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A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-55...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group US
2023
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518255/ https://www.ncbi.nlm.nih.gov/pubmed/37640930 http://dx.doi.org/10.1038/s43018-023-00614-y |
| _version_ | 1785109472480329728 |
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| author | Chitty, Jessica L. Yam, Michelle Perryman, Lara Parker, Amelia L. Skhinas, Joanna N. Setargew, Yordanos F. I. Mok, Ellie T. Y. Tran, Emmi Grant, Rhiannon D. Latham, Sharissa L. Pereira, Brooke A. Ritchie, Shona C. Murphy, Kendelle J. Trpceski, Michael Findlay, Alison D. Melenec, Pauline Filipe, Elysse C. Nadalini, Audrey Velayuthar, Sipiththa Major, Gretel Wyllie, Kaitlin Papanicolaou, Michael Ratnaseelan, Shivanjali Phillips, Phoebe A. Sharbeen, George Youkhana, Janet Russo, Alice Blackwell, Antonia Hastings, Jordan F. Lucas, Morghan C. Chambers, Cecilia R. Reed, Daniel A. Stoehr, Janett Vennin, Claire Pidsley, Ruth Zaratzian, Anaiis Da Silva, Andrew M. Tayao, Michael Charlton, Brett Herrmann, David Nobis, Max Clark, Susan J. Biankin, Andrew V. Johns, Amber L. Croucher, David R. Nagrial, Adnan Gill, Anthony J. Grimmond, Sean M. Pajic, Marina Timpson, Paul Jarolimek, Wolfgang Cox, Thomas R. |
| author_facet | Chitty, Jessica L. Yam, Michelle Perryman, Lara Parker, Amelia L. Skhinas, Joanna N. Setargew, Yordanos F. I. Mok, Ellie T. Y. Tran, Emmi Grant, Rhiannon D. Latham, Sharissa L. Pereira, Brooke A. Ritchie, Shona C. Murphy, Kendelle J. Trpceski, Michael Findlay, Alison D. Melenec, Pauline Filipe, Elysse C. Nadalini, Audrey Velayuthar, Sipiththa Major, Gretel Wyllie, Kaitlin Papanicolaou, Michael Ratnaseelan, Shivanjali Phillips, Phoebe A. Sharbeen, George Youkhana, Janet Russo, Alice Blackwell, Antonia Hastings, Jordan F. Lucas, Morghan C. Chambers, Cecilia R. Reed, Daniel A. Stoehr, Janett Vennin, Claire Pidsley, Ruth Zaratzian, Anaiis Da Silva, Andrew M. Tayao, Michael Charlton, Brett Herrmann, David Nobis, Max Clark, Susan J. Biankin, Andrew V. Johns, Amber L. Croucher, David R. Nagrial, Adnan Gill, Anthony J. Grimmond, Sean M. Pajic, Marina Timpson, Paul Jarolimek, Wolfgang Cox, Thomas R. |
| author_sort | Chitty, Jessica L. |
| collection | PubMed |
| description | The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma. |
| format | Online Article Text |
| id | pubmed-10518255 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2023 |
| publisher | Nature Publishing Group US |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-105182552023-09-26 A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer Chitty, Jessica L. Yam, Michelle Perryman, Lara Parker, Amelia L. Skhinas, Joanna N. Setargew, Yordanos F. I. Mok, Ellie T. Y. Tran, Emmi Grant, Rhiannon D. Latham, Sharissa L. Pereira, Brooke A. Ritchie, Shona C. Murphy, Kendelle J. Trpceski, Michael Findlay, Alison D. Melenec, Pauline Filipe, Elysse C. Nadalini, Audrey Velayuthar, Sipiththa Major, Gretel Wyllie, Kaitlin Papanicolaou, Michael Ratnaseelan, Shivanjali Phillips, Phoebe A. Sharbeen, George Youkhana, Janet Russo, Alice Blackwell, Antonia Hastings, Jordan F. Lucas, Morghan C. Chambers, Cecilia R. Reed, Daniel A. Stoehr, Janett Vennin, Claire Pidsley, Ruth Zaratzian, Anaiis Da Silva, Andrew M. Tayao, Michael Charlton, Brett Herrmann, David Nobis, Max Clark, Susan J. Biankin, Andrew V. Johns, Amber L. Croucher, David R. Nagrial, Adnan Gill, Anthony J. Grimmond, Sean M. Pajic, Marina Timpson, Paul Jarolimek, Wolfgang Cox, Thomas R. Nat Cancer Article The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma. Nature Publishing Group US 2023-08-28 2023 /pmc/articles/PMC10518255/ /pubmed/37640930 http://dx.doi.org/10.1038/s43018-023-00614-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
| spellingShingle | Article Chitty, Jessica L. Yam, Michelle Perryman, Lara Parker, Amelia L. Skhinas, Joanna N. Setargew, Yordanos F. I. Mok, Ellie T. Y. Tran, Emmi Grant, Rhiannon D. Latham, Sharissa L. Pereira, Brooke A. Ritchie, Shona C. Murphy, Kendelle J. Trpceski, Michael Findlay, Alison D. Melenec, Pauline Filipe, Elysse C. Nadalini, Audrey Velayuthar, Sipiththa Major, Gretel Wyllie, Kaitlin Papanicolaou, Michael Ratnaseelan, Shivanjali Phillips, Phoebe A. Sharbeen, George Youkhana, Janet Russo, Alice Blackwell, Antonia Hastings, Jordan F. Lucas, Morghan C. Chambers, Cecilia R. Reed, Daniel A. Stoehr, Janett Vennin, Claire Pidsley, Ruth Zaratzian, Anaiis Da Silva, Andrew M. Tayao, Michael Charlton, Brett Herrmann, David Nobis, Max Clark, Susan J. Biankin, Andrew V. Johns, Amber L. Croucher, David R. Nagrial, Adnan Gill, Anthony J. Grimmond, Sean M. Pajic, Marina Timpson, Paul Jarolimek, Wolfgang Cox, Thomas R. A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer |
| title | A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer |
| title_full | A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer |
| title_fullStr | A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer |
| title_full_unstemmed | A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer |
| title_short | A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer |
| title_sort | first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518255/ https://www.ncbi.nlm.nih.gov/pubmed/37640930 http://dx.doi.org/10.1038/s43018-023-00614-y |
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