Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient
High-grade mucinous colorectal cancer (HGM CRC) is particularly aggressive, prone to metastasis and treatment resistance, frequently accompanied by “signet ring” cancer cells. A sizeable fraction of HGM CRCs (20-40%) arises in the context of the Lynch Syndrome, an autosomal hereditary syndrome that...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1130852/full |
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| author | Erica Torchiaro Consalvo Petti Sabrina Arena Sabrina Arena Francesco Sassi Giorgia Migliardi Alfredo Mellano Roberta Porporato Marco Basiricò Loretta Gammaitoni Enrico Berrino Enrico Berrino Monica Montone Giorgio Corti Giovanni Crisafulli Caterina Marchiò Caterina Marchiò Alberto Bardelli Alberto Bardelli Enzo Medico Enzo Medico |
| author_facet | Erica Torchiaro Consalvo Petti Sabrina Arena Sabrina Arena Francesco Sassi Giorgia Migliardi Alfredo Mellano Roberta Porporato Marco Basiricò Loretta Gammaitoni Enrico Berrino Enrico Berrino Monica Montone Giorgio Corti Giovanni Crisafulli Caterina Marchiò Caterina Marchiò Alberto Bardelli Alberto Bardelli Enzo Medico Enzo Medico |
| author_sort | Erica Torchiaro |
| collection | DOAJ |
| description | High-grade mucinous colorectal cancer (HGM CRC) is particularly aggressive, prone to metastasis and treatment resistance, frequently accompanied by “signet ring” cancer cells. A sizeable fraction of HGM CRCs (20-40%) arises in the context of the Lynch Syndrome, an autosomal hereditary syndrome that predisposes to microsatellite instable (MSI) CRC. Development of patient-derived preclinical models for this challenging subtype of colorectal cancer represents an unmet need in oncology. We describe here successful propagation of preclinical models from a case of early-onset, MSI-positive metastatic colorectal cancer in a male Lynch syndrome patient, refractory to standard care (FOLFOX6, FOLFIRI-Panitumumab) and, surprisingly, also to immunotherapy. Surgical material from a debulking operation was implanted in NOD/SCID mice, successfully yielding one patient-derived xenograft (PDX). PDX explants were subsequently used to generate 2D and 3D cell cultures. Histologically, all models resembled the tumor of origin, displaying a high-grade mucinous phenotype with signet ring cells. For preclinical exploration of alternative treatments, in light of recent findings, we considered inhibition of the proteasome by bortezomib and of the related NEDD8 pathway by pevonedistat. Indeed, sensitivity to bortezomib was observed in mucinous adenocarcinoma of the lung, and we previously found that HGM CRC is preferentially sensitive to pevonedistat in models with low or absent expression of cadherin 17 (CDH17), a differentiation marker. We therefore performed IHC on the tumor and models, and observed no CDH17 expression, suggesting sensitivity to pevonedistat. Both bortezomib and pevonedistat showed strong activity on 2D cells at 72 hours and on 3D organoids at 7 days, thus providing valid options for in vivo testing. Accordingly, three PDX cohorts were treated for four weeks, respectively with vehicle, bortezomib and pevonedistat. Both drugs significantly reduced tumor growth, as compared to the vehicle group. Interestingly, while bortezomib was more effective in vitro, pevonedistat was more effective in vivo. Drug efficacy was further substantiated by a reduction of cellularity and of Ki67-positive cells in the treated tumors. These results highlight proteasome and NEDD8 inhibition as potentially effective therapeutic approaches against Lynch syndrome-associated HGM CRC, also when the disease is refractory to all available treatment options. |
| first_indexed | 2024-04-10T18:15:00Z |
| format | Article |
| id | doaj.art-a4d991eacaeb4b91b2c17db7c0dd2e37 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T18:15:00Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-a4d991eacaeb4b91b2c17db7c0dd2e372023-02-02T09:32:44ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-02-011310.3389/fonc.2023.11308521130852Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patientErica Torchiaro0Consalvo Petti1Sabrina Arena2Sabrina Arena3Francesco Sassi4Giorgia Migliardi5Alfredo Mellano6Roberta Porporato7Marco Basiricò8Loretta Gammaitoni9Enrico Berrino10Enrico Berrino11Monica Montone12Giorgio Corti13Giovanni Crisafulli14Caterina Marchiò15Caterina Marchiò16Alberto Bardelli17Alberto Bardelli18Enzo Medico19Enzo Medico20Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyDepartment of Oncology, University of Torino, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyDepartment of Medical Sciences, University of Turin, Torino, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyDepartment of Oncology, University of Torino, Candiolo, ItalyIFOM ETS, The AIRC Institute of Molecular Oncology, Milano, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyDepartment of Medical Sciences, University of Turin, Torino, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyDepartment of Oncology, University of Torino, Candiolo, ItalyCandiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, ItalyDepartment of Oncology, University of Torino, Candiolo, ItalyHigh-grade mucinous colorectal cancer (HGM CRC) is particularly aggressive, prone to metastasis and treatment resistance, frequently accompanied by “signet ring” cancer cells. A sizeable fraction of HGM CRCs (20-40%) arises in the context of the Lynch Syndrome, an autosomal hereditary syndrome that predisposes to microsatellite instable (MSI) CRC. Development of patient-derived preclinical models for this challenging subtype of colorectal cancer represents an unmet need in oncology. We describe here successful propagation of preclinical models from a case of early-onset, MSI-positive metastatic colorectal cancer in a male Lynch syndrome patient, refractory to standard care (FOLFOX6, FOLFIRI-Panitumumab) and, surprisingly, also to immunotherapy. Surgical material from a debulking operation was implanted in NOD/SCID mice, successfully yielding one patient-derived xenograft (PDX). PDX explants were subsequently used to generate 2D and 3D cell cultures. Histologically, all models resembled the tumor of origin, displaying a high-grade mucinous phenotype with signet ring cells. For preclinical exploration of alternative treatments, in light of recent findings, we considered inhibition of the proteasome by bortezomib and of the related NEDD8 pathway by pevonedistat. Indeed, sensitivity to bortezomib was observed in mucinous adenocarcinoma of the lung, and we previously found that HGM CRC is preferentially sensitive to pevonedistat in models with low or absent expression of cadherin 17 (CDH17), a differentiation marker. We therefore performed IHC on the tumor and models, and observed no CDH17 expression, suggesting sensitivity to pevonedistat. Both bortezomib and pevonedistat showed strong activity on 2D cells at 72 hours and on 3D organoids at 7 days, thus providing valid options for in vivo testing. Accordingly, three PDX cohorts were treated for four weeks, respectively with vehicle, bortezomib and pevonedistat. Both drugs significantly reduced tumor growth, as compared to the vehicle group. Interestingly, while bortezomib was more effective in vitro, pevonedistat was more effective in vivo. Drug efficacy was further substantiated by a reduction of cellularity and of Ki67-positive cells in the treated tumors. These results highlight proteasome and NEDD8 inhibition as potentially effective therapeutic approaches against Lynch syndrome-associated HGM CRC, also when the disease is refractory to all available treatment options.https://www.frontiersin.org/articles/10.3389/fonc.2023.1130852/fullLynch syndromemucinous colorectal cancersignet ring cellsNEDD8 pathway inhibitionproteasome inhibitionpreclinical study |
| spellingShingle | Erica Torchiaro Consalvo Petti Sabrina Arena Sabrina Arena Francesco Sassi Giorgia Migliardi Alfredo Mellano Roberta Porporato Marco Basiricò Loretta Gammaitoni Enrico Berrino Enrico Berrino Monica Montone Giorgio Corti Giovanni Crisafulli Caterina Marchiò Caterina Marchiò Alberto Bardelli Alberto Bardelli Enzo Medico Enzo Medico Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient Frontiers in Oncology Lynch syndrome mucinous colorectal cancer signet ring cells NEDD8 pathway inhibition proteasome inhibition preclinical study |
| title | Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient |
| title_full | Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient |
| title_fullStr | Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient |
| title_full_unstemmed | Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient |
| title_short | Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient |
| title_sort | case report preclinical efficacy of nedd8 and proteasome inhibitors in patient derived models of signet ring high grade mucinous colorectal cancer from a lynch syndrome patient |
| topic | Lynch syndrome mucinous colorectal cancer signet ring cells NEDD8 pathway inhibition proteasome inhibition preclinical study |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1130852/full |
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