Preclinical Models of Neuroendocrine Neoplasia

Sedlack, Andrew J. H.; Saleh-Anaraki, Kimia; Kumar, Suresh; Ear, Po Hien; Lines, Kate E; Roper, Nitin; Pacák, Karel; Bergsland, Emily K.; Quelle, Dawn E.; Howe, James R.; Pommier, ﻿Yves; Rivero, Jaydira del

doi:10.3390/cancers14225646

Cited by 7 publications

(6 citation statements)

References 253 publications

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“…The tissues were immediately subjected to enzymatic disassociation. Human small‐cell organoids were cultured in minimal basal media (MBM) as described previously (Kim et al , 2019 ; Sedlack et al , 2022 ). Briefly, PDOs were cultured in drop of growth factor‐reduced basement membrane extract (BME; Corning), and medium was refreshed every 4 days.…”

Section: Methodsmentioning

confidence: 99%

ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer

et al. 2023

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Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

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Section: Methodsmentioning

confidence: 99%

ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer

et al. 2023

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“…Nonetheless, the use of human cell lines avoids some of the major issues that occur in murine studies where manipulation of transgenic mice yields benefits that do not translate to humans. It is important to use both types of approaches in a complementary fashion to move stepwise toward human clinical trials [69]. Future experiments will reinforce the role of P110 in counteracting the deposition of Aβ and reducing anomalies in mitochondria in primary human neurons and other, more complex cell systems.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer’s Disease

Srivastava,

Johnson,

Renna

et al. 2023

Life

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Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer’s disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-β accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-β generation and improving neuronal health by maintaining mitochondrial function in neurons.

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“…Even if not included in this review, data published in the literature have also underlined the role of PET/CT imaging in PCa and NEPC in preclinical settings. In this scenario, it has been proposed that specific forms of NEPC, depending on their origin, can be imaged with different radiopharmaceuticals based on preclinical evidence [41,43,46,47]. Moreover, new tracers able to evaluate the presence of NEPC or its progression from CRPC are continuously developed and hopefully will help in the assessment of the disease [34,[48][49][50].…”

Section: Discussionmentioning

confidence: 99%

PET/CT and Conventional Imaging for the Assessment of Neuroendocrine Prostate Cancer: A Systematic Review

Dondi,

Antonelli,

Suardi

et al. 2023

Cancers

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Background: Neuroendocrine prostate cancer (NEPC) is a rare neoplasm, and the role of both conventional imaging (CI) and positron emission tomography/computed tomography (PET/CT) for its assessment has not been clearly evaluated and demonstrated. The aim of this systematic review was to analyze the diagnostic performances of these imaging modalities in this setting. Methods: A wide literature search of the PubMed/MEDLINE, Scopus, and Web of Science databases was made to find relevant published articles about the role of CI and PET/CT for the evaluation of NEPC. Results: 13 studies were included in the systematic review. PET/CT imaging with different radiopharmaceuticals has been evaluated in many studies (10) compared to CI (3 studies), which has only a limited role in NEPC. Focusing on PET/CT, a study used [18F]FDG, labeled somatostatin analogs were used in 5 cases, a study used [68Ga]Ga-FAPI-04, [68Ga]Ga-PSMA-11 was evaluated in a single case, and two works used different tracers. Conclusion: Published data on the role of PET/CT for the assessment of NEPC are limited. At present, it is still uncertain which tracer performs best, and although [18F]FDG has been evaluated and seems to offer some advantages in availability and clinical staging, other tracers may be more useful to understand tumor biology or identify targets for subsequent radioligand therapy. Further research is therefore desirable. In contrast, data are still limited to draw a final conclusion on the role and the specific characteristics of CI in this rare form of neoplasm, and therefore, more studies are needed in this setting.

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Preclinical Models of Neuroendocrine Neoplasia

Cited by 7 publications

References 253 publications

ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer

ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer’s Disease

PET/CT and Conventional Imaging for the Assessment of Neuroendocrine Prostate Cancer: A Systematic Review

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