Hendrika M. Duivenvoorden

La Trobe University

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Belinda S. Parker

University of Melbourne

Natasha K. Brockwell

Peter MacCallum Cancer Centre

Alex Spurling

La Trobe University

Damien Zanker

La Trobe University

Katie L. Owen

Peter MacCallum Cancer Centre

Jai Rautela

Walter and Eliza Hall Institute of Medical Research

Franco Caramia

Peter MacCallum Cancer Centre

Nikola Baschuk

QIMR Berghofer Medical Research Institute

Phillip K. Darcy

Peter MacCallum Cancer Centre

Elgene Lim

St Vincent's Clinic

Cooperative Institutions

University of Melbourne

La Trobe University

Monash University

Peter MacCallum Cancer Centre

Garvan Institute of Medical Research

UNSW Sydney

The Kinghorn Cancer Centre

St Vincent's Clinic

Scripps Research Institute

Walter and Eliza Hall Institute of Medical Research

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Supplementary figure legends from Neoadjuvant Interferons: Critical for Effective PD-1–Based Immunotherapy in TNBC

Natasha K. Brockwell Katie L. Owen Damien Zanker Alex Spurling Jai Rautela

<p>Figure legends for supplementary figures 1, 2 & 3</p>

10.1158/2326-6066.22537178.v1

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Unbalanced translocations of 20q in AML and MDS often involve interstitial rather than terminal deletions of 20q

Cancer Genetics (2011)

Ruth N. MacKinnon Hendrika M. Duivenvoorden Lynda J. Campbell

Dicentric chromosome

Breakpoint

Chromosomal rearrangement

10.1016/j.cancergen.2010.12.001

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Citations (7)

Neoadjuvant Interferons: Critical for Effective PD-1–Based Immunotherapy in TNBC

Cancer Immunology Research (2017)

Natasha K. Brockwell Katie L. Owen Damien Zanker Alex Spurling Jai Rautela

The lack of targeted therapies available for triple-negative breast cancer (TNBC) patients who fail to respond to first-line chemotherapy has sparked interest in immunotherapeutic approaches. However, trials utilizing checkpoint inhibitors targeting the PD-1/PD-L1 axis in TNBC have had underwhelming responses. Here, we investigated the interplay between type I IFN signaling and the PD-1/PD-L1 axis and tested the impact of combining IFN inducers, as immune activators, with anti-PD-1, to induce an antimetastatic immune response. Using models of TNBC, we demonstrated an interplay between type I IFN signaling and tumor cell PD-L1 expression that affected therapeutic response. The data revealed that the type I IFN-inducer poly(I:C) was an effective immune activator and antimetastatic agent, functioning better than anti-PD-1, which was ineffective as a single agent. Poly(I:C) treatment induced PD-L1 expression on TNBC cells, and combined poly(I:C) and anti-PD-1 treatment prolonged metastasis-free survival in a neoadjuvant setting via the induction of a tumor-specific T-cell response. Use of this combination in a late treatment setting did not impact metastasis-free survival, indicating that timing was critical for immunotherapeutic benefit. Together, these data demonstrated anti-PD-1 as an ineffective single agent in preclinical models of TNBC. However, type I IFN inducers were effective immune activators, and neoadjuvant trials combining them with anti-PD-1 to induce a sustained antitumor immune response are warranted. Cancer Immunol Res; 5(10); 871-84. ©2017 AACR.

Triple-negative breast cancer

10.1158/2326-6066.cir-17-0150

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Figure S3 from Neoadjuvant Interferons: Critical for Effective PD-1–Based Immunotherapy in TNBC

Natasha K. Brockwell Katie L. Owen Damien Zanker Alex Spurling Jai Rautela

<p>The effect of combination treatment on T cell activation</p>

10.1158/2326-6066.22537181

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Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

Angewandte Chemie (2019)

Christopher J. Smedley Qinheng Zheng Bing Gao Suhua Li Andrew Molino

Abstract SuFEx is a new‐generation click chemistry transformation that exploits the unique properties of S−F bonds and their ability to undergo near‐perfect reactions with nucleophiles. We report here the first SuFEx‐based procedure for the efficient synthesis of pharmaceutically important triflones and bis(trifluoromethyl)sulfur oxyimines from sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new process involves rapid S−F exchange with trifluoromethyltrimethylsilane (TMSCF 3 ) upon activation by potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. A tentative mechanism is proposed involving nucleophilic displacement of S−F by the trifluoromethyl anion via a five‐coordinate intermediate. The utility of late‐stage SuFEx trifluoromethylation is demonstrated through the synthesis and selective anticancer properties of a bis(trifluoromethyl)sulfur oxyimine.

Trifluoromethylation

Sulfonyl

Anhydrous

10.1002/ange.201813761

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Citations (25)

Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

Angewandte Chemie International Edition (2019)

Christopher J. Smedley Qinheng Zheng Bing Gao Suhua Li Andrew Molino

Trifluoromethylation

Sulfonyl

Anhydrous

10.1002/anie.201813761

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Citations (81)

Myoepithelial cell‐specific expression of stefin A as a suppressor of early breast cancer invasion

The Journal of Pathology (2017)

Hendrika M. Duivenvoorden Jai Rautela Laura E. Edgington-Mitchell Alex Spurling David W. Greening

Mammography screening has increased the detection of early pre-invasive breast cancers, termed ductal carcinoma in situ (DCIS), increasing the urgency of identifying molecular regulators of invasion as prognostic markers to predict local relapse. Using the MMTV-PyMT breast cancer model and pharmacological protease inhibitors, we reveal that cysteine cathepsins have important roles in early-stage tumorigenesis. To characterize the cell-specific roles of cathepsins in early invasion, we developed a DCIS-like model, incorporating an immortalized myoepithelial cell line (N1ME) that restrained tumor cell invasion in 3D culture. Using this model, we identified an important myoepithelial-specific function of the cysteine cathepsin inhibitor stefin A in suppressing invasion, whereby targeted stefin A loss in N1ME cells blocked myoepithelial-induced suppression of breast cancer cell invasion. Enhanced invasion observed in 3D cultures with N1ME stefin A-low cells was reliant on cathepsin B activation, as addition of the small molecule inhibitor CA-074 rescued the DCIS-like non-invasive phenotype. Importantly, we confirmed that stefin A was indeed abundant in myoepithelial cells in breast tissue. Use of a 138-patient cohort confirmed that myoepithelial stefin A (cystatin A) is abundant in normal breast ducts and low-grade DCIS but reduced in high-grade DCIS, supporting myoepithelial stefin A as a candidate marker of lower risk of invasive relapse. We have therefore identified myoepithelial cell stefin A as a suppressor of early tumor invasion and a candidate marker to distinguish patients who are at low risk of developing invasive breast cancer, and can therefore be spared further treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cathepsin L

10.1002/path.4990

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Citations (49)

Bifluoride Ion Catalyzed Late-Stage SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

Christopher J. Smedley Bing Gao Suhua Li Qinheng Zheng Andrew Molino

Sulfur-Fluoride Exchange (SuFEx) is a new generation click chemistry transformation that exploits the unique properties of S-F bonds and their ability to undergo near-perfect reactions with nucleophiles. We report here the first SuFEx based protocol for the efficient late-stage synthesis of pharmaceutically important trifluoromethyl sulfones and bis(trifluoromethyl)sulfur oxyimines from the corresponding sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new protocol involves the rapid exchange of the S-F bond with trifluoromethyltrimethylsilane (TMSCF 3 , Ruppert’s reagent), upon activation with catalytic potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. DFT calculations provide the first reported mechanism of anhydrous SuFEx reactivity, which confirms catalytic bifluoride behaviour with a five-coordinate sulfur intermediate. The preparation of a benzothiazole derived bis(trifluoromethyl)sulfur oxyimine with cytotoxic selectivity for MCF7 breast cancer cells demonstrates the utility of this methodology for the late stage functionalization of bioactive molecules.

Anhydrous

Trifluoromethylation

Sulfonyl

Potassium fluoride

Reactivity

10.26434/chemrxiv.7312595.v1

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Tubulin-Jerantinine B acetate complex

C.J. Smedley Paul A. Stanley Munir Qazzaz A.E. Prota Natacha Olieric

10.2210/pdb6gf3/pdb

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High-content siRNA 3D co-cultures to identify myoepithelial cell-derived breast cancer suppressor proteins

Scientific Data (2021)

Hendrika M. Duivenvoorden Natasha K. Brockwell Cameron J. Nowell Kaylene J. Simpson Belinda S. Parker

Abstract Understanding how cancer cells interact with the surrounding microenvironment early in breast cancer development can provide insight into the initiation and progression of invasive breast cancers. The myoepithelial cell layer surrounding breast ducts acts as a physical barrier in early breast cancer, preventing cancer cells from invading the surrounding stroma. Changes to the expression profile and properties of myoepithelial cells have been implicated in progression to invasive carcinoma. Identifying the molecular drivers of myoepithelial cell-mediated tumour suppression may offer new approaches to predict and block the earliest stages of cancer invasion. We employed a high-content approach to knock down 87 different genes using siRNA in an immortalised myoepithelial cell line, prior to co-culture with invasive breast cancer cells in 3D. Combined with high-content imaging and a customised analysis pipeline, this system was used to identify myoepithelial proteins that are necessary to control cancer cell invasion. This dataset has identified prospective myoepithelial suppressors of early breast cancer invasion which may be used by researchers to investigate their clinical validity and utility.

10.1038/s41597-021-00924-9

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Citations (3)