable and metastatic neuroendocrine neoplasms (NEN). Though high radiation doses can be delivered to the tumors, complete remission is still rare. Radiosensitization prior to PRRT is therefore considered to be a promising strategy to improve the treatment effect. In this study, effect and mechanism of mTOR inhibitors were investigated in a comprehensive panel of five NEN cell lines (BON, QGP-1, LCC-18, H727, UMC-11), employing assays for cellular proliferation, clonogenic survival, cell cycle modification and signaling. mTOR inhibition lead to growth arrest with a biphasic concentration-response pattern: a partial response at approximately 1 nM and full response at micromolar concentrations (8–48 µM). All cell lines demonstrated elevated p70S6K phosphorylation yet also increased phosphorylation of counterregulatory Akt. The pulmonary NEN cell line UMC-11 showed the lowest induction of phospho-Akt and strongest growth arrest by mTOR inhibitors. Radiation sensitivity of the cells (50% reduction versus control) was found to range between 4 and 8 Gy. Further, mTOR inhibition was employed together with irradiation to evaluate radiosensitizing effects of this combination treatment. mTOR inhibition was found to radiosensitize all five NEN cells in an additive manner with a moderate overall effect. The radiation-induced G2/M arrest was diminished under combination treatment, leading to an increased G1 arrest. Further investigation involving a suitable animal model as well as radioligand application such as 177Lu-DOTATATE or 177Lu-DOTATOC will have to demonstrate the full potential of this strategy for radiosensitization in NEN.

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Summary of emerging personalized medicine in neuroendocrine tumors: are we on track?

Cited by 9 publications

References 111 publications

The Role of Receptor–Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

The Role of Receptor–Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

Role of Somatostatin Signalling in Neuroendocrine Tumours

mTOR Inhibitors as Radiosensitizers in Neuroendocrine Neoplasms

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