Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

Prada, Elke Tatjana Aristizabal; Auernhammer, Christoph J.

doi:10.1530/ec-17-0286

Cited by 22 publications

(29 citation statements)

References 269 publications

(452 reference statements)

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“…Many are the drugs under preclinical assessment or in phase 1 trials, including PI3K inhibitors, dual mTOR inhibitors, or multikinase inhibitors targeting both tyrosine kinase receptors and cyclin-dependent kinases (268). The experimental approaches to validate their use on GEP-NETs should take into account the existence of a large diversity in alterations of the very same pathways, possibly leading to different response to similar treatments.…”

Section: Advances In Targeted Therapy and Detection Of Gep-nets In LImentioning

confidence: 99%

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

2019

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Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.

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Section: Advances In Targeted Therapy and Detection Of Gep-nets In LImentioning

confidence: 99%

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

2019

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“…Additional pathways involving focal adhesion kinase (FAK) have also been identified to play a role in the development of resistance [6]. However, approaches targeting PI3K, Akt, mTORC2, IGF, or FAK have not made any meaningful clinical impact on metastatic PNET [7]. Such persistent failures in targeted approaches indicate that there is a void in our understanding of the mechanisms of therapy resistance in PNET.…”

Section: Introductionmentioning

confidence: 99%

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

Mpilla

Aboukameel

Muqbil

et al. 2019

Cancers

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Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation.

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“…mTOR inhibitors and TKIs are the most representative examples, but other novel pathway-directed therapeutic compounds are also currently being evaluated in (pre-)clinical studies [ 205 ]. Current clinical trials include head-to-head comparisons between novel therapies (PRRT vs. everolimus/sunitinib/capecitabine-temozolomide) and combination therapies (everolimus with bevacizumab/cisplatinum/temozolomide; PRRT with capecitabine-temozolomide).…”

Section: Future Directionsmentioning

confidence: 99%

Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives

Herrera‐Martínez

Hofland

et al. 2018

Drugs

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Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.

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Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

Cited by 22 publications

References 269 publications

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives

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