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Enzastaurin

Description of enzastaurin hydrochloride:   Enzastaurin HCL is the hydrochloride salt of enzastaurin, a synthetic macrocyclic bisindolemaleimide with potential antineoplastic activity. Binding to the ATP-binding site, enzastaurin selectively inhibits protein kinase C beta, an enzyme involved in the induction of vascular endothelial growth factor (VEGF)-stimulated neo-angiogenesis. This agent may decrease tumor blood supply and so tumor burden. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Eli Lilly Inc

Enzastaurin is a synthetic bisindolemaleimide with potential antineoplastic activity. Binding to the ATP-binding site, enzastaurin selectively inhibits protein kinase C beta, an enzyme involved in the induction of vascular endothelial growth factor (VEGF)-stimulated neo-angiogenesis. This agent may decrease tumor blood supply, preventing growth.

Enzastauri is a substance being studied in the treatment of certain types of cancer, including non-Hodgkin lymphoma, breast, colon, lung, ovarian, and prostate. Enzastaurin blocks certain cell signaling pathways, and may prevent the growth of new blood vessels that tumors need to grow. It is a type of serine threonine kinase inhibitor and a type of antiangiogenesis agent. Also called enzastaurin hydrochloride and LY317615.

 Highlight of recent results on Enzastaurin

Data published in 2011

Phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma: This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB-IVB, or Sézary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with ≥7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1-2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related (source: Leuk Lymphoma. 2011 Aug;52(8):1474-80. Epub 2011 Jun 8. Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma. Querfeld C, Kuzel TM, Kim YH, Porcu P, Duvic M, Musiek A, Rook AH, Mark LA, Pinter-Brown L, Hamid O, Lin B, Bian Y, Boye M, Day JM, Rosen ST.)

Data published in 2011

Phase I safety study of enzastaurin plus bortezomib:  The purpose of this study was to assess the safety and identify the recommended doses of enzastaurin and bortezomib in combination for future Phase II studies in patients with relapsed or refractory multiple myeloma. Three dose levels (DLs) of oral enzastaurin and intravenous bortezomib were used according to a conventional "3 + 3" design. A loading dose of enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by enzastaurin 125 mg BID for 1 week, after which bortezomib was added (Cycle 1, 28 days, 1.0 mg/m(2) : Days 8, 11, 15, and 18; seven subsequent 21-day cycles, 1.3 mg/m(2) : Days 1, 4, 8, and 11). Twenty-three patients received treatment; all patients received prior systemic therapy. Most patients received ≥3 regimens; 17 patients were bortezomib-refractory. A median of four treatment cycles (range 1-24) was completed. No dose-limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug-related Grade 3/4 toxicities were thrombocytopenia (n = 6) and anemia (n = 2). No patients died on therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory multiple myeloma are as follows: enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 of a 21-day cycle. The combination was well-tolerated and demonstrated some antimyeloma activity. Am. J. Hematol. 2011. © 2011 Wiley-Liss, Inc. (source: Am J Hematol. 2011 Jul;86(7):573-8. doi: 10.1002/ajh.22048. Epub 2011 May 31. A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma. Ghobrial IM, Munshi NC, Harris BN, Shi P, Porter NM, Schlossman RL, Laubach JP, Anderson KC, Desaiah D, Myrand SP, Wooldridge JE, Richardson PG, Abonour R. The Multiple Myeloma/Waldenstrom's Macroglobulinemia Program, Dana-Farber Cancer Institute, Boston, Massachusetts. irene_ghobrial@dfci.harvard.edu.).

Data published in 2010.

Phase II, double-blind, randomized trial of capecitabine plus enzastaurin. Capecitabine is frequently used in the treatment of recurrent/progressive metastatic breast cancer (MBC) after prior anthracycline and taxane therapy. With the intention of improving the efficacy of single agent capecitabine, we initiated a randomized, double-blind, placebo-controlled Phase II study of the novel serine/threonine kinase inhibitor enzastaurin in combination with capecitabine in a heavily pretreated patient population. Patients received capecitabine 1,250 mg/m(2) twice daily plus enzastaurin 500 mg/day, or capecitabine plus placebo. The capecitabine was administered for the first 14 days of each 21 day cycle. The primary outcome was progression-free survival (PFS) using the log-rank test (1-sided significance level of 0.20). Of 109 patients assessed for eligibility, 85 were enrolled, randomized, and treated (42 and 43 patients in each respective treatment group). The study was terminated early following a preplanned futility analysis. Median PFS (95% CI) was 2.8 (2.1-4.6) months with capecitabine plus enzastaurin versus 4.3 (2.9-6.2) months with capecitabine plus placebo (adjusted hazard ratio: 1.728 [1.00-2.97]; P = 0.048). Median overall survival (95% CI) was lower with capecitabine plus enzastaurin than with capecitabine plus placebo (9.9 [7.0-16.6] months vs 14.9 [9.9-19.3] months, P = 0.181). Grade 3/4 adverse events were more frequent with capecitabine plus enzastaurin (42.9% vs 32.6%). Given the lack of PFS benefit, capecitabine plus enzastaurin is unsuitable as therapy for patients with recurrent/progressive MBC after prior anthracycline and taxane therapy. This trial is registered on www.clinicaltrials.gov (identifier: NCT00437294). (source: Breast Cancer Res Treat. 2010 Nov;124(1):177-86. Epub 2010 Sep 3. Phase II, double-blind, randomized trial of capecitabine plus enzastaurin versus capecitabine plus placebo in patients with metastatic or recurrent breast cancer after prior anthracycline and taxane therapy. Clemons M, Joy AA, Abdulnabi R, Kotliar M, Lynch J, Jordaan JP, Iscoe N, Gelmon K.
Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, Canada. mclemons@toh.on.ca).

Data published in 2010

Phase III study of enzastaurin compared with lomustine.  This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4).  RESULTS:  Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001). CONCLUSION:
Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma. (source: J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Department of Neurooncology, University of Heidelberg, Im Neuenheimer Feld, 400 D-69120 Heidelberg. wolfgang.wick@med.uni-heidelberg.de).

1: Civallero M, Cosenza M, Bari A, Sacchi S. Rational combinations of enzastaurin with novel targeted agents for patients with B-cell non-Hodgkin's lymphoma. Expert Opin Investig Drugs. 2011 Aug;20(8):1029-31. Epub 2011 Jun 25. PubMed PMID: 21702717.

2: Bodo J, Sedlak J, Maciejewski JP, Almasan A, Hsi ED. HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells. Apoptosis. 2011 Jun 11. [Epub ahead of print] PubMed PMID: 21667043.

3: Schmidinger M, Szczylik C, Sternberg CN, Kania M, Kelly CS, Decker R, Hamid O, Faelker T, Escudier B. Dose Escalation and Pharmacokinetics Study of Enzastaurin and Sunitinib Versus Placebo and Sunitinib in Patients With Metastatic Renal Cell Carcinoma. Am J Clin Oncol. 2011 Jun 4. [Epub ahead of print] PubMed PMID: 21654314.

4: Querfeld C, Kuzel TM, Kim YH, Porcu P, Duvic M, Musiek A, Rook AH, Mark LA, Pinter-Brown L, Hamid O, Lin B, Bian Y, Boye M, Day JM, Rosen ST. Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma. Leuk Lymphoma. 2011 Aug;52(8):1474-80. Epub 2011 Jun 8. PubMed PMID: 21649541.

5: Ysebaert L, Morschhauser F. Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies. Expert Opin Investig Drugs. 2011 Aug;20(8):1167-74. Epub 2011 Jun 5. PubMed PMID: 21639821.

6: Ghobrial IM, Munshi NC, Harris BN, Shi P, Porter NM, Schlossman RL, Laubach JP, Anderson KC, Desaiah D, Myrand SP, Wooldridge JE, Richardson PG, Abonour R. A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma. Am J Hematol. 2011 Jul;86(7):573-8. doi: 10.1002/ajh.22048. Epub 2011 May 31. PubMed PMID: 21630305.

7: Molè D, Gagliano T, Gentilin E, Tagliati F, Pasquali C, Ambrosio MR, Pansini G, Degli Uberti EC, Zatelli MC. Targeting protein kinase C by Enzastaurin restrains proliferation and secretion in human pancreatic endocrine tumors. Endocr Relat Cancer. 2011 Jul 1;18(4):439-50. Print 2011. PubMed PMID: 21606156.

8: Rovedo MA, Krett NL, Rosen ST. Inhibition of glycogen synthase kinase-3 increases the cytotoxicity of enzastaurin. J Invest Dermatol. 2011 Jul;131(7):1442-9. doi: 10.1038/jid.2011.70. Epub 2011 Apr 7. PubMed PMID: 21471986; PubMed Central PMCID: PMC3116015.

9: Liu J, Kuo WL, Seiwert TY, Lingen M, Ciaccio MF, Jones RB, Rosner MR, Cohen EE. Effect of complementary pathway blockade on efficacy of combination enzastaurin and rapamycin. Head Neck. 2011 Mar 24. doi: 10.1002/hed.21701. [Epub ahead of print] PubMed PMID: 21438065.

10: Usha L, Sill MW, Darcy KM, Benbrook DM, Hurteau JA, Michelin DP, Mannel RS, Hanjani P, De Geest K, Godwin AK. A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol Oncol. 2011 Jun 1;121(3):455-61. Epub 2011 Mar 17. PubMed PMID: 21414654; PubMed Central PMCID: PMC3100412.

11: Ruvolo PP, Zhou L, Watt JC, Ruvolo VR, Burks JK, Jiffar T, Kornblau S, Konopleva M, Andreeff M. Targeting PKC-mediated signal transduction pathways using enzastaurin to promote apoptosis in acute myeloid leukemia-derived cell lines and blast cells. J Cell Biochem. 2011 Jun;112(6):1696-707. doi: 10.1002/jcb.23090. PubMed PMID: 21360576.

12: Wang M, Xu L, Gao M, Miller KD, Sledge GW, Zheng QH. [11C]enzastaurin, the first design and radiosynthesis of a new potential PET agent for imaging of protein kinase C. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1649-53. Epub 2011 Jan 31. PubMed PMID: 21320780.

13: Socinski MA, Raju RN, Stinchcombe T, Kocs DM, Couch LS, Barrera D, Rousey SR, Choksi JK, Jotte R, Patt DA, Periman PO, Schlossberg HR, Weissman CH, Wang Y, Asmar L, Pritchard S, Bromund J, Peng G, Treat J, Obasaju CK. Randomized, phase II trial of pemetrexed and carboplatin with or without enzastaurin versus docetaxel and carboplatin as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer. J Thorac Oncol. 2010 Dec;5(12):1963-9. PubMed PMID: 21102260.

14: Civallero M, Cosenza M, Neri A, Bari A. Genomic profiling of enzastaurin-treated B cell lymphoma RL cells. Hematol Oncol. 2010 Oct 27. [Epub ahead of print] PubMed PMID: 20981886.

15: Dumstorf CA, Konicek BW, McNulty AM, Parsons SH, Furic L, Sonenberg N, Graff JR. Modulation of 4E-BP1 function as a critical determinant of enzastaurin-induced apoptosis. Mol Cancer Ther. 2010 Dec;9(12):3158-63. Epub 2010 Oct 22. PubMed PMID: 20971826.

16: Yin X, Hayes DN, Shores CG. Antitumor activity of enzastaurin as radiation sensitizer in head and neck squamous cell carcinoma. Head Neck. 2011 Aug;33(8):1106-14. doi: 10.1002/hed.21578. Epub 2010 Oct 21. PubMed PMID: 20967867.

17: Ogbomo H, Biru T, Michaelis M, Loeschmann N, Doerr HW, Cinatl J Jr. The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β. Biochem Pharmacol. 2011 Jan 15;81(2):251-8. Epub 2010 Oct 8. PubMed PMID: 20934407.

18: Casey EM, Harb W, Bradford D, Bufill J, Nattam S, Patel J, Fisher W, Latz JE, Li X, Wu J, Hanna N. Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and bevacizumab with enzastaurin or placebo in chemonaïve patients with stage IIIB/IV non-small cell lung cancer: Hoosier Oncology Group LUN06-116. J Thorac Oncol. 2010 Nov;5(11):1815-20. PubMed PMID: 20881647.

19: Kuo WL, Liu J, Mauceri H, Vokes EE, Weichselbaum R, Rosner MR, Cohen EE. Efficacy of the multi-kinase inhibitor enzastaurin is dependent on cellular signaling context. Mol Cancer Ther. 2010 Oct;9(10):2814-24. Epub 2010 Sep 28. PubMed PMID: 20876745; PubMed Central PMCID: PMC2953602.

20: Clemons M, Joy AA, Abdulnabi R, Kotliar M, Lynch J, Jordaan JP, Iscoe N, Gelmon K. Phase II, double-blind, randomized trial of capecitabine plus enzastaurin versus capecitabine plus placebo in patients with metastatic or recurrent breast cancer after prior anthracycline and taxane therapy. Breast Cancer Res Treat. 2010 Nov;124(1):177-86. Epub 2010 Sep 3. PubMed PMID: 20814815.

21: Körner A, Mudduluru G, Manegold C, Allgayer H. Enzastaurin inhibits invasion and metastasis in lung cancer by diverse molecules. Br J Cancer. 2010 Sep 7;103(6):802-11. Epub 2010 Aug 24. PubMed PMID: 20736951; PubMed Central PMCID: PMC2966618.

22: Mukohara T, Nagai S, Koshiji M, Yoshizawa K, Minami H. Phase I dose escalation and pharmacokinetic study of oral enzastaurin (LY317615) in advanced solid tumors. Cancer Sci. 2010 Oct;101(10):2193-9. doi: 10.1111/j.1349-7006.2010.01677.x. Epub 2010 Aug 12. PubMed PMID: 20707806.

23: Tanai C, Yamamoto N, Ohe Y, Takahashi T, Kunitoh H, Murakami H, Yamamoto N, Nakamura Y, Nokihara H, Shukuya T, Baldwin JR, Koshiji M, Tamura T. A phase I study of enzastaurin combined with pemetrexed in advanced non-small cell lung cancer. J Thorac Oncol. 2010 Jul;5(7):1068-74. PubMed PMID: 20453691.

24: Lee SH, Chen T, Zhou J, Hofmann J, Bepler G. Protein kinase C-beta gene variants, pathway activation, and enzastaurin activity in lung cancer. Clin Lung Cancer. 2010 May;11(3):169-75. PubMed PMID: 20439192.

25: Cadron I, Van Gorp T, Mihalyi A, Luyten C, Drijkoningen K, Amant F, Leunen K, Vergote I. The impact of enzastaurin (LY317615.HCl) on CA125 biosynthesis and shedding in ovarian cancer cells. Gynecol Oncol. 2010 Jul;118(1):64-8. Epub 2010 May 1. PubMed PMID: 20439112.

26: Serova M, Astorgues-Xerri L, Bieche I, Albert S, Vidaud M, Benhadji KA, Emami S, Vidaud D, Hammel P, Theou-Anton N, Gespach C, Faivre S, Raymond E. Epithelial-to-mesenchymal transition and oncogenic Ras expression in resistance to the protein kinase Cbeta inhibitor enzastaurin in colon cancer cells. Mol Cancer Ther. 2010 May;9(5):1308-17. Epub 2010 Apr 20. PubMed PMID: 20406951.

27: Dreicer R, Garcia J, Hussain M, Rini B, Vogelzang N, Srinivas S, Somer B, Zhao YD, Kania M, Raghavan D. Oral enzastaurin in prostate cancer: A two-cohort phase II trial in patients with PSA progression in the non-metastatic castrate state and following docetaxel-based chemotherapy for castrate metastatic disease. Invest New Drugs. 2010 Apr 6. [Epub ahead of print] PubMed PMID: 20369375.

28: Civallero M, Cosenza M, Grisendi G, Marcheselli L, Todoerti K, Sacchi S. Effects of enzastaurin, alone or in combination, on signaling pathway controlling growth and survival of B-cell lymphoma cell lines. Leuk Lymphoma. 2010 Apr;51(4):671-9. PubMed PMID: 20218811.

29: Butowski N, Chang SM, Lamborn KR, Polley MY, Parvataneni R, Hristova-Kazmierski M, Musib L, Nicol SJ, Thornton DE, Prados MD. Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study. Neuro Oncol. 2010 Jun;12(6):608-13. Epub 2010 Feb 15. PubMed PMID: 20156802; PubMed Central PMCID: PMC2940647.

30: Kreisl TN, Kotliarova S, Butman JA, Albert PS, Kim L, Musib L, Thornton D, Fine HA. A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol. 2010 Feb;12(2):181-9. Epub 2010 Jan 22. PubMed PMID: 20150385; PubMed Central PMCID: PMC2940576.

31: Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. PubMed PMID: 20124186; PubMed Central PMCID: PMC2834468.

32: Galanis E, Buckner JC. Enzastaurin in the treatment of recurrent glioblastoma: a promise that did not materialize. J Clin Oncol. 2010 Mar 1;28(7):1097-8. Epub 2010 Feb 1. PubMed PMID: 20124164.

33: Chiappori A, Bepler G, Barlesi F, Soria JC, Reck M, Bearz A, Barata F, Scagliotti G, Park K, Wagle A, Liepa AM, Zhao YD, Chouaki N, Iscoe N, von Pawel J. Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2010 Mar;5(3):369-75. PubMed PMID: 20090562.

34: Weinkauf M, Hutter G, Zimmermann Y, Hartmann E, Rosenwald A, Dreyling M. Combined RNA-expression and 2D-PAGE-screening identifies comprehensive interaction networks affected after bortezomib or enzastaurin exposure of mantle cell lymphoma. Talanta. 2010 Feb 15;80(4):1539-44. Epub 2009 Jun 17. PubMed PMID: 20082812.

35: Vergote I, Amant F, Oskay-Oezcelik G, Musib L, Michel AL, Darstein C, Kania M, Bauknecht T, Sehouli J. Carboplatin and paclitaxel in combination with oral enzastaurin in advanced ovarian or primary peritoneal cancer: results from a safety lead-in study. Int J Gynecol Cancer. 2009 Dec;19(9):1505-10. PubMed PMID: 19955926.

36: Glimelius B, Spindler KL, Frödin JE, Berglund A, Byström P, Qvortrup C, Jakobsen A, Pfeiffer P. Long-term follow-up of chemonaive patients with asymptomatic metastatic colorectal cancer treated with enzastaurin in a window of opportunity phase II study. Ann Oncol. 2010 May;21(5):1127-8. Epub 2009 Nov 13. PubMed PMID: 19914961.

37: Jane EP, Pollack IF. Enzastaurin induces H2AX phosphorylation to regulate apoptosis via MAPK signalling in malignant glioma cells. Eur J Cancer. 2010 Jan;46(2):412-9. Epub 2009 Nov 11. PubMed PMID: 19913408; PubMed Central PMCID: PMC2818487.

38: Willey CD, Xiao D, Tu T, Kim KW, Moretti L, Niermann KJ, Tawtawy MN, Quarles CC, Lu B. Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation. Int J Radiat Oncol Biol Phys. 2010 Aug 1;77(5):1518-26. Epub 2009 Nov 10. PubMed PMID: 19906497.

39: Glimelius B, Lahn M, Gawande S, Cleverly A, Darstein C, Musib L, Liu Y, Spindler KL, Frödin JE, Berglund A, Byström P, Qvortrup C, Jakobsen A, Pfeiffer P. A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer. Ann Oncol. 2010 May;21(5):1020-6. Epub 2009 Nov 9. PubMed PMID: 19901015.

40: Meng XW, Heldebrant MP, Flatten KS, Loegering DA, Dai H, Schneider PA, Gomez TS, Peterson KL, Trushin SA, Hess AD, Smith BD, Karp JE, Billadeau DD, Kaufmann SH. Protein kinase Cbeta modulates ligand-induced cell surface death receptor accumulation: a mechanistic basis for enzastaurin-death ligand synergy. J Biol Chem. 2010 Jan 8;285(2):888-902. Epub 2009 Nov 3. PubMed PMID: 19887445; PubMed Central PMCID: PMC2801290.

41: Giovannetti E, Honeywell R, Hanauske AR, Tekle C, Kuenen B, Sigmond J, Giaccone G, Peters GJ. Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small cell lung cancer (NSCLC). Curr Drug Targets. 2010 Jan;11(1):12-28. Review. PubMed PMID: 19839931.

42: Richards DA, Kuefler PR, Becerra C, Wilfong LS, Gersh RH, Boehm KA, Zhan F, Asmar L, Myrand SP, Hozak RR, Zhao L, Gill JF, Mullaney BP, Obasaju CK, Nicol SJ. Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study. Invest New Drugs. 2011 Feb;29(1):144-53. Epub 2009 Aug 28. PubMed PMID: 19714296.

43: Bräutigam K, Bauerschlag DO, Weigel MT, Biernath-Wüpping J, Bauknecht T, Arnold N, Maass N, Meinhold-Heerlein I. Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation. Transl Oncol. 2009 Aug 18;2(3):164-73. PubMed PMID: 19701501; PubMed Central PMCID: PMC2730140.

44: Li XY, Chen XG. [Role of PKCbeta in the malignant tumors and enzastaurin, a PKCbeta inhibitor]. Yao Xue Xue Bao. 2009 May;44(5):449-55. Review. Chinese. PubMed PMID: 19618717.

45: Jian W, Yamashita H, Levitt JM, Lerner SP, Sonpavde G. Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine. Mol Cancer Ther. 2009 Jul;8(7):1772-8. Epub 2009 Jun 9. PubMed PMID: 19509273.

46: Pollok KE, Lahn M, Enas N, McNulty A, Graff J, Cai S, Hartwell JR, Ernstberger A, Thornton D, Brail L, Hutchins G. In Vivo Measurements of Tumor Metabolism and Growth after Administration of Enzastaurin Using Small Animal FDG Positron Emission Tomography. J Oncol. 2009;2009:596560. Epub 2009 May 27. PubMed PMID: 19503801; PubMed Central PMCID: PMC2688651.

47: Hanauske AR, Lahn M, Musib LC, Weigang-Köhler K, Yilmaz E, Graefe T, Kuenen B, Thornton D, McNealy P, Giaccone G. Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer. Ann Oncol. 2009 Sep;20(9):1565-75. Epub 2009 Jun 1. PubMed PMID: 19487488.

48: Kreisl TN, Kim L, Moore K, Duic P, Kotliarova S, Walling J, Musib L, Thornton D, Albert PS, Fine HA. A phase I trial of enzastaurin in patients with recurrent gliomas. Clin Cancer Res. 2009 May 15;15(10):3617-23. Epub 2009 May 5. PubMed PMID: 19417015.

49: Mina L, Krop I, Zon RT, Isakoff SJ, Schneider CJ, Yu M, Johnson C, Vaughn LG, Wang Y, Hristova-Kazmierski M, Shonukan OO, Sledge GW, Miller KD. A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen. Invest New Drugs. 2009 Feb 13. [Epub ahead of print] PubMed PMID: 19214387.

50: Vogl UM, Berger W, Micksche M, Pirker C, Lamm W, Pichelmeyer O, Zielinski CC, Schmidinger M. Synergistic effect of Sorafenib and Sunitinib with Enzastaurin, a selective protein kinase C inhibitor in renal cell carcinoma cell lines. Cancer Lett. 2009 May 18;277(2):218-26. Epub 2009 Jan 25. PubMed PMID: 19171421.

51: Spalding AC, Zeitlin BD, Wilder-Romans K, Davis ME, Nor JE, Lawrence TS, Ben-Josef E. Enzastaurin, an inhibitor of PKCbeta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells. Transl Oncol. 2008 Dec;1(4):195-201. PubMed PMID: 19043530; PubMed Central PMCID: PMC2582168.

52: Verdelli D, Nobili L, Todoerti K, Intini D, Cosenza M, Civallero M, Bertacchini J, Deliliers GL, Sacchi S, Lombardi L, Neri A. Molecular targeting of the PKC-beta inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression. Hematol Oncol. 2009 Mar;27(1):23-30. PubMed PMID: 18759374.

53: Tekle C, Giovannetti E, Sigmond J, Graff JR, Smid K, Peters GJ. Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells. Br J Cancer. 2008 Sep 2;99(5):750-9. Epub 2008 Aug 19. PubMed PMID: 18728666; PubMed Central PMCID: PMC2528136.

54: Smetak M, Weigang-Koehler K, Hanauske A, Ohnmacht U, Lahn M, Wilhelm M, Birkmann J. Reduction of HLA-DR+ lymphocytes after treatment with enzastaurin in patients with metastatic thyroid cancer. Chemotherapy. 2008;54(4):268-73. Epub 2008 Jul 31. PubMed PMID: 18667816.

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