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

Humans Gemcitabine Protein-Lysine 6-Oxidase Pancreatic Neoplasms / drug therapy Pancreatic Diseases

Journal

Nature cancer

ISSN: 2662-1347

Titre abrégé: Nat Cancer

Pays: England

ID NLM: 101761119

Informations de publication

Date de publication:
09 2023

Historique:

received: 28 09 2021

accepted: 07 07 2023

medline: 26 9 2023

pubmed: 29 8 2023

entrez: 28 8 2023

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s43018-023-00614-y PMID: 37640930 PMC: PMC10518255

pubmed: 37640930

doi: 10.1038/s43018-023-00614-y

pii: 10.1038/s43018-023-00614-y

pmc: PMC10518255

doi:

Substances chimiques

Gemcitabine 0

Protein-Lysine 6-Oxidase EC 1.4.3.13

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1326-1344

Subventions

Organisme : Cancer Research UK

ID : 25813

Pays : United Kingdom

Investigateurs

Lorraine A Chantrill (LA)

Angela Chou (A)

Tanya Dwarte (T)

Xanthe L Metcalf (XL)

Gloria Jeong (G)

Lara Kenyon (L)

Nicola Waddell (N)

John V Pearson (JV)

Ann-Marie Patch (AM)

Katia Nones (K)

Felicity Newell (F)

Pamela Mukhopadhyay (P)

Venkateswar Addala (V)

Stephen Kazakoff (S)

Oliver Holmes (O)

Conrad Leonard (C)

Scott Wood (S)

Oliver Hofmann (O)

Jaswinder S Samra (JS)

Nick Pavlakis (N)

Jennifer Arena (J)

Hilda A High (HA)

Ray Asghari (R)

Neil D Merrett (ND)

Amitabha Das (A)

Peter H Cosman (PH)

Kasim Ismail (K)

Alina Stoita (A)

David Williams (D)

Allan Spigellman (A)

Duncan McLeo (D)

Judy Kirk (J)

James G Kench (JG)

Peter Grimison (P)

Charbel Sandroussi (C)

Annabel Goodwin (A)

R Scott Mead (RS)

Katherine Tucker (K)

Lesley Andrews (L)

Michael Texler (M)

Cindy Forrest (C)

Mo Ballal (M)

David Fletcher (D)

Maria Beilin (M)

Kynan Feeney (K)

Krishna Epari (K)

Sanjay Mukhedkar (S)

Nikolajs Zeps (N)

Nan Q Nguyen (NQ)

Andrew R Ruszkiewicz (AR)

Chris Worthley (C)

John Chen (J)

Mark E Brooke-Smith (ME)

Virginia Papangelis (V)

Andrew D Clouston (AD)

Andrew P Barbour (AP)

Thomas J O'Rourke (TJ)

Jonathan W Fawcett (JW)

Kellee Slater (K)

Michael Hatzifotis (M)

Peter Hodgkinson (P)

Mehrdad Nikfarjam (M)

James R Eshleman (JR)

Ralph H Hruban (RH)

Christopher L Wolfgang (CL)

Aldo Scarpa (A)

Rita T Lawlor (RT)

Vincenzo Corbo (V)

Claudio Bassi (C)

Nigel B Jamieson (NB)

David K Chang (DK)

Stephan B Dreyer (SB)

Lea Abdulkhalek (L)

Tatjana Schmitz (T)

Victoria Lee (V)

Kym Pham Stewart (KP)

Mehreen Arshi (M)

Angela M Steinmann (AM)

Informations de copyright

Références

Cox, T. R. The matrix in cancer. Nat. Rev. Cancer 21, 217–238 (2021).

pubmed: 33589810 doi: 10.1038/s41568-020-00329-7

Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).

pubmed: 24840647 doi: 10.1158/0008-5472.CAN-14-0155

Piersma, B., Hayward, M.-K. & Weaver, V. M. Fibrosis and cancer: a strained relationship. Biochim. Biophys. Acta Rev. Cancer 1873, 188356 (2020).

pubmed: 32147542 pmcid: 7733542 doi: 10.1016/j.bbcan.2020.188356

Biffi, G. & Tuveson, D. A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 101, 147–176 (2021).

pubmed: 32466724 doi: 10.1152/physrev.00048.2019

Hemmings, C. & Connor, S. Pathological assessment of tumour regression following neoadjuvant therapy in pancreatic carcinoma. Pathology 52, 621–626 (2020).

pubmed: 32800331 doi: 10.1016/j.pathol.2020.07.001

Pereira, B. A. et al. CAF subpopulations: A new reservoir of stromal targets in pancreatic cancer. Trends Cancer 5, 724–741 (2019).

pubmed: 31735290 doi: 10.1016/j.trecan.2019.09.010

Cox, T. R. & Erler, J. T. Fibrosis and cancer: partners in crime or opposing forces? Trends Cancer 2, 279–282 (2016).

pubmed: 28741525 doi: 10.1016/j.trecan.2016.05.004

Neesse, A. et al. Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut 68, 159–171 (2019).

pubmed: 30177543 doi: 10.1136/gutjnl-2018-316451

Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

pubmed: 24856585 pmcid: 4096698 doi: 10.1016/j.ccr.2014.04.021

Özdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

pubmed: 24856586 pmcid: 4180632 doi: 10.1016/j.ccr.2014.04.005

Vennin, C. et al. Reshaping the tumor stroma for treatment of pancreatic cancer. Gastroenterology 154, 820–838 (2018).

pubmed: 29287624 doi: 10.1053/j.gastro.2017.11.280

Chitty, J. L., Setargew, Y. F. I. & Cox, T. R. Targeting the lysyl oxidases in tumour desmoplasia. Biochem. Soc. Trans. 47, 1661–1678 (2019).

pubmed: 31754702 doi: 10.1042/BST20190098

Barker, H. E., Cox, T. R. & Erler, J. T. The rationale for targeting the LOX family in cancer. Nat. Rev. Cancer 12, 540–552 (2012).

pubmed: 22810810 doi: 10.1038/nrc3319

Chopra, V., Sangarappillai, R. M., Romero‐Canelón, I. & Jones, A. M. Lysyl oxidase like‐2 (LOXL2): an emerging oncology target. Adv. Therap. 3, 1900119 (2020).

doi: 10.1002/adtp.201900119

Cox, T. R. et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73, 1721–1732 (2013).

pubmed: 23345161 pmcid: 3672851 doi: 10.1158/0008-5472.CAN-12-2233

Miller, B. W. et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol. Med. 7, 1063–1076 (2015).

pubmed: 26077591 pmcid: 4551344 doi: 10.15252/emmm.201404827

Benson, A. B. et al. A phase II randomized, double-blind, placebo-controlled study of simtuzumab or placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist 22, 241 (2017).

pubmed: 28246206 pmcid: 5344644 doi: 10.1634/theoncologist.2017-0024

Hecht, J. R. et al. A phase II, randomized, double-blind, placebo-controlled study of simtuzumab in combination with FOLFIRI for the second-line treatment of metastatic KRAS mutant colorectal adenocarcinoma. Oncologist 22, 243 (2017).

pubmed: 28246207 pmcid: 5344646 doi: 10.1634/theoncologist.2016-0479

Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).

pubmed: 20818376 doi: 10.1038/nm.2208

Yao, Y. et al. Pan-lysyl oxidase inhibitor PXS-5505 ameliorates multiple-organ fibrosis by inhibiting collagen crosslinks in rodent models of systemic sclerosis. Int. J. Mol. Sci. 23, 5533 (2022).

pubmed: 35628342 pmcid: 9146019 doi: 10.3390/ijms23105533

Biankin, A. V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).

pubmed: 23103869 pmcid: 3530898 doi: 10.1038/nature11547

Rissin, D. M. et al. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat. Biotechnol. 28, 595–599 (2010).

pubmed: 20495550 pmcid: 2919230 doi: 10.1038/nbt.1641

Raghu, G. et al. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir. Med. 5, 22–32 (2017).

pubmed: 27939076 doi: 10.1016/S2213-2600(16)30421-0

Gopinathan, A., Morton, J. P., Jodrell, D. I. & Sansom, O. J. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis. Model. Mech. 8, 1185–1200 (2015).

pubmed: 26438692 pmcid: 4610236 doi: 10.1242/dmm.021055

Neesse, A., Algül, H., Tuveson, D. A. & Gress, T. M. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 64, 1476–1484 (2015).

pubmed: 25994217 doi: 10.1136/gutjnl-2015-309304

Nielsen, S. R. et al. Corrigendum: macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat. Cell Biol. 18, 822 (2016).

pubmed: 27350447 doi: 10.1038/ncb3377

Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).

pubmed: 31980749 pmcid: 7046529 doi: 10.1038/s41568-019-0238-1

Vennin, C. et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nat. Commun. 10, 3637 (2019).

pubmed: 31406163 pmcid: 6691013 doi: 10.1038/s41467-019-10968-6

Keiser, H. R. & Sjoerdsma, A. Studies on β-aminopropionitrile in patients with scleroderma. Clin. Pharmacol. Ther. 8, 593–602 (1967).

pubmed: 4951976 doi: 10.1002/cpt196784593

Aslam, T. et al. Optical molecular imaging of lysyl oxidase activity – detection of active fibrogenesis in human lung tissue. Chem. Sci. 6, 4946–4953 (2015).

pubmed: 30155003 pmcid: 6088439 doi: 10.1039/C5SC01258A

Findlay, A. D. et al. Identification and optimization of mechanism-based fluoroallylamine inhibitors of lysyl oxidase-like 2/3. J. Med. Chem. 62, 9874–9889 (2019).

pubmed: 31580073 doi: 10.1021/acs.jmedchem.9b01283

Holt, A. & Palcic, M. M. A peroxidase-coupled continuous absorbance plate-reader assay for flavin monoamine oxidases, copper-containing amine oxidases and related enzymes. Nat. Protoc. 1, 2498–2505 (2006).

pubmed: 17406497 doi: 10.1038/nprot.2006.402

Sharbeen, G. et al. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition. Cancer Res. 81, 3461–3479 (2021).

pubmed: 33980655 doi: 10.1158/0008-5472.CAN-20-2496

Vennin, C. et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci. Transl. Med. 9, eaai8504 (2017).

pubmed: 28381539 pmcid: 5777504 doi: 10.1126/scitranslmed.aai8504

Chang, J. et al. Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer. Oncotarget 8, 26066–26078 (2017).

pubmed: 28199967 pmcid: 5432238 doi: 10.18632/oncotarget.15257

Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

pubmed: 25719666 pmcid: 4523082 doi: 10.1038/nature14169

Dosch, A. R. et al. Targeting tumor-stromal IL6/STAT3 signaling through IL1 receptor inhibition in pancreatic cancer. Mol. Cancer Ther. 20, 2280–2290 (2021).

pubmed: 34518296 pmcid: 8571047 doi: 10.1158/1535-7163.MCT-21-0083

Lankadasari, M. B. et al. Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine. Theranostics 8, 3824–3840 (2018).

pubmed: 30083262 pmcid: 6071521 doi: 10.7150/thno.25308

Long, K. B. et al. IL6 receptor blockade enhances chemotherapy efficacy in pancreatic ductal adenocarcinoma. Mol. Cancer Ther. 16, 1898–1908 (2017).

pubmed: 28611107 pmcid: 5587413 doi: 10.1158/1535-7163.MCT-16-0899

Gong, J. et al. Downregulation of STAT3/NF-κB potentiates gemcitabine activity in pancreatic cancer cells. Mol. Carcinog. 56, 402–411 (2017).

pubmed: 27208550 doi: 10.1002/mc.22503

Chen, Y. et al. Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. J. Clin. Invest. 125, 1147–1162 (2015).

pubmed: 25664850 pmcid: 4362236 doi: 10.1172/JCI74725

Sun, L. et al. IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway. Cancer Lett. 500, 132–146 (2021).

pubmed: 33309859 doi: 10.1016/j.canlet.2020.12.008

Morton, J. P. et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl Acad. Sci. USA 107, 246–251 (2010).

pubmed: 20018721 doi: 10.1073/pnas.0908428107

Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

pubmed: 15894267 doi: 10.1016/j.ccr.2005.04.023

Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).

pubmed: 31912902 doi: 10.3322/caac.21590

Isaji, S. et al. International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. Pancreatology 18, 2–11 (2018).

pubmed: 29191513 doi: 10.1016/j.pan.2017.11.011

Jiang, H. et al. Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. J. Clin. Invest. 130, 4704–4709 (2020).

pubmed: 32749238 pmcid: 7456216 doi: 10.1172/JCI136760

Le Calvé, B. et al. Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution. Oncotarget 7, 32100–32112 (2016).

pubmed: 27050073 pmcid: 5078000 doi: 10.18632/oncotarget.8527

Wang, S. et al. CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling. Nat. Cell Biol. 23, 758–770 (2021).

pubmed: 34226698 doi: 10.1038/s41556-021-00702-0

Vonlaufen, A. et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 68, 2085–2093 (2008).

pubmed: 18381413 doi: 10.1158/0008-5472.CAN-07-2477

Chitty, J. L. et al. The Mini-Organo: a rapid high-throughput 3D coculture organotypic assay for oncology screening and drug development. Cancer Rep. 3, e1209 (2020).

doi: 10.1002/cnr2.1209

Conway, J. R. W. et al. Three-dimensional organotypic matrices from alternative collagen sources as pre-clinical models for cell biology. Sci. Rep. 7, 16887 (2017).

pubmed: 29203823 pmcid: 5715059 doi: 10.1038/s41598-017-17177-5

Morton, J. P. et al. Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 139, 292–303 (2010).

pubmed: 20303350 doi: 10.1053/j.gastro.2010.03.034

Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

pubmed: 19111879 pmcid: 3050620 doi: 10.1016/j.ccr.2008.11.012

Baker, A.-M. et al. The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. J. Natl Cancer Inst. 103, 407–424 (2011).

pubmed: 21282564 doi: 10.1093/jnci/djq569

Baker, A. M., Bird, D., Lang, G., Cox, T. R. & Erler, J. T. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene 32, 1863–1868 (2013).

pubmed: 22641216 doi: 10.1038/onc.2012.202

Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).

pubmed: 29203879 pmcid: 5715110 doi: 10.1038/s41598-017-17204-5

Mayorca-Guiliani, A. E. et al. ISDoT: in situ decellularization of tissues for high-resolution imaging and proteomic analysis of native extracellular matrix. Nat. Med. 23, 890–898 (2017).

pubmed: 28604702 doi: 10.1038/nm.4352

Trackman, P. C. & Bais, M. V. Measurement of lysyl oxidase activity from small tissue samples and cell cultures. Methods Cell Biol. 143, 147–156 (2018).

pubmed: 29310775 doi: 10.1016/bs.mcb.2017.08.009

Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-seq data with or without a reference genome. BMC Bioinform. 12, 323 (2011).

doi: 10.1186/1471-2105-12-323

Joshi, A., Zahoor, A. & Buson, A. Measurement of collagen cross-links from tissue samples by mass spectrometry. Methods Mol. Biol. 1944, 79–93 (2019).

pubmed: 30840236 doi: 10.1007/978-1-4939-9095-5_6