Relevance of somatostatin receptor expression in pancreatic neuroendocrine tumors for treatment with somatostatin analogues

The heterogeneous nature of the neuroendocrine tumors (NET) makes it challenging to find one uniformly applicable management protocol which is especially true for diagnosis. The discovery of the overexpression of somatostatin receptors (SMS-R) on neuroendocrine tumor cells lead to the generalized and rapid acceptance of radiolabeled somatostatin receptor analogs for staging and restaging of NET as well as for Peptide Receptor Radionuclide Therapy (PRRNT) using Y-90 and Lu-177 DOTATATE/DOTATOC. In this present work we tried to look in to the effect of PRRNT on the glucose metabolism assessed by F-18 FDG PET/CT and SMS-R density assessed by Ga-68 DOTANOC PET/CT. We observed a complex relationship between the somatostatin receptor expression and glucose metabolism with only 56% (77/138) of the lesions showing match, while the others show mismatch between the receptor status and metabolism. The match between receptor expression and glucose metabolism increases with the grade of NET. In grade 3 NET, there is a concurrence between the changes in glucose metabolism and somatostatin receptor expression. PRRNT was found to be more effective in lesions with higher receptor expression.

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Targeting Angiogenesis in Pancreatic Neuroendocrine Tumors: Resistance Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms20194949 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4949 ◽

Cited By ~ 2

Author(s):

Pozas ◽

San Román ◽

Alonso-Gordoa ◽

Pozas ◽

Caracuel ◽

...

Keyword(s):

Clinical Trials ◽

Neuroendocrine Tumors ◽

Peptide Receptor Radionuclide Therapy ◽

Standard Of Care ◽

Initial Response ◽

Somatostatin Analogues ◽

Resistance Mechanisms ◽

Phase Iii ◽

Pancreatic Neuroendocrine Tumors ◽

Optimal Sequence

Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.

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Treatment of Advanced Hepatocellular Carcinoma with Somatostatin Analogues: A Review of the Literature

International Journal of Molecular Sciences ◽

10.3390/ijms20194811 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4811

Author(s):

Hendrik Reynaert ◽

Isabelle Colle

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Current Knowledge ◽

Primary Liver Cancer ◽

Somatostatin Receptor ◽

Somatostatin Receptors ◽

Somatostatin Analogues ◽

Receptor Expression ◽

Surrounding Tissue ◽

Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma, one of the most dreaded complications of cirrhosis, is a frequent cancer with high mortality. Early primary liver cancer can be treated by surgery or ablation techniques, but advanced hepatocellular carcinoma remains a challenge for clinicians. Most of these patients have underlying cirrhosis, which complicates or even precludes treatment. Therefore, efficacious treatments without major side effects are welcomed. Initial results of treatment of advanced hepatocellular carcinoma with somatostatin analogues were promising, but subsequent trials have resulted in conflicting outcomes. This might be explained by different patient populations, differences in dosage and type of treatment and differences in somatostatin receptor expression in the tumor or surrounding tissue. It has been shown that the expression of somatostatin receptors in the tumor might be of importance to select patients who could benefit from treatment with somatostatin analogues. Moreover, somatostatin receptor expression in hepatocellular carcinoma has been shown to correlate with recurrence, prognosis, and survival. In this review, we will summarize the available data on treatment of primary liver cancer with somatostatin analogues and analyze the current knowledge of somatostatin receptor expression in hepatocellular carcinoma and its possible clinical impact.

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Asphericity of Somatostatin Receptor Expression in Neuroendocrine Tumors: An Innovative Predictor of Outcome in Everolimus Treatment?

Diagnostics ◽

10.3390/diagnostics10090732 ◽

2020 ◽

Vol 10 (9) ◽

pp. 732

Author(s):

Christoph Wetz ◽

Julian Rogasch ◽

Philipp Genseke ◽

Imke Schatka ◽

Christian Furth ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Progression Free Survival ◽

Receptor Expression ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Primary Tumor Site ◽

Risk Benefit Assessment ◽

Octreotide Scintigraphy

Background: in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET), the mTOR inhibitor everolimus is associated with significant improvement in progression-free survival (PFS). This study evaluated the lesional asphericity (ASP) in pretherapeutic somatostatin receptor (SSR) imaging as the first imaging-based prognostic marker for PFS. Methods: this retrospective bicentric cohort study included 30 patients (f = 13, median age, 66.5 (48–81) years) with pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®). ASP of functional volumes of up to three leading lesions per patient (n = 74) was calculated after semiautomatic, background-adapted segmentation. Uni- and multivariable Cox regression regarding PFS for clinical factors and the maximum ASP per patient was obtained. Results: all 30 patients showed metachronous or progressive liver metastases. ASP, primary tumor site, metastases pattern, and prior peptide receptor radionuclide therapy (PRRT) were significantly associated with PFS in univariable Cox regression. Only ASP > 12.9% (hazard ratio (HR), 3.33; p = 0.024) and prior PRRT (HR, 0.35; p = 0.043) remained significant in multivariable Cox. Median PFS was 6.7 months for ASP > 12.9% (95% confidence interval (CI), 2.1–11.4 months) versus 14.4 (12.5–16.3) months for ASP ≤ 12.9% (log-rank, p = 0.028). Conclusion: pretherapeutic ASP of SSR positive lesions independently predicted PFS for treatment with everolimus in GEP-NET. ASP may supplement risk-benefit assessment before patient inclusion to treatment.

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Erratum: Okuwaki K, Kida M, Mikami T, Yamauchi H, Imaizumi H, Miyazawa S, Iwai T, Takezawa M, Saegusa M, Watanabe M and Koizumi W. Clinicopathologic characteristics of pancreatic neuroendocrine tumors and relation of somatostatin receptor type 2A to outco

Cancer ◽

10.1002/cncr.28584 ◽

2014 ◽

Vol 120 (8) ◽

pp. 1283-1285

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Receptor Type ◽

Pancreatic Neuroendocrine Tumors ◽

Clinicopathologic Characteristics

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Clinicopathologic characteristics of pancreatic neuroendocrine tumors and relation of somatostatin receptor type 2A to outcomes

Cancer ◽

10.1002/cncr.28341 ◽

2013 ◽

Vol 119 (23) ◽

pp. 4094-4102 ◽

Cited By ~ 31

Author(s):

Kosuke Okuwaki ◽

Mitsuhiro Kida ◽

Tetuo Mikami ◽

Hiroshi Yamauchi ◽

Hiroshi Imaizumi ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Receptor Type ◽

Pancreatic Neuroendocrine Tumors ◽

Clinicopathologic Characteristics

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Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors

Medicine ◽

10.1097/md.0000000000001281 ◽

2015 ◽

Vol 94 (40) ◽

pp. e1281 ◽

Cited By ~ 27

Author(s):

Shreya Mehta ◽

Philip R. de Reuver ◽

Preetjote Gill ◽

Juliana Andrici ◽

Lisa D’Urso ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67

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Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Cancers ◽

10.3390/cancers13205117 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5117

Author(s):

Chandra K. Maharjan ◽

Po Hien Ear ◽

Catherine G. Tran ◽

James R. Howe ◽

Chandrikha Chandrasekharan ◽

...

Keyword(s):

Drug Resistance ◽

Neuroendocrine Tumors ◽

Molecular Mechanisms ◽

Treatment Options ◽

Somatostatin Receptor ◽

Therapeutic Targets ◽

Model Systems ◽

Pancreatic Neuroendocrine Tumors ◽

Acquired Drug Resistance ◽

Molecular Alterations

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

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