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Cancers
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Resistant Gastroenteropancreatic Neuroendocrine Tumors
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Resistant Gastroenteropancreatic Neuroendocrine Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 22930

Special Issue Editor

Dr. Lowell B. Anthony

E-Mail Website
Guest Editor
Division of Medical Oncology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA
Interests: neuroendocrine cancer; gastrointestinal malignancies

Special Issue Information

Dear Colleagues,

From their first histologic description in 1867 to defining their genetic basis, neuroendocrine tumors (NE) have generated much controversy with respect to their classification, clinical behavior and complex biomarkers.  Advances in NE biology over the last century include the discovery and description of the NE cells that are present in all embryonic germ layers.  Kulchitsky, enterochromaffin-like (ECL), islet and Merkel cells comprise the NE system of the lung, gastrointestinal, pancreas and skin, respectively.  Common characteristics of NE cells include the expression of the somatostatin receptor and the release of bioactive amines and peptides including serotonin, histamine, kinins, gastrin, insulin, glucagon, vasoactive intestinal peptide, somatostatin, ghrelin and other substances that may give rise to paraneoplastic syndromes such as ectopic ACTH, PTHrp and ADH.  Linking these bioactive substances to specific clinical syndromes has resulted in the basis of our understanding of the pathophysiology. Now, after advances in both the basic and clinical sciences, including nucleic acid and protein chemistry and genomics, there is a comprehensive understanding of GEPNETs resulting in improved outcomes.  Advances in pathology, procedural techniques, imaging, medical and radiation therapeutics, GEPNETs patients are commonly managed by multi-specialty teams focused on the unique characteristics of NETs.  As we move into the next decade of GEPNETs, the challenges now include the recognition and management of refractory disease.  This special issue of Cancers is focused on identifying and targeting molecular pathways of resistance, reporting original clinical research and reviewing the clinical management of GEPNETs 'beyond the first line'.

Dr. Lowell B. Anthony
Guest Editor

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Keywords

  • pancreatic neuroendocrine neoplasms
  • preclinical models
  • pathophysiology
  • molecular genetics
  • diagnosis
  • biomarkers
  • surgical management
  • medical management
  • theranostics
  • clinical trials
  • neuroendocrine tumors
  • carcinoid tumor
  • carcinoid syndrome
  • GEP-NET
  • serotonin
  • gastrointestinal neoplasms
  • colorectal neoplasms

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Published Papers (6 papers)

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Research

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8 pages, 1462 KiB  
Article
hPG80 (Circulating Progastrin), a Novel Blood-Based Biomarker for Detection of Poorly Differentiated Neuroendocrine Carcinoma and Well Differentiated Neuroendocrine Tumors
by Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Léa Payen, Younes Mahi, Berengere Vire, Madison Sands, B. Mark Evers, Dominique Joubert and Lowell Anthony
Cancers 2022, 14(4), 863; https://doi.org/10.3390/cancers14040863 - 9 Feb 2022
Cited by 4 | Viewed by 3768
Abstract
Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. Human circulating progastrin (hPG80) is a novel biomarker that can be easily measured in plasma by ELISA. This study is the first to examine hPG80 in NENs. Plasma [...] Read more.
Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. Human circulating progastrin (hPG80) is a novel biomarker that can be easily measured in plasma by ELISA. This study is the first to examine hPG80 in NENs. Plasma hPG80 was quantified from 95 stage IV NEN patients, using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in two cohorts of healthy donor controls aged 50–80 (n = 252) and 18–25 (n = 137). Median hPG80 in NENs patients was 5.54 pM compared to 1.5 pM for the 50–80 controls and 0.29 pM the 18–25 cohort (p < 0.0001). Subgroup analysis revealed median hPG80 levels significantly higher than for either control cohort in neuroendocrine carcinoma (NEC; n = 25) and neuroendocrine tumors (NET; n = 70) including the small-cell lung cancer (SCLC) sub-cohort (n = 13). Diagnostic accuracy, estimated by AUCs, was high for NENs, as well as both sub-groups (NEC/NET) when compared to the younger and older control groups. Plasma hPG80 in NENs may be a diagnostic blood biomarker for both low- and high-grade NENs; further study is warranted. A prospective multi-center trial is ongoing in NET to evaluate hPG80 as a means of monitoring disease (NCT04750954). Full article
(This article belongs to the Special Issue Resistant Gastroenteropancreatic Neuroendocrine Tumors)
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Review

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18 pages, 524 KiB  
Review
Grade Progression and Intrapatient Tumor Heterogeneity as Potential Contributors to Resistance in Gastroenteropancreatic Neuroendocrine Tumors
by Diana Grace Varghese, Jaydira Del Rivero and Emily Bergsland
Cancers 2023, 15(14), 3712; https://doi.org/10.3390/cancers15143712 - 21 Jul 2023
Cited by 2 | Viewed by 1808
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (NENs) are a heterogenous group of tumors that are incurable when metastatic, regardless of grade. The aim of this article is to understand tumor heterogeneity and grade progression as possible contributors to drug resistance in gastroentropancreatic neuroendocrine tumors (GEP-NETs). Heterogeneity [...] Read more.
Gastroenteropancreatic neuroendocrine neoplasms (NENs) are a heterogenous group of tumors that are incurable when metastatic, regardless of grade. The aim of this article is to understand tumor heterogeneity and grade progression as possible contributors to drug resistance in gastroentropancreatic neuroendocrine tumors (GEP-NETs). Heterogeneity has been observed in the genetic, pathological, and imaging features of these tumors at baseline. Diagnostic challenges related to tumor sampling and the potential for changes in grade over time further confound our ability to optimize therapy for patients. A better understanding of NEN biology and tumor heterogeneity at baseline and over time could lead to the development of new therapeutic avenues. Full article
(This article belongs to the Special Issue Resistant Gastroenteropancreatic Neuroendocrine Tumors)
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14 pages, 3851 KiB  
Review
Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors
by Chanjuan Shi and Michael A. Morse
Cancers 2022, 14(24), 6114; https://doi.org/10.3390/cancers14246114 - 12 Dec 2022
Cited by 2 | Viewed by 1924
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary [...] Read more.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising. Full article
(This article belongs to the Special Issue Resistant Gastroenteropancreatic Neuroendocrine Tumors)
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14 pages, 1652 KiB  
Review
Treatment Sequencing Strategies in Advanced Neuroendocrine Tumors: A Review
by Aman Chauhan, Jaydira Del Rivero, Robert A. Ramirez, Heloisa P. Soares and Daneng Li
Cancers 2022, 14(21), 5248; https://doi.org/10.3390/cancers14215248 - 26 Oct 2022
Cited by 7 | Viewed by 3658
Abstract
Neuroendocrine tumor (NET) incidence has grown. The treatment landscape for advanced NETs is rapidly evolving, but there are limited head-to-head data to guide treatment sequencing decisions. We assessed the available clinical data to aid practicing clinicians in their routine clinical decision-making. Clinical trials [...] Read more.
Neuroendocrine tumor (NET) incidence has grown. The treatment landscape for advanced NETs is rapidly evolving, but there are limited head-to-head data to guide treatment sequencing decisions. We assessed the available clinical data to aid practicing clinicians in their routine clinical decision-making. Clinical trials have demonstrated efficacy benefits for new therapies in advanced NETs. Emerging long-term data from these trials have enabled clinicians to make more accurate risk-benefit assessments, particularly for patients receiving multiple lines of therapy. However, clinical data specifically regarding treatment sequencing are limited. In lieu of definitive data, treatment sequencing should be based on disease-related factors (e.g., site of tumor origin, volume of disease) and patient-related characteristics (e.g., comorbidities, patient preferences). Clinical decision-making in advanced NETs remains highly individualized and complex; important evidence gaps regarding treatment sequencing remain. Given this, advanced NET management should be a joint effort of multidisciplinary teams at referring and high-volume centers. Additional clinical trial and real-world evidence are needed to meet the challenge of understanding how to sequence available NET therapies. Until these trials are conducted, the best practices provided in this review may serve as a guide for clinicians making treatment sequencing decisions based on the available data. Full article
(This article belongs to the Special Issue Resistant Gastroenteropancreatic Neuroendocrine Tumors)
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22 pages, 1625 KiB  
Review
Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors
by Kristen McClellan, Emerson Y. Chen, Adel Kardosh, Charles D. Lopez, Jaydira Del Rivero, Nadine Mallak, Flavio G. Rocha, Yilun Koethe, Rodney Pommier, Erik Mittra and Guillaume J. Pegna
Cancers 2022, 14(19), 4769; https://doi.org/10.3390/cancers14194769 - 29 Sep 2022
Cited by 6 | Viewed by 2756
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogenous group of malignancies originating from neuroendocrine cells of the gastrointestinal tract, the incidence of which has been increasing for several decades. While there has been significant progress in the development of therapeutic options for patients with [...] Read more.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogenous group of malignancies originating from neuroendocrine cells of the gastrointestinal tract, the incidence of which has been increasing for several decades. While there has been significant progress in the development of therapeutic options for patients with advanced or metastatic disease, these remain limited both in quantity and durability of benefit. This review examines the latest research elucidating the mechanisms of both up-front resistance and the eventual development of resistance to the primary systemic therapeutic options including somatostatin analogues, peptide receptor radionuclide therapy with lutetium Lu 177 dotatate, everolimus, sunitinib, and temozolomide-based chemotherapy. Further, potential strategies for overcoming these mechanisms of resistance are reviewed in addition to a comprehensive review of ongoing and planned clinical trials addressing this important challenge. Full article
(This article belongs to the Special Issue Resistant Gastroenteropancreatic Neuroendocrine Tumors)
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49 pages, 2586 KiB  
Review
Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies
by Lingaku Lee, Irene Ramos-Alvarez and Robert T. Jensen
Cancers 2022, 14(5), 1250; https://doi.org/10.3390/cancers14051250 - 28 Feb 2022
Cited by 8 | Viewed by 7727
Abstract
Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number [...] Read more.
Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed. Full article
(This article belongs to the Special Issue Resistant Gastroenteropancreatic Neuroendocrine Tumors)
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