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

Jordan F Hastings | David R. Croucher | J. Kench | L. Andrews | R. Hruban | J. Eshleman | A. Biankin | M. Pajic | N. Waddell | S. Grimmond | R. Pidsley | N. Pavlakis | S. Clark | J. Kirk | A. Scarpa | P. Timpson | A. Patch | A. Johns | K. Nones | O. Holmes | S. Kazakoff | C. Leonard | F. Newell | S. Wood | A. Nagrial | L. Chantrill | A. Steinmann | A. Chou | J. Samra | K. Epari | A. Barbour | N. Zeps | N. Jamieson | elliot k fishman | R. Lawlor | V. Corbo | C. Bassi | A. Gill | R. S. Mead | P. Grimison | R. Asghari | M. Lucas | K. Murphy | D. Herrmann | P. Phillips | Alice G. Russo | A. Ruszkiewicz | M. Texler | C. Sandroussi | C. Vennin | W. Jarolimek | P. Mukhopadhyay | A. Clouston | L. Perryman | P. Cosman | V. Addala | Sharissa L. Latham | M. Nikfarjam | Andrew M. Da Silva | M. Papanicolaou | A. Stoita | S. Dreyer | A. Findlay | Katherine Tucker | Amelia L. Parker | Elysse C Filipe | Brooke A. Pereira | Joanna N Skhinas | A. Goodwin | M. Yam | M. Brooke-Smith | G. Sharbeen | Gretel S Major | K. Feeney | Jessica L. Chitty | K. Slater | John Chen | Joanna N. Skhinas | Thomas R. Cox | Rhiannon Grant | Ellie Mok | J. Arena | Peter Hodgkinson | D. Fletcher | Victoria Lee | M. Hatzifotis | M. Arshi | H. High | J. Youkhana | V. Papangelis | K. Ismail | Amitabha Das | Kaitlin Wyllie | Emmi Tran | A. Nadalini | A. Zaratzian | Michael Trpceski | Oliver Hofmann | Shona Ritchie | Pauline Mélénec | M. Beilin | N. Merrett | M. Nobis | Tanya M. Dwarte | Michael Tayao | Yordanos F I Setargew | M. Ballal | Xanthe L Metcalf | David B. Williams | Allan Spigellman | Sanjay Mukhedkar | Nan Q. Nguyen | C. Worthley | T. J. O'Rourke | John V. Pearson | G. Jeong | Daniel A. Reed | T. Schmitz | Janett Stoehr | Lea Abdulkhalek | Cindy Forrest | C. Chambers | Kym Pham Stewart | D. Chang | Bret Charlton | Sipiththa Velayuthar | Shivanjali Ratnaseelan | Antonia Blackwell | Lara Kenyon | Duncan McLeo | J. W. Fawcett | Kellee Slater | Gretel S. Major | Anaiis Zaratzian | T. Cox

[1]  K. Ask,et al.  Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis , 2021, International journal of molecular sciences.

[2]  N. Merchant,et al.  Targeting Tumor–Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer , 2021, Molecular Cancer Therapeutics.

[3]  K. Pietras,et al.  CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling , 2021, Nature Cell Biology.

[4]  T. Cox.  The matrix in cancer , 2021, Nature Reviews Cancer.

[5]  Wei Zhang,et al.  IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway. , 2020, Cancer letters.

[6]  S. Connor,et al.  Pathological assessment of tumour regression following neoadjuvant therapy in pancreatic carcinoma. , 2020, Pathology.

[7]  Keith E. Volmar,et al.  Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. , 2020, The Journal of clinical investigation.

[8]  V. Gebski,et al.  Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition , 2020, Cancer Research.

[9]  D. Tuveson,et al.  DIVERSITY AND BIOLOGY OF CANCER-ASSOCIATED FIBROBLASTS. , 2020, Physiological reviews.

[10]  V. Weaver,et al.  The fibrotic tumor stroma. , 2020, Biochimica et biophysica acta. Reviews on cancer.

[11]  I. Romero‐Canelón,et al.  Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target , 2020 .

[12]  Thea D. Tlsty,et al.  A framework for advancing our understanding of cancer-associated fibroblasts , 2020, Nature Reviews Cancer.

[13]  A. Jemal,et al.  Cancer statistics, 2020 , 2020, CA: a cancer journal for clinicians.

[14]  T. Cox,et al.  Targeting the lysyl oxidases in tumour desmoplasia. , 2019, Biochemical Society transactions.

[15]  P. Timpson,et al.  CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer. , 2019, Trends in cancer.

[16]  H. Schilter,et al.  Identification and Optimization of Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-Like 2/3. , 2019, Journal of medicinal chemistry.

[17]  David R. Croucher,et al.  CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan , 2019, Nature Communications.

[18]  P. Timpson,et al.  The Mini‐Organo: A rapid high‐throughput 3D coculture organotypic assay for oncology screening and drug development , 2019, Cancer reports.

[19]  D. Tuveson,et al.  Stromal biology and therapy in pancreatic cancer: ready for clinical translation? , 2018, Gut.

[20]  K. Harikumar,et al.  Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine , 2018, Theranostics.

[21]  M. Pajic,et al.  Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer. , 2017, Gastroenterology.

[22]  M. Pajic,et al.  Three-dimensional organotypic matrices from alternative collagen sources as pre-clinical models for cell biology , 2017, Scientific Reports.

[23]  J. Windsor,et al.  International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. , 2017, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[24]  Xiaoqing Pan,et al.  IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma , 2017, Molecular Cancer Therapeutics.

[25]  J. Erler,et al.  ISDoT: in situ decellularization of tissues for high-resolution imaging and proteomic analysis of native extracellular matrix , 2017, Nature Medicine.

[26]  Max Nobis,et al.  Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis , 2017, Science Translational Medicine.

[27]  J. Bendell,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 , 2017, The oncologist.

[28]  Z. Wainberg,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 , 2017, The oncologist.

[29]  Wolfgang,et al.  Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer , 2017, Oncotarget.

[30]  J. Freeman,et al.  Downregulation of STAT3/NF‐κB potentiates gemcitabine activity in pancreatic cancer cells , 2017, Molecular carcinogenesis.

[31]  Peter Bankhead,et al.  QuPath: Open source software for digital pathology image analysis , 2017, Scientific Reports.

[32]  D. Tuveson,et al.  Corrigendum: Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis , 2016, Nature Cell Biology.

[33]  J. Erler,et al.  Fibrosis and Cancer: Partners in Crime or Opposing Forces? , 2016, Trends in cancer.

[34]  P. Dubus,et al.  Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution , 2016, Oncotarget.

[35]  O. Sansom,et al.  GEMMs as preclinical models for testing pancreatic cancer therapies , 2015, Disease Models & Mechanisms.

[36]  Karin Oien,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 , 2015, EMBO molecular medicine.

[37]  D. Tuveson,et al.  Stromal biology and therapy in pancreatic cancer: a changing paradigm , 2015, Gut.

[38]  J. Kench,et al.  Whole genomes redefine the mutational landscape of pancreatic cancer , 2015, Nature.

[39]  Daniel S. Puperi,et al.  Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. , 2015, The Journal of clinical investigation.

[40]  L. Chin,et al.  Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. , 2014, Cancer Cell.

[41]  Stephen A. Sastra,et al.  Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. , 2014, Cancer cell.

[42]  Benjamin D. Smith,et al.  Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. , 2014, Cancer research.

[43]  J. Erler,et al.  Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK , 2013, Oncogene.

[44]  J. Erler,et al.  LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. , 2013, Cancer research.

[45]  Lincoln D. Stein,et al.  Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes , 2012, Nature.

[46]  Thomas R. Cox,et al.  The rationale for targeting the LOX family in cancer , 2012, Nature Reviews Cancer.

[47]  Colin N. Dewey,et al.  RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome , 2011, BMC Bioinformatics.

[48]  Thomas R Cox,et al.  The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. , 2011, Journal of the National Cancer Institute.

[49]  C. Wai,et al.  Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment , 2010, Nature Medicine.

[50]  Jennifer P Morton,et al.  Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma. , 2010, Gastroenterology.

[51]  David M. Rissin,et al.  Single-Molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations , 2010, Nature Biotechnology.

[52]  Paul Timpson,et al.  Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer , 2010, Proceedings of the National Academy of Sciences.

[53]  J. Erler,et al.  Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. , 2009, Cancer cell.

[54]  David Goldstein,et al.  Pancreatic stellate cells: partners in crime with pancreatic cancer cells. , 2008, Cancer research.

[55]  M. Palcic,et al.  A peroxidase-coupled continuous absorbance plate-reader assay for flavin monoamine oxidases, copper-containing amine oxidases and related enzymes , 2006, Nature Protocols.

[56]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[57]  A. Sjoerdsma,et al.  Studies on beta‐aminopropionitrile in patients with scleroderma , 1967, Clinical pharmacology and therapeutics.

[58]  Amna Zahoor,et al.  Measurement of Collagen Cross-Links from Tissue Samples by Mass Spectrometry. , 2019, Methods in molecular biology.

[59]  P. Trackman,et al.  Measurement of lysyl oxidase activity from small tissue samples and cell cultures. , 2018, Methods in cell biology.

[60]  H. Collard,et al.  Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. , 2017, The Lancet. Respiratory medicine.