A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Jessica L. Chitty; Michelle Yam; Lara Perryman; Amelia L. Parker; Joanna N. Skhinas; Yordanos F. I. Setargew; Ellie T. Y. Mok; Emmi Tran; Rhiannon D. Grant; Sharissa L. Latham; Brooke A. Pereira; Shona C. Ritchie; Kendelle J. Murphy; Michael Trpceski; Alison D. Findlay; Pauline Melenec; Elysse C. Filipe; Audrey Nadalini; Sipiththa Velayuthar; Gretel Major; Kaitlin Wyllie; Michael Papanicolaou; Shivanjali Ratnaseelan; Phoebe Phillips; George Sharbeen; Janet Youkhana; Alice Russo; Antonia Blackwell; Jordan F. Hastings; Morghan C. Lucas; Cecilia R. Chambers; Daniel A. Reed; Janett Stoehr; Claire Vennin; Ruth Pidsley; Anaiis Zaratzian; Andrew M. Da Silva; Michael Tayao; Brett Charlton; David Herrmann; Max Nobis; Susan J. Clark; Andrew V. Biankin; Amber L. Johns; David R. Croucher; Adnan Nagrial; Anthony J. Gill; Sean M. Grimmond; Australian Pancreatic Cancer Genome Initiative (APGI); Australian Pancreatic Cancer Matrix Atlas (APMA); Marina Pajic; Paul Timpson; Wolfgang Jarolimek; Thomas R. Cox

doi:10.1038/s43018-023-00614-y

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Jessica L. Chitty, Michelle Yam, Lara Perryman, Amelia L. Parker, Joanna N. Skhinas, Yordanos F. I. Setargew, Ellie T. Y. Mok, Emmi Tran, Rhiannon D. Grant, Sharissa L. Latham, Brooke A. Pereira, Shona C. Ritchie, Kendelle J. Murphy, Michael Trpceski, Alison D. Findlay, Pauline Melenec, Elysse C. Filipe, Audrey Nadalini, Sipiththa Velayuthar, Gretel MajorKaitlin Wyllie, Michael Papanicolaou, Shivanjali Ratnaseelan, Phoebe Phillips, George Sharbeen, Janet Youkhana, Alice Russo, Antonia Blackwell, Jordan F. Hastings, Morghan C. Lucas, Cecilia R. Chambers, Daniel A. Reed, Janett Stoehr, Claire Vennin, Ruth Pidsley, Anaiis Zaratzian, Andrew M. Da Silva, Michael Tayao, Brett Charlton, David Herrmann, Max Nobis, Susan J. Clark, Andrew V. Biankin, Amber L. Johns, David R. Croucher, Adnan Nagrial, Anthony J. Gill, Sean M. Grimmond, Australian Pancreatic Cancer Genome Initiative (APGI), Australian Pancreatic Cancer Matrix Atlas (APMA), Marina Pajic, Paul Timpson, Wolfgang Jarolimek^*, Thomas R. Cox^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

88 Citations (Scopus)

78 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	1326-1344
Number of pages	32
Journal	Nature Cancer
Volume	4
Issue number	9
Early online date	28 Aug 2023
DOIs	https://doi.org/10.1038/s43018-023-00614-y
Publication status	Published - Sept 2023
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Access to Document

10.1038/s43018-023-00614-y

Publisher version (open access)Final published version, 13.1 MBLicence: CC BY

Cite this

Chitty, J. L., Yam, M., Perryman, L., Parker, A. L., Skhinas, J. N., Setargew, Y. F. I., Mok, E. T. Y., Tran, E., Grant, R. D., Latham, S. L., Pereira, B. A., Ritchie, S. C., Murphy, K. J., Trpceski, M., Findlay, A. D., Melenec, P., Filipe, E. C., Nadalini, A., Velayuthar, S., ... Cox, T. R. (2023). A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer. Nature Cancer, 4(9), 1326-1344. https://doi.org/10.1038/s43018-023-00614-y

@article{49780dd181ef4b93a7def0f39d2c469d,

title = "A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer",

abstract = "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.",

author = "Chitty, \{Jessica L.\} and Michelle Yam and Lara Perryman and Parker, \{Amelia L.\} and Skhinas, \{Joanna N.\} and Setargew, \{Yordanos F. I.\} and Mok, \{Ellie T. Y.\} and Emmi Tran and Grant, \{Rhiannon D.\} and Latham, \{Sharissa L.\} and Pereira, \{Brooke A.\} and Ritchie, \{Shona C.\} and Murphy, \{Kendelle J.\} and Michael Trpceski and Findlay, \{Alison D.\} and Pauline Melenec and Filipe, \{Elysse C.\} and Audrey Nadalini and Sipiththa Velayuthar and Gretel Major and Kaitlin Wyllie and Michael Papanicolaou and Shivanjali Ratnaseelan and Phoebe Phillips and George Sharbeen and Janet Youkhana and Alice Russo and Antonia Blackwell and Hastings, \{Jordan F.\} and Lucas, \{Morghan C.\} and Chambers, \{Cecilia R.\} and Reed, \{Daniel A.\} and Janett Stoehr and Claire Vennin and Ruth Pidsley and Anaiis Zaratzian and Silva, \{Andrew M. Da\} and Michael Tayao and Brett Charlton and David Herrmann and Max Nobis and Clark, \{Susan J.\} and Biankin, \{Andrew V.\} and Johns, \{Amber L.\} and Croucher, \{David R.\} and Adnan Nagrial and Gill, \{Anthony J.\} and Grimmond, \{Sean M.\} and \{Australian Pancreatic Cancer Genome Initiative (APGI)\} and \{Australian Pancreatic Cancer Matrix Atlas (APMA)\} and Marina Pajic and Paul Timpson and Wolfgang Jarolimek and Cox, \{Thomas R.\}",

note = "Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher. ",

year = "2023",

month = sep,

doi = "10.1038/s43018-023-00614-y",

language = "English",

volume = "4",

pages = "1326--1344",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Springer, Springer Nature",

number = "9",

}

Chitty, JL, Yam, M, Perryman, L, Parker, AL, Skhinas, JN, Setargew, YFI, Mok, ETY, Tran, E, Grant, RD, Latham, SL, Pereira, BA, Ritchie, SC, Murphy, KJ, Trpceski, M, Findlay, AD, Melenec, P, Filipe, EC, Nadalini, A, Velayuthar, S, Major, G, Wyllie, K, Papanicolaou, M, Ratnaseelan, S, Phillips, P, Sharbeen, G, Youkhana, J, Russo, A, Blackwell, A, Hastings, JF, Lucas, MC, Chambers, CR, Reed, DA, Stoehr, J, Vennin, C, Pidsley, R, Zaratzian, A, Silva, AMD, Tayao, M, Charlton, B, Herrmann, D, Nobis, M, Clark, SJ, Biankin, AV, Johns, AL, Croucher, DR, Nagrial, A, Gill, AJ, Grimmond, SM, Australian Pancreatic Cancer Genome Initiative (APGI), Australian Pancreatic Cancer Matrix Atlas (APMA), Pajic, M, Timpson, P, Jarolimek, W & Cox, TR 2023, 'A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer', Nature Cancer, vol. 4, no. 9, pp. 1326-1344. https://doi.org/10.1038/s43018-023-00614-y

TY - JOUR

T1 - A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

AU - Chitty, Jessica L.

AU - Yam, Michelle

AU - Perryman, Lara

AU - Parker, Amelia L.

AU - Skhinas, Joanna N.

AU - Setargew, Yordanos F. I.

AU - Mok, Ellie T. Y.

AU - Tran, Emmi

AU - Grant, Rhiannon D.

AU - Latham, Sharissa L.

AU - Pereira, Brooke A.

AU - Ritchie, Shona C.

AU - Murphy, Kendelle J.

AU - Trpceski, Michael

AU - Findlay, Alison D.

AU - Melenec, Pauline

AU - Filipe, Elysse C.

AU - Nadalini, Audrey

AU - Velayuthar, Sipiththa

AU - Major, Gretel

AU - Wyllie, Kaitlin

AU - Papanicolaou, Michael

AU - Ratnaseelan, Shivanjali

AU - Phillips, Phoebe

AU - Sharbeen, George

AU - Youkhana, Janet

AU - Russo, Alice

AU - Blackwell, Antonia

AU - Hastings, Jordan F.

AU - Lucas, Morghan C.

AU - Chambers, Cecilia R.

AU - Reed, Daniel A.

AU - Stoehr, Janett

AU - Vennin, Claire

AU - Pidsley, Ruth

AU - Zaratzian, Anaiis

AU - Silva, Andrew M. Da

AU - Tayao, Michael

AU - Charlton, Brett

AU - Herrmann, David

AU - Nobis, Max

AU - Clark, Susan J.

AU - Biankin, Andrew V.

AU - Johns, Amber L.

AU - Croucher, David R.

AU - Nagrial, Adnan

AU - Gill, Anthony J.

AU - Grimmond, Sean M.

AU - Australian Pancreatic Cancer Genome Initiative (APGI)

AU - Australian Pancreatic Cancer Matrix Atlas (APMA)

AU - Pajic, Marina

AU - Timpson, Paul

AU - Jarolimek, Wolfgang

AU - Cox, Thomas R.

N1 - Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85169024721

U2 - 10.1038/s43018-023-00614-y

DO - 10.1038/s43018-023-00614-y

M3 - Article

C2 - 37640930

SN - 2662-1347

VL - 4

SP - 1326

EP - 1344

JO - Nature Cancer

JF - Nature Cancer

IS - 9

ER -

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this