PTC596 in Patients With Advanced Solid Tumors

Summary

This is a Phase 1, open-label, first-in-human, safety and pharmacokinetic study of PTC596 in patients with advanced cancer.

Timeline

Start

2016-01

Primary completion

2017-02-06

Completion

2017-02-06

Publications

• Background Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, Bernier G. BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci. 2009 Jul 15;29(28):8884-96. doi: 10.1523/JNEUROSCI.0968-09.2009.
• Background American Society of Clinical Oncology; Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, Morrow GR, Chinnery LW, Chesney MJ, Gralla RJ, Grunberg SM. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006 Jun 20;24(18):2932-47. doi: 10.1200/JCO.2006.06.9591. Epub 2006 May 22.
• Background Beck B, Blanpain C. Unravelling cancer stem cell potential. Nat Rev Cancer. 2013 Oct;13(10):727-38. doi: 10.1038/nrc3597.
• Background Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005 Dec 22;20(6):845-54. doi: 10.1016/j.molcel.2005.12.002.
• Background Chiba T, Miyagi S, Saraya A, Aoki R, Seki A, Morita Y, Yonemitsu Y, Yokosuka O, Taniguchi H, Nakauchi H, Iwama A. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res. 2008 Oct 1;68(19):7742-9. doi: 10.1158/0008-5472.CAN-07-5882.
• Background Cho JH, Dimri M, Dimri GP. A positive feedback loop regulates the expression of polycomb group protein BMI1 via WNT signaling pathway. J Biol Chem. 2013 Feb 1;288(5):3406-18. doi: 10.1074/jbc.M112.422931. Epub 2012 Dec 13.
• Background Costa DB, Li S, Kocher O, Feins RH, Keller SM, Schiller JH, Johnson DH, Tenen DG, Halmos B. Immunohistochemical analysis of C/EBPalpha in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: a correlative study of E3590. Lung Cancer. 2007 Apr;56(1):97-103. doi: 10.1016/j.lungcan.2006.11.023. Epub 2007 Jan 18.
• Background Douglas D, Hsu JH, Hung L, Cooper A, Abdueva D, van Doorninck J, Peng G, Shimada H, Triche TJ, Lawlor ER. BMI-1 promotes ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res. 2008 Aug 15;68(16):6507-15. doi: 10.1158/0008-5472.CAN-07-6152.
• Background Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
• Background Facchino S, Abdouh M, Chatoo W, Bernier G. BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci. 2010 Jul 28;30(30):10096-111. doi: 10.1523/JNEUROSCI.1634-10.2010.
• Background Fan C, He L, Kapoor A, Rybak AP, De Melo J, Cutz JC, Tang D. PTEN inhibits BMI1 function independently of its phosphatase activity. Mol Cancer. 2009 Nov 10;8:98. doi: 10.1186/1476-4598-8-98.
• Background Glinsky GV, Berezovska O, Glinskii AB. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest. 2005 Jun;115(6):1503-21. doi: 10.1172/JCI23412.
• Background Guney I, Wu S, Sedivy JM. Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a). Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3645-50. doi: 10.1073/pnas.0600069103. Epub 2006 Feb 28.
• Background Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L, Baiazitov R, Du W, Sydorenko N, Moon YC, Gibson L, Wang Y, Leung C, Iscove NN, Arrowsmith CH, Szentgyorgyi E, Gallinger S, Dick JE, O'Brien CA. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014 Jan;20(1):29-36. doi: 10.1038/nm.3418. Epub 2013 Dec 1.
• Background Li DW, Tang HM, Fan JW, Yan DW, Zhou CZ, Li SX, Wang XL, Peng ZH. Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer. J Cancer Res Clin Oncol. 2010 Jul;136(7):997-1006. doi: 10.1007/s00432-009-0745-7. Epub 2009 Dec 19.
• Background Liu L, Andrews LG, Tollefsbol TO. Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death. Oncogene. 2006 Jul 20;25(31):4370-5. doi: 10.1038/sj.onc.1209454. Epub 2006 Feb 27.
• Background Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 2003 Oct 30;425(6961):962-7. doi: 10.1038/nature02060. Epub 2003 Oct 22.
• Background Nacerddine K, Beaudry JB, Ginjala V, Westerman B, Mattiroli F, Song JY, van der Poel H, Ponz OB, Pritchard C, Cornelissen-Steijger P, Zevenhoven J, Tanger E, Sixma TK, Ganesan S, van Lohuizen M. Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer. J Clin Invest. 2012 May;122(5):1920-32. doi: 10.1172/JCI57477. Epub 2012 Apr 16.
• Background Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012 Oct;3(5):241-53. doi: 10.1177/2042098612454283.
• Background Nakamura S, Oshima M, Yuan J, Saraya A, Miyagi S, Konuma T, Yamazaki S, Osawa M, Nakauchi H, Koseki H, Iwama A. Bmi1 confers resistance to oxidative stress on hematopoietic stem cells. PLoS One. 2012;7(5):e36209. doi: 10.1371/journal.pone.0036209. Epub 2012 May 11.
• Background O'Connor ML, Xiang D, Shigdar S, Macdonald J, Li Y, Wang T, Pu C, Wang Z, Qiao L, Duan W. Cancer stem cells: A contentious hypothesis now moving forward. Cancer Lett. 2014 Mar 28;344(2):180-7. doi: 10.1016/j.canlet.2013.11.012. Epub 2013 Dec 11.
• Background Pan MR, Peng G, Hung WC, Lin SY. Monoubiquitination of H2AX protein regulates DNA damage response signaling. J Biol Chem. 2011 Aug 12;286(32):28599-607. doi: 10.1074/jbc.M111.256297. Epub 2011 Jun 15.
• Background Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ, Clarke MF. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003 May 15;423(6937):302-5. doi: 10.1038/nature01587. Epub 2003 Apr 20.
• Background Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest. 2004 Jan;113(2):175-9. doi: 10.1172/JCI20800.
• Background Siddique HR, Parray A, Tarapore RS, Wang L, Mukhtar H, Karnes RJ, Deng Y, Konety BR, Saleem M. BMI1 polycomb group protein acts as a master switch for growth and death of tumor cells: regulates TCF4-transcriptional factor-induced BCL2 signaling. PLoS One. 2013 May 6;8(5):e60664. doi: 10.1371/journal.pone.0060664. Print 2013.
• Background Silva J, Garcia JM, Pena C, Garcia V, Dominguez G, Suarez D, Camacho FI, Espinosa R, Provencio M, Espana P, Bonilla F. Implication of polycomb members Bmi-1, Mel-18, and Hpc-2 in the regulation of p16INK4a, p14ARF, h-TERT, and c-Myc expression in primary breast carcinomas. Clin Cancer Res. 2006 Dec 1;12(23):6929-36. doi: 10.1158/1078-0432.CCR-06-0788.
• Background Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006 Nov;6(11):846-56. doi: 10.1038/nrc1991.
• Background Vrzalikova K, Skarda J, Ehrmann J, Murray PG, Fridman E, Kopolovic J, Knizetova P, Hajduch M, Klein J, Kolek V, Radova L, Kolar Z. Prognostic value of Bmi-1 oncoprotein expression in NSCLC patients: a tissue microarray study. J Cancer Res Clin Oncol. 2008 Sep;134(9):1037-42. doi: 10.1007/s00432-008-0361-y. Epub 2008 Feb 9.
• Background Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010 Apr 10;28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15.
• Background Wu Z, Min L, Chen D, Hao D, Duan Y, Qiu G, Wang Y. Overexpression of BMI-1 promotes cell growth and resistance to cisplatin treatment in osteosarcoma. PLoS One. 2011 Feb 2;6(2):e14648. doi: 10.1371/journal.pone.0014648.
• Background Wu X, Liu X, Sengupta J, Bu Y, Yi F, Wang C, Shi Y, Zhu Y, Jiao Q, Song F. Silencing of Bmi-1 gene by RNA interference enhances sensitivity to doxorubicin in breast cancer cells. Indian J Exp Biol. 2011 Feb;49(2):105-12.
• Background Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM, Shigematsu H, Levantini E, Huettner CS, Lekstrom-Himes JA, Akashi K, Tenen DG. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity. 2004 Dec;21(6):853-63. doi: 10.1016/j.immuni.2004.11.006.
• Background Zhang R, Xu LB, Yue XJ, Yu XH, Wang J, Liu C. Bmi1 gene silencing inhibits the proliferation and invasiveness of human hepatocellular carcinoma cells and increases their sensitivity to 5-fluorouracil. Oncol Rep. 2013 Mar;29(3):967-74. doi: 10.3892/or.2012.2189. Epub 2012 Dec 14.
• Yong KJ, Basseres DS, Welner RS, Zhang WC, Yang H, Yan B, Alberich-Jorda M, Zhang J, de Figueiredo-Pontes LL, Battelli C, Hetherington CJ, Ye M, Zhang H, Maroni G, O'Brien K, Magli MC, Borczuk AC, Varticovski L, Kocher O, Zhang P, Moon YC, Sydorenko N, Cao L, Davis TW, Thakkar BM, Soo RA, Iwama A, Lim B, Halmos B, Neuberg D, Tenen DG, Levantini E. Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPalpha expression. Sci Transl Med. 2016 Aug 3;8(350):350ra104. doi: 10.1126/scitranslmed.aad6066.

Drugs

Indications