Treatment of Cushing's Disease With R-roscovitine

Summary

The investigators hypothesize that R-roscovitine will suppress pituitary corticotroph tumor ACTH production and normalize urinary free cortisol levels in patients with Cushing disease. To date, R-roscovitine has been evaluated in several Phase I and II studies and has shown early signs of anti-cancer activity in approximately 240 patients.

Timeline

Start

2014-05

Primary completion

2018-10

Completion

2018-10

Publications

• Background Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. doi: 10.1210/jc.2008-0125. Epub 2008 Mar 11.
• Background Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62. doi: 10.1210/jc.2007-2734. Epub 2008 Apr 15.
• Background Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013 Aug;98(8):3446-53. doi: 10.1210/jc.2013-1771. Epub 2013 Jun 3.
• Background Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012 Jun;97(6):2039-49. doi: 10.1210/jc.2011-3350. Epub 2012 Mar 30.
• Background Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol. 2011 May;7(5):257-66. doi: 10.1038/nrendo.2011.40. Epub 2011 Mar 22.
• Background Quereda V, Malumbres M. Cell cycle control of pituitary development and disease. J Mol Endocrinol. 2009 Feb;42(2):75-86. doi: 10.1677/JME-08-0146. Epub 2008 Nov 5.
• Background Jordan S, Lidhar K, Korbonits M, Lowe DG, Grossman AB. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol. 2000 Jul;143(1):R1-6. doi: 10.1530/eje.0.143r001.
• Background Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC. Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell. 2000 Mar 31;101(1):79-89. doi: 10.1016/S0092-8674(00)80625-X.
• Background Geng Y, Eaton EN, Picon M, Roberts JM, Lundberg AS, Gifford A, Sardet C, Weinberg RA. Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene. 1996 Mar 21;12(6):1173-80.
• Background Sengupta T, Abraham G, Xu Y, Clurman BE, Minella AC. Hypoxia-inducible factor 1 is activated by dysregulated cyclin E during mammary epithelial morphogenesis. Mol Cell Biol. 2011 Sep;31(18):3885-95. doi: 10.1128/MCB.05089-11. Epub 2011 Jul 11.
• Background Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney BJ, Bernstein ID, Roberts JM, Clurman BE. Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev. 2008 Jun 15;22(12):1677-89. doi: 10.1101/gad.1650208.
• Background Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP. The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. J Clin Invest. 2010 Nov;120(11):3820-33. doi: 10.1172/JCI41959. Epub 2010 Oct 11.
• Background Ma Y, Fiering S, Black C, Liu X, Yuan Z, Memoli VA, Robbins DJ, Bentley HA, Tsongalis GJ, Demidenko E, Freemantle SJ, Dmitrovsky E. Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4089-94. doi: 10.1073/pnas.0606537104. Epub 2007 Feb 27.
• Background Loeb KR, Kostner H, Firpo E, Norwood T, D Tsuchiya K, Clurman BE, Roberts JM. A mouse model for cyclin E-dependent genetic instability and tumorigenesis. Cancer Cell. 2005 Jul;8(1):35-47. doi: 10.1016/j.ccr.2005.06.010.
• Background Roussel-Gervais A, Bilodeau S, Vallette S, Berthelet F, Lacroix A, Figarella-Branger D, Brue T, Drouin J. Cooperation between cyclin E and p27(Kip1) in pituitary tumorigenesis. Mol Endocrinol. 2010 Sep;24(9):1835-45. doi: 10.1210/me.2010-0091. Epub 2010 Jul 21.
• Background Bilodeau S, Vallette-Kasic S, Gauthier Y, Figarella-Branger D, Brue T, Berthelet F, Lacroix A, Batista D, Stratakis C, Hanson J, Meij B, Drouin J. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 2006 Oct 15;20(20):2871-86. doi: 10.1101/gad.1444606.
• Background Liu NA, Jiang H, Ben-Shlomo A, Wawrowsky K, Fan XM, Lin S, Melmed S. Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8414-9. doi: 10.1073/pnas.1018091108. Epub 2011 May 2.
• Background Vlotides G, Eigler T, Melmed S. Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr Rev. 2007 Apr;28(2):165-86. doi: 10.1210/er.2006-0042. Epub 2007 Feb 26.
• Background Pei L, Melmed S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol. 1997 Apr;11(4):433-41. doi: 10.1210/mend.11.4.9911.
• Background Chesnokova V, Zonis S, Kovacs K, Ben-Shlomo A, Wawrowsky K, Bannykh S, Melmed S. p21(Cip1) restrains pituitary tumor growth. Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17498-503. doi: 10.1073/pnas.0804810105. Epub 2008 Nov 3.
• Background Chesnokova V, Zonis S, Zhou C, Ben-Shlomo A, Wawrowsky K, Toledano Y, Tong Y, Kovacs K, Scheithauer B, Melmed S. Lineage-specific restraint of pituitary gonadotroph cell adenoma growth. PLoS One. 2011 Mar 25;6(3):e17924. doi: 10.1371/journal.pone.0017924.
• Background Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. doi: 10.1038/nrd2907.
• Background Legraverend M, Grierson DS. The purines: potent and versatile small molecule inhibitors and modulators of key biological targets. Bioorg Med Chem. 2006 Jun 15;14(12):3987-4006. doi: 10.1016/j.bmc.2005.12.060. Epub 2006 Feb 24.
• Background Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, Drouin J. A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell. 2001 Mar 23;104(6):849-59. doi: 10.1016/s0092-8674(01)00282-3.
• Background Wesierska-Gadek J, Krystof V. Selective cyclin-dependent kinase inhibitors discriminating between cell cycle and transcriptional kinases: future reality or utopia? Ann N Y Acad Sci. 2009 Aug;1171:228-41. doi: 10.1111/j.1749-6632.2009.04726.x.
• Background Siegel-Lakhai Wea. ASCO Proceedings, Abs 2060. 2005.
• Background Yeo et al. J Clin Oncol 2009 27-15s (Suppl abstr 6026).

Drugs

Indications