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

J. L. Chitty; M. Yam; L. Perryman; A. L. Parker; J. N. Skhinas; Y. F. I. Setargew; E. T. Y. Mok; E. Tran; R. D. Grant; S. L. Latham; B. A. Pereira; S. C. Ritchie; K. J. Murphy; M. Trpceski; A. D. Findlay; P. Melenec; E. C. Filipe; A. Nadalini; S. Velayuthar; G. Major; K. Wyllie; M. Papanicolaou; S. Ratnaseelan; P. A. Phillips; G. Sharbeen; J. Youkhana; A. Russo; A. Blackwell; J. F. Hastings; M. C. Lucas; C. R. Chambers; D. A. Reed; J. Stoehr; C. Vennin; R. Pidsley; A. Zaratzian; A. M. Da Silva; M. Tayao; B. Charlton; D. Herrmann; M. Nobis; S .J. Clark; A. V. Biankin; A. L. Johns; D. R. Croucher; A. Nagrial; A.J. Gill; S. M. Grimmond; L. A. Chantrill; A. Chou; T. Dwarte; X. L. Metcalf; G. Jeong; L. Kenyon; N. Waddell; J. V. Pearson; A.- M. Patch; K. Nones; F. Newell; P. Mukhopadhyay; V. Addala; S. Kazakoff; O. Holmes; C. Leonard; S. Wood; O. Hofmann; J. S. Samra; N. Pavlakis; J. Arena; H. A. High; R. Asghari; Neil D. Merrett; A. Das; P. H. Cosman; Kasim Ismail; A. Stoita; D. Williams; A. Spigellman; D. McLeo; J. Kirk; J. G. Kench; P. Grimison; C. Sandroussi; A. Goodwin; R. S. Mead; K. Tucker; L. Andrews; M. Texler; C. Forrest; M. Ballal; D. Fletcher; M. Beilin; K. Feeney; K. Epari; S. Mukhedkar; N. Zeps; N. Q. Nguyen; A. R. Ruszkiewicz; C. Worthley; J. Chen; M. E. Brooke-Smith; V. Papangelis; A. D. Clouston; A. P. Barbour; T. J. O’Rourke; J. W. Fawcett; K. Slater; M. Hatzifotis; P. Hodgkinson; M. Nikfarjam; J. R. Eshleman; R. H. Hruban; C. L. Wolfgang; A. Scarpa; R. T. Lawlor; V. Corbo; C. Bassi; N. B. Jamieson; D. K. Chang; S. B. Dreyer; L. Abdulkhalek; T. Schmitz; V. Lee; K. P. Stewart; M. Arshi; A. M. Steinmann; M. Pajic; P. Timpson; W. Jarolimek; T. 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

J. L. Chitty
, M. Yam
, L. Perryman
, A. L. Parker
, J. N. Skhinas
, Y. F. I. Setargew
, E. T. Y. Mok
, E. Tran
, R. D. Grant
, S. L. Latham
, B. A. Pereira
, S. C. Ritchie
, K. J. Murphy
, M. Trpceski
, A. D. Findlay
, P. Melenec
, E. C. Filipe
, A. Nadalini
, S. Velayuthar
, G. Major

K. Wyllie, M. Papanicolaou, S. Ratnaseelan, P. A. Phillips, G. Sharbeen, J. Youkhana, A. Russo, A. Blackwell, J. F. Hastings, M. C. Lucas, C. R. Chambers, D. A. Reed, J. Stoehr, C. Vennin, R. Pidsley, A. Zaratzian, A. M. Da Silva, M. Tayao, B. Charlton, D. Herrmann, M. Nobis, S .J. Clark, A. V. Biankin, A. L. Johns, D. R. Croucher, A. Nagrial, A.J. Gill, S. M. Grimmond, L. A. Chantrill, A. Chou, T. Dwarte, X. L. Metcalf, G. Jeong, L. Kenyon, N. Waddell, J. V. Pearson, A.- M. Patch, K. Nones, F. Newell, P. Mukhopadhyay, V. Addala, S. Kazakoff, O. Holmes, C. Leonard, S. Wood, O. Hofmann, J. S. Samra, N. Pavlakis, J. Arena, H. A. High, R. Asghari, Neil D. Merrett, A. Das, P. H. Cosman, Kasim Ismail, A. Stoita, D. Williams, A. Spigellman, D. McLeo, J. Kirk, J. G. Kench, P. Grimison, C. Sandroussi, A. Goodwin, R. S. Mead, K. Tucker, L. Andrews, M. Texler, C. Forrest, M. Ballal, D. Fletcher, M. Beilin, K. Feeney, K. Epari, S. Mukhedkar, N. Zeps, N. Q. Nguyen, A. R. Ruszkiewicz, C. Worthley, J. Chen, M. E. Brooke-Smith, V. Papangelis, A. D. Clouston, A. P. Barbour, T. J. O’Rourke, J. W. Fawcett, K. Slater, M. Hatzifotis, P. Hodgkinson, M. Nikfarjam, J. R. Eshleman, R. H. Hruban, C. L. Wolfgang, A. Scarpa, R. T. Lawlor, V. Corbo, C. Bassi, N. B. Jamieson, D. K. Chang, S. B. Dreyer, L. Abdulkhalek, T. Schmitz, V. Lee, K. P. Stewart, M. Arshi, A. M. Steinmann, M. Pajic, P. Timpson, W. Jarolimek, T. R. Cox

Bankstown-Lidcombe Hospital

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

106 Citations (Scopus)

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	19
Journal	Nature Cancer
Volume	4
Issue number	9
DOIs	https://doi.org/10.1038/s43018-023-00614-y
Publication status	Published - Sept 2023

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Publisher Copyright:
© 2023, The Author(s).

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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{8a1c4fe787914cc394c224be4289a834,

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, \{J. L.\} and M. Yam and L. Perryman and Parker, \{A. L.\} and Skhinas, \{J. N.\} and Setargew, \{Y. F. I.\} and Mok, \{E. T. Y.\} and E. Tran and Grant, \{R. D.\} and Latham, \{S. L.\} and Pereira, \{B. A.\} and Ritchie, \{S. C.\} and Murphy, \{K. J.\} and M. Trpceski and Findlay, \{A. D.\} and P. Melenec and Filipe, \{E. C.\} and A. Nadalini and S. Velayuthar and G. Major and K. Wyllie and M. Papanicolaou and S. Ratnaseelan and Phillips, \{P. A.\} and G. Sharbeen and J. Youkhana and A. Russo and A. Blackwell and Hastings, \{J. F.\} and Lucas, \{M. C.\} and Chambers, \{C. R.\} and Reed, \{D. A.\} and J. Stoehr and C. Vennin and R. Pidsley and A. Zaratzian and \{Da Silva\}, \{A. M.\} and M. Tayao and B. Charlton and D. Herrmann and M. Nobis and Clark, \{S .J.\} and Biankin, \{A. V.\} and Johns, \{A. L.\} and Croucher, \{D. R.\} and A. Nagrial and A.J. Gill and Grimmond, \{S. M.\} and Chantrill, \{L. A.\} and A. Chou and T. Dwarte and Metcalf, \{X. L.\} and G. Jeong and L. Kenyon and N. Waddell and Pearson, \{J. V.\} and Patch, \{A.- M.\} and K. Nones and F. Newell and P. Mukhopadhyay and V. Addala and S. Kazakoff and O. Holmes and C. Leonard and S. Wood and O. Hofmann and Samra, \{J. S.\} and N. Pavlakis and J. Arena and High, \{H. A.\} and R. Asghari and Merrett, \{Neil D.\} and A. Das and Cosman, \{P. H.\} and Kasim Ismail and A. Stoita and D. Williams and A. Spigellman and D. McLeo and J. Kirk and Kench, \{J. G.\} and P. Grimison and C. Sandroussi and A. Goodwin and Mead, \{R. S.\} and K. Tucker and L. Andrews and M. Texler and C. Forrest and M. Ballal and D. Fletcher and M. Beilin and K. Feeney and K. Epari and S. Mukhedkar and N. Zeps and Nguyen, \{N. Q.\} and Ruszkiewicz, \{A. R.\} and C. Worthley and J. Chen and Brooke-Smith, \{M. E.\} and V. Papangelis and Clouston, \{A. D.\} and Barbour, \{A. P.\} and O{\textquoteright}Rourke, \{T. J.\} and Fawcett, \{J. W.\} and K. Slater and M. Hatzifotis and P. Hodgkinson and M. Nikfarjam and Eshleman, \{J. R.\} and Hruban, \{R. H.\} and Wolfgang, \{C. L.\} and A. Scarpa and Lawlor, \{R. T.\} and V. Corbo and C. Bassi and Jamieson, \{N. B.\} and Chang, \{D. K.\} and Dreyer, \{S. B.\} and L. Abdulkhalek and T. Schmitz and V. Lee and Stewart, \{K. P.\} and M. Arshi and Steinmann, \{A. M.\} and M. Pajic and P. Timpson and W. Jarolimek and Cox, \{T. R.\}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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 = "Nature Research",

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, PA, Sharbeen, G, Youkhana, J, Russo, A, Blackwell, A, Hastings, JF, Lucas, MC, Chambers, CR, Reed, DA, Stoehr, J, Vennin, C, Pidsley, R, Zaratzian, A, Da Silva, AM, Tayao, M, Charlton, B, Herrmann, D, Nobis, M, Clark, SJ, Biankin, AV, Johns, AL, Croucher, DR, Nagrial, A, Gill, AJ, Grimmond, SM, Chantrill, LA, Chou, A, Dwarte, T, Metcalf, XL, Jeong, G, Kenyon, L, Waddell, N, Pearson, JV, Patch, AM, Nones, K, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Leonard, C, Wood, S, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, High, HA, Asghari, R, Merrett, ND, Das, A, Cosman, PH, Ismail, K, Stoita, A, Williams, D, Spigellman, A, McLeo, D, Kirk, J, Kench, JG, Grimison, P, Sandroussi, C, Goodwin, A, Mead, RS, Tucker, K, Andrews, L, Texler, M, Forrest, C, Ballal, M, Fletcher, D, Beilin, M, Feeney, K, Epari, K, Mukhedkar, S, Zeps, N, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Chen, J, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Barbour, AP, O’Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, JR, Hruban, RH, Wolfgang, CL, Scarpa, A, Lawlor, RT, Corbo, V, Bassi, C, Jamieson, NB, Chang, DK, Dreyer, SB, Abdulkhalek, L, Schmitz, T, Lee, V, Stewart, KP, Arshi, M, Steinmann, AM, 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, J. L.

AU - Yam, M.

AU - Perryman, L.

AU - Parker, A. L.

AU - Skhinas, J. N.

AU - Setargew, Y. F. I.

AU - Mok, E. T. Y.

AU - Tran, E.

AU - Grant, R. D.

AU - Latham, S. L.

AU - Pereira, B. A.

AU - Ritchie, S. C.

AU - Murphy, K. J.

AU - Trpceski, M.

AU - Findlay, A. D.

AU - Melenec, P.

AU - Filipe, E. C.

AU - Nadalini, A.

AU - Velayuthar, S.

AU - Major, G.

AU - Wyllie, K.

AU - Papanicolaou, M.

AU - Ratnaseelan, S.

AU - Phillips, P. A.

AU - Sharbeen, G.

AU - Youkhana, J.

AU - Russo, A.

AU - Blackwell, A.

AU - Hastings, J. F.

AU - Lucas, M. C.

AU - Chambers, C. R.

AU - Reed, D. A.

AU - Stoehr, J.

AU - Vennin, C.

AU - Pidsley, R.

AU - Zaratzian, A.

AU - Da Silva, A. M.

AU - Tayao, M.

AU - Charlton, B.

AU - Herrmann, D.

AU - Nobis, M.

AU - Clark, S .J.

AU - Biankin, A. V.

AU - Johns, A. L.

AU - Croucher, D. R.

AU - Nagrial, A.

AU - Gill, A.J.

AU - Grimmond, S. M.

AU - Chantrill, L. A.

AU - Chou, A.

AU - Dwarte, T.

AU - Metcalf, X. L.

AU - Jeong, G.

AU - Kenyon, L.

AU - Waddell, N.

AU - Pearson, J. V.

AU - Patch, A.- M.

AU - Nones, K.

AU - Newell, F.

AU - Mukhopadhyay, P.

AU - Addala, V.

AU - Kazakoff, S.

AU - Holmes, O.

AU - Leonard, C.

AU - Wood, S.

AU - Hofmann, O.

AU - Samra, J. S.

AU - Pavlakis, N.

AU - Arena, J.

AU - High, H. A.

AU - Asghari, R.

AU - Merrett, Neil D.

AU - Das, A.

AU - Cosman, P. H.

AU - Ismail, Kasim

AU - Stoita, A.

AU - Williams, D.

AU - Spigellman, A.

AU - McLeo, D.

AU - Kirk, J.

AU - Kench, J. G.

AU - Grimison, P.

AU - Sandroussi, C.

AU - Goodwin, A.

AU - Mead, R. S.

AU - Tucker, K.

AU - Andrews, L.

AU - Texler, M.

AU - Forrest, C.

AU - Ballal, M.

AU - Fletcher, D.

AU - Beilin, M.

AU - Feeney, K.

AU - Epari, K.

AU - Mukhedkar, S.

AU - Zeps, N.

AU - Nguyen, N. Q.

AU - Ruszkiewicz, A. R.

AU - Worthley, C.

AU - Chen, J.

AU - Brooke-Smith, M. E.

AU - Papangelis, V.

AU - Clouston, A. D.

AU - Barbour, A. P.

AU - O’Rourke, T. J.

AU - Fawcett, J. W.

AU - Slater, K.

AU - Hatzifotis, M.

AU - Hodgkinson, P.

AU - Nikfarjam, M.

AU - Eshleman, J. R.

AU - Hruban, R. H.

AU - Wolfgang, C. L.

AU - Scarpa, A.

AU - Lawlor, R. T.

AU - Corbo, V.

AU - Bassi, C.

AU - Jamieson, N. B.

AU - Chang, D. K.

AU - Dreyer, S. B.

AU - Abdulkhalek, L.

AU - Schmitz, T.

AU - Lee, V.

AU - Stewart, K. P.

AU - Arshi, M.

AU - Steinmann, A. M.

AU - Pajic, M.

AU - Timpson, P.

AU - Jarolimek, W.

AU - Cox, T. R.

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://hdl.handle.net/1959.7/uws:73697

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

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