Dr Pierre Dilda
Field: Basic Pharmacology
Phone: +61 2 93858796
Fax: +61 2 93851510
Overcoming the acquired or innate chemotherapy resistance of malignant tumours has been an ongoing challenge ever since the development of the first chemotherapeutic agents.
The discovery that arsenic trioxide induces complete remission in a high percentage of patients with acute promyelocytic leukaemia has renewed interest in arsenic for the treatment of cancer. Organic arsenicals are currently being investigated in cancer therapy due to their generally better toxicity profile compared to inorganic derivatives. Dr Dilda has specialised in organic arsenical anti-cancer compounds.
GSAO (4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide), an arsenic-based GSH-conjugate, is a mitochondrial poison that inhibits proliferating, but not growth-quiescent, endothelial cells in vitro and angiogenesis in vivo. It demonstrated anti tumor activity evaluated in clinical. For GSAO, extracellular γGT activity is an essential and limiting step in its activation into membrane permeable compounds. Indeed, it has recently been demonstrated that tumor γGT could be used for therapeutic delivery.
PENAO, (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid), a second generation compound, shares the same mitochondrial molecular target as GSAO. PENAO, 20-fold more potent than GSAO, demonstrates both in vitro and in animal models anti-proliferative and anti-angiogenic activities. The combination of these two properties leads to strong anti-tumour activity. Interestingly, PENAO has a strong anti-proliferative activity against glioblastoma cell lines and primary isolates of diffuse intrinsic pontine glioma. In vivo, PENAO demonstrated preclinical activity without signs of toxicity in tumor models of glioblastoma, pancreatic carcinoma and ovarian carcinoma. PENAO is currently tested in clinical Phase I/IIa in patients with solid tumours refractory to standard chemotherapy. Our recent work demonstrated that when combined with other drugs such as mTOR and EGFR inhibitors, PENAO anti-tumour activity is massively enhanced notably on drug resistant tumour cells. This discovery offers valuable options to the clinicians for the design of PENAO clinical Phase II.
We have recently characterised a novel polyarsenic adamantane-type class of compounds. The potency of the novel polyarsenic adamantane-type class of compounds was demonstrated in three types of drug resistant cancers. These compounds, not affected by resistance mechanisms responsible for the failure of cancer chemotherapeutics, are notably a hope for the treatment of cancers with a poor overall survival.
Dr Dilda's research has been published in the top 3 cancer biology journals such as Cancer Cell, Journal of the National Cancer Institute and Cancer Research and was the subject of commentaries in Nature Reviews Cancer and Science-Business eXchange.
PhD (UniParisV, France)
Broad Research Areas:
Pharmacology, Biochemistry, Cancer, Molecular Structure & Drug Design, Metabolism
Specific Research Keywords:
Drug Discovery, Cancer Drug Development and Pharmacology, Drug Resistance, Medicinal Chemistry, Arsenical-based drugs
The Cancer Council NSW. Campfires Against Cancer Research Fellowship 2006-2010. Project title: “New arsenical-based cancer drugs” ($500,000 over 5 years).
NHMRC Project Grant 2010-2012. Project title: “Investigation of a tumour enzyme as a predictor of patient response to an Australian anti-cancer drug”. I am chief investigator A and am responsible for the preliminary data presented in the application. Dr Hendrik-Tobias Arkenau is CIB. Associate investigators are Prof. M. Apte, Dr. A. de Fazio, Prof. R. Ward, Dr. S. Decollogne and Prof. A. Pompella ($348,750 over 3 years).
- The Cancer Council NSW. Research Program Grant 2011-2015. Project title: “Metabolism inhibitors for the treatment of brain and pancreatic cancer”. Chief investigators Prof. Philip Hogg, Dr Pierre Dilda, Associate investigators are Dr. Kerrie McDonald, Prof Minoti Apte and Prof. Ian Dawes ($2,250,000 over 5 years).
- The Cancer Institute NSW. Translational Program Grant 2007-2011. Project title: “Anti-mitochondrial cancer drugs”. Chief investigators are Prof. Philip Hogg, Prof. Robyn Ward, Prof. Ian Dawes, Dr. Richard Lock and Dr Paul de Souza ($3,750,000 over 5 years). Dr Pierre Dilda is associate investigator responsible for the preliminary data presented in the application (in vitro characterization of PENAO).
- The Cancer Council NSW. Research Program Grant 2006-2010. Project title: “New arsenical-based cancer drugs”.Chief investigators are Prof. Philip Hogg, Prof. Ian Dawes and Dr. Richard Lock ($3,800,000 over 5 years). Dr Pierre Dilda is associate investigator #1 responsible for the preliminary data of 2 out of 3 projects presented (tumour angiogenesis and acute promyelocytic leukemia).
- Faculty of Medicine, University of New South Wales, Faculty Research Grant 2012. Project title: “Effects of an adamantane-type polyarsenic compound in drug-resistant ovarian cancers”. Chief investigator A: Dr Pierre Dilda; Chief investigator B: Dr Viola Heinzelmann-Schwarz ($20,000 for one year).
- Faculty of Medicine, University of New South Wales, Faculty Research Grant 2011. Project title: “Investigation of an arsenical-based metabolic inhibitor in glioblastoma”. Chief investigator A: Dr Pierre Dilda; Chief investigator B: Dr Kerrie McDonald; AI: Prof Philip Hogg; AI: Dr Charles Teo ($20,000 for one year).
Australian Academy of Science. Travel Grant. “Scientific Visits to Europe 2009-2010”. Host: Prof. Pompella laboratory in Department of Experimental Pathology, University of Pisa Medical School, Italy. Project title: “Identification of cancer patients that will better respond to treatment with GSAO”.
Senior Research Fellow
- Cancer and Related Disorders
Shen H; Luk PP; Chung SA; Decollogne S; Dilda PJ; Hogg PJ; McDonald KL, 2013, '
Abstract 1701: PENAO, a novel mitochondria-targeted agent, has shown potent antitumor effect on glioblastoma in vitro and in vivo.', in Cancer Research
, pp. 1701 - 1701, presented at , http://dx.doi.org/10.1158/1538-7445.AM2013-1701
Chung S; Decollogne P; Luk P; Shen H; Ha W; Day B; Stringer B; Hogg P; Dilda P; McDonald K, 2013, 'PRECLINICAL EVALUATION OF PENAO: A POTENT MITOCHONDRIAL SPECIFIC, ARSENICAL-BASED INHIBITOR FOR GLIOBLASTOMA', in NEURO-ONCOLOGY, OXFORD UNIV PRESS INC, pp. 40 - 40, presented at 4th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology (WFNO) held in conjunction with the 18th Annual Meeting of the Society-for-Neuro-Oncology (SNO), San Francisco, CA, 21 - 24 November 2013
Shen H; Decollogne S; Dilda P; Chung S; Luk P; Hogg P; McDonald K, 2013, 'PENAO, A NOVEL MITOCHONDRIA-TARGETED AGENT, SYNERGIZES WITH DICHLOROACETATE TO TARGET ABERRANT GLUCOSE METABOLISM IN GLIOBLASTOMA', in NEURO-ONCOLOGY, OXFORD UNIV PRESS INC, pp. 58 - 58, presented at 4th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology (WFNO) held in conjunction with the 18th Annual Meeting of the Society-for-Neuro-Oncology (SNO), San Francisco, CA, 21 - 24 November 2013
Tsoli M; Luk P; Dilda P; Hogg P; Haber M; Ziegler D, 2013, 'TARGETING MITOCHONDRIA AND METABOLISM AS A NOVEL THERAPEUTIC APPROACH IN THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA', in NEURO-ONCOLOGY, OXFORD UNIV PRESS INC, pp. 21 - 21, presented at 2nd Annual Pediatric Neuro-Oncology Basic and Translational Research Conference, Fort Lauderdale, FL, 16 - 17 May 2013
Park D; Chiu J; Perrone GG; Dilda PJ; Hogg PJ, 2012, 'The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase.', Cancer Cell International
, vol. 12, no. 1, pp. 11, http://dx.doi.org/10.1186/1475-2867-12-11
Dilda PJ; Joshi S; Lu D; Decollogne S; Allen JD; Heinzelmann-Schwarz V; Salem G; Wild SB, 2012, 'Polyarsenic Adamantane-type Compounds - a Promising New Class of Drugs for the Treatment of Drug-resistant Ovarian Cancers', in EUROPEAN JOURNAL OF CANCER, ELSEVIER SCI LTD, pp. S250 - S251, presented at 22nd Biennial Congress of the European-Association-for-Cancer-Research, Barcelona, SPAIN, 7 - 10 July 2012
Decollogne S; Ramsay EE; Joshi S; Corti A; Pompella A; Apte M; Hogg PJ; Dilda PJ, 2012, 'Both Pancreatic Cancer and Pancreatic Stellate Cells Express High Levels of Gamma-glutamyl Transferase That May Be Employed to Deliver a Metabolism Inhibitor to the Tumour Mass', in EUROPEAN JOURNAL OF CANCER, ELSEVIER SCI LTD, pp. S251 - S251, presented at 22nd Biennial Congress of the European-Association-for-Cancer-Research, Barcelona, SPAIN, 7 - 10 July 2012
Lu D; Coote ML; Ho J; Kilah NL; Lin C-Y; Salem G; Weir ML; Willis AC; Wild SB; Dilda PJ, 2012, '
Resolution and Improved Synthesis of (±)-Arsenicin A: A Natural Adamantane-Type Tetraarsenical Possessing Strong Anti-Acute Promelocytic Leukemia Cell Line Activity', Organometallics
, vol. 31, no. 5, pp. 1808 - 1816, http://dx.doi.org/10.1021/om201180d
Park D; Don AS; Massamiri T; Karwa A; Warner B; MacDonald J; Hemenway C; Naik A; Kuan KT; Dilda PJ, 2011, 'Noninvasive imaging of cell death using an Hsp90 ligand.', Journal of the American Chemical Society
, vol. 133, no. 9, pp. 2832 - 2835, http://dx.doi.org/10.1021/ja110226y
Chung SA; McDonald KL; Shen H; Day BW; Stringer BW; Johns T; Decollogne S; Teo C; Hogg PJ; Dilda PJ, 2011, 'TARGETING GLIOBLASTOMA METABOLISM WITH A NOVEL ARSENIC-BASED METABOLIC INHIBITOR, PENAO', in NEURO-ONCOLOGY, OXFORD UNIV PRESS INC, pp. 118 - 118, presented at
Dilda PJ; Decollogne S; Weerakoon L; Norris MD; Haber M; Allen JD; Hogg PJ, 2009, 'Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol.', Journal of Medicinal Chemistry
, vol. 52, no. 20, pp. 6209 - 6216, http://dx.doi.org/10.1021/jm9008339
Dilda PJ; Ramsay EE; Corti A; Pompella A; Hogg PJ, 2008, 'Metabolism of the tumor angiogenesis inhibitor 4-(N-(S-Glutathionylacetyl)amino)phenylarsonous acid.', Journal of Biological Chemistry
, vol. 283, no. 51, pp. 35428 - 35434, http://dx.doi.org/10.1074/jbc.m804470200
Adjou KT; Dilda P; Aumond P; Gueddari S; Deslys JP; Dormont D; Seman M, 2008, 'Increase of monoamine oxidase-B activity in the brain of scrapie-infected hamsters.', Neurochemistry International: the journal for the publication of cellular and molecular aspects of neurochemistry
, vol. 52, no. 8, pp. 1416 - 1421, http://dx.doi.org/10.1016/j.neuint.2008.03.002
Dilda PJ; Perrone GG; Philp A; Lock RB; Dawes IW; Hogg PJ, 2008, 'Insight into the selectivity of arsenic trioxide for acute promyelocytic leukemia cells by characterizing Saccharomyces cerevisiae deletion strains that are sensitive or resistant to the metalloid.', The International Journal of Biochemistry and Cell Biology
, vol. 40, no. 5, pp. 1016 - 1029, http://dx.doi.org/10.1016/j.biocel.2007.11.002
Corti A; Duarte TL; Paolicchi A; Dominici S; Jones GDD; Dilda P; Hogg PJ; Pompella A, 2008, 'GAMMA-GLUTAMYLTRANSFERASE OF CANCER CELLS AT THE CROSSROADS OF REDOX REGULATION, TUMOR PROGRESSION, DRUG RESISTANCE AND DRUG TARGETING', in ANTICANCER RESEARCH, INT INST ANTICANCER RESEARCH, pp. 3451 - 3452, presented at
Dilda PJ; Decollogne S; Rossiter-Thornton M; Hogg PJ, 2005, 'Para to ortho repositioning of the arsenical moiety of the angiogenesis inhibitor 4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide results in a markedly increased cellular accumulation and antiprolif', Cancer Research
, vol. 65, no. 24, pp. 11729 - 11734, http://dx.doi.org/10.1158/0008-5472.can-05-2797
Dilda PJ; Don AS; Tanabe KM; Higgins VJ; Allen JD; Dawes IW; Hogg PJ, 2005, 'Mechanism of selectivity of an angiogenesis inhibitor from screening a genome-wide set of Saccharomyces cerevisiae deletion strains.', Journal of the National Cancer Institute
, vol. 97, no. 20, pp. 1539 - 1547, http://dx.doi.org/10.1093/jnci/dji316
Dilda PJ; Hogg PJ, 2005, 'Selective targeting of mitochondria for the treatment of cancer.', Discovery medicine, vol. 5, no. 25, pp. 70 - 73
Dilda P; Perrone G; Dawes IW; Hogg PJ, 2005, 'Mechanism of selectivity of arsenic trioxide for acute promyelocytic leukemia cells from screening a genome wide set of Saccharomyces cerevisiae deletion strains', in Blood, American Society of Hematology, pp. 694A - 694A, presented at
Don AS; Kisker O; Dilda P; Donoghue N; Zhao X; Decollogne S; Creighton B; Flynn E; Folkman J; Hogg PJ, 2003, 'A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells.', Cancer Cell
, vol. 3, no. 5, pp. 497 - 509, http://dx.doi.org/10.1016/s1535-6108(03)00109-0
Tronchet JM; Chalard F; Rivara-Minten E; Seman M; De Clercq E; Balzarini J; Dilda P, 2002, 'Synthesis and in vitro cytotoxic and antiviral activities of 1-(2,5,6-trideoxy-6-halogenohept-5-enofuranurononitrile)thymine and derivatives.', Nucleosides, Nucleotides and Nucleic Acids: an international journal for rapid communication
, vol. 21, no. 3, pp. 191 - 206, http://dx.doi.org/10.1081/ncn-120003285
Tronchet JM; Kovacs I; Dilda P; Seman M; Andrei G; Snoeck R; De Clercq E; Balzarini J, 2001, 'Synthesis and anti-HIV activity of thymidine analogues bearing a 4'-cyanovinyl group and some derivatives thereof.', Nucleosides, Nucleotides and Nucleic Acids: an international journal for rapid communication
, vol. 20, no. 12, pp. 1927 - 1939, http://dx.doi.org/10.1081/ncn-100108323
Tronchet JM; Grivet C; Grand E; Seman M; Dilda P, 2000, 'Synthesis and antiproliferative activity of O-silylated nucleoside triazene N-oxide derivatives.', Carbohydrate Letters, vol. 4, no. 1, pp. 5 - 12
Tronchet JM; Kovacs I; Seman M; Dilda P; De Clercq E; Balzarini J, 2000, 'Highly stereoselective synthesis and biological properties of nucleoside analogues bearing a spiro inserted oxirane ring.', Nucleosides, Nucleotides and Nucleic Acids: an international journal for rapid communication
, vol. 19, no. 4, pp. 775 - 794, http://dx.doi.org/10.1080/15257770008035024
Gigout L; Vaslin B; Matheux F; Caufour P; Neildez O; Chéret A; Lebel-Binay S; Théodoro F; Dilda P; Benveniste O, 1998, 'Consequences of ddI-induced reduction of acute SIVmac251 virus load on cytokine profiles in cynomolgus macaques.', Research in Virology
, vol. 149, no. 6, pp. 341 - 354, http://dx.doi.org/10.1016/s0923-2516(99)80002-8
Gérard V; Rouzaire-Dubois B; Dilda P; Dubois J-M, 1998, 'Alterations of ionic membrane permeabilities in multidrug resistant neuroblastoma x glioma hybrid cells', The Journal of Experimental Biology, vol. 201, no. 1, pp. 21 - 31
Tronchet JMJ; Grand E; Montes IF; Criton M; Seman M; Dilda P, 1998, 'Synthesis, antiviral and antiproliferative activity of nucleoside-3'-C-acetamides and nucleoside-3'-C-acetamide oximes', Carbohydrate Letters, vol. 3, no. 3, pp. 203 - 210
Dilda P; Lelièvre LG, 1994, 'Functional characterization of cystic fibrosis transmembrane conductance regulator (CFTR) in apical membranes purified from bovine tracheal epithelium.', Journal of Biological Chemistry, vol. 269, no. 10, pp. 7801 - 7806