Originally published as JCO Early Release 10.1200/JCO.2006.09.3146 on March 26 2007

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Phase II Study of Enzastaurin, a Protein Kinase C Beta Inhibitor, in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Michael J. Robertson, Brad S. Kahl, Julie M. Vose, Sven de Vos, Mary Laughlin, Patrick J. Flynn, Kendrith Rowland, Jose C. Cruz, Stuart L. Goldberg, Luna Musib, Christelle Darstein, Nathan Enas, Jeffery L. Kutok, Jon C. Aster, Donna Neuberg, Kerry J. Savage, Ann LaCasce, Donald Thornton, Christopher A. Slapak, Margaret A. Shipp

From the Indiana University Medical Center; Eli Lilly and Company, Indianapolis, IN; University of Wisconsin Hospital & Clinics, Madison, WI; University of Nebraska Medical Center, Omaha, NE; UCLA School of Medicine, Los Angeles, CA; Case Western Reserve University/University Hospitals, Cleveland, OH; Minnesota Oncology Hematology, PA, Minneapolis, MN; Carle Clinic Associates, Urbana, IL; Joe Arrington Research & Cancer Center, Lubbock, TX; Cancer Center, Hackensack University Medical Center, Hackensack, NJ; Department of Pathology, Brigham and Women's Hospital; and the Dana-Farber Cancer Institute, Boston, MA

Address reprint requests to Margaret Shipp, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: margaret_shipp{at}dfci.harvard.edu

	ABSTRACT

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Purpose Protein kinase C beta (PKCß) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCß, enzastaurin, in patients with relapsed or refractory DLBCL.

Patients and Methods Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for two cycles (one cycle = 28 days), objective response, and toxicity.

Results Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for two cycles, and eight patients remained free from progression for four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry.

Conclusion Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

	INTRODUCTION

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Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, accounting for more than 30,000 new cases each year and nearly 40% of all non-Hodgkin's lymphomas.^1,2 Although DLBCL is a chemotherapy-responsive tumor, approximately 50% of patients with this disease will not be cured with conventional empiric therapy. Clinical models have been developed to identify patients with DLBCL who are less likely to benefit from standard treatment and to facilitate the interpretation of clinical trial results.²

In the absence of molecular insights into the clinical heterogeneity of DLBCL, therapeutic approaches to high-risk patients have focused on increasing the doses of conventional chemotherapeutic agents and adding stem-cell support. However, these empiric regimens have limited efficacy and considerable toxicity, underscoring the need for more clearly defined rational treatment targets.²

Gene-expression profiling has been used to identify DLBCLs with similar molecular signatures, elucidate potential pathogenetic mechanisms, and highlight promising therapeutic targets.^2-5 In earlier profiling studies and companion immunohistochemical analyses, the serine/threonine kinase, protein kinase C beta (PKCß), was found to be overexpressed in fatal/refractory DLBCLs.³ PKCß expression was also associated with poor outcome and shortened survival in a large independent series of primary DLBCLs.⁶

PKCß is the major PKC expressed by normal and malignant B lymphocytes and a downstream effector of multiple critical signaling pathways. This serine/threonine kinase is specifically required for B-cell receptor survival signals, including activation of nuclear factor kappa B (NFB).^7,8 PKCß was recently found to phosphorylate CARMA1, which brings the kinases transforming growth factor ß-activated kinase 1 (TAK1) and I inhibitor kinase (IK) into close proximity, and allows TAK to phosphorylate IK, the initial step in NFB signaling.^9-11

PKCß is also a critical component of the vascular endothelial growth factor (VEGF) signaling pathway, implicating this kinase in VEGF-mediated tumor angiogenesis.^12-14 These observations are of particular interest because increased VEGF levels and tumor angiogenesis have been linked with a poor prognosis in DLBCL.^15,16 The expression of PKCß in high-risk DLBCLs and the role of the kinase in B-cell receptor signaling, NFB activation, and VEGF-mediated tumor angiogenesis suggested that PKCß might be a rational therapeutic target in DLBCL and prompted analysis of candidate target inhibitors.

Enzastaurin HCl is an acyclic bisindolylmaleimide that was initially developed as an adenosine triphosphate-competitive, selective inhibitor of PKCß.^17,18 The compound also modulates the PI3K/AKT pathway in selected tumor models.¹⁹ Enzastaurin is primarily metabolized by cytochrome P4503A (CYP3A) to form the major and minor metabolites, LY326020 and LY485912, respectively.¹⁸ These two metabolites are comparably active against PKCß and LY326020 is itself a substrate of CYP3A.¹⁸

In preclinical studies, enzastaurin induced apoptosis and inhibited the proliferation of DLBCL, glioblastoma, and colon carcinoma cell lines and xenografts at low micromolar doses.^19-21 In in vitro kinase assays, comparable concentrations of enzastaurin inhibited PKCß and other PKC isoforms by approximately 90% with little effect on multiple other serine/threonine and tyrosine kinases.¹⁹

The preclinical activity and safety profile of enzastaurin led to a recent phase I study of the oral agent in patients with advanced cancer.¹⁸ Since the enzastaurin inhibitory concentration (IC) 90 for PKC was 70 nmol/L and 95% of the drug is protein bound, the targeted mean steady-state concentration for clinical efficacy was estimated to be 1.4 µmol/L.¹⁸ Based on plasma exposures and safety data in the phase I study, enzastaurin 525 mg was the recommended dose for additional phase II trials.¹⁸ This 525 mg/day dose yielded mean steady-state plasma concentrations of 2 µmol/L.^18,19 Of note, enzastaurin was well-tolerated at this recommended dose with no clinically significant grade 3 or 4 toxicities. For these reasons, we conducted a phase II multicenter trial of oral enzastaurin in patients with relapsed/refractory DLBCL.

	PATIENTS AND METHODS

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Eligibility Criteria
Adult patients (age 18 years) with a morphologically confirmed diagnosis of DLBCL²² or composite follicular and DLBCL whose disease relapsed after the administration of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), CHOP-based chemotherapy, or a subsequent salvage regimen were eligible for inclusion. Relapsed disease (after CHOP or subsequent salvage therapy) was defined as radiographic progression after a complete response to chemotherapy or clinical or radiographic evidence of active disease after a partial response or stable disease. Patients who progressed while receiving CHOP-based induction therapy were ineligible for this study. In addition, patients who met the entry criteria but were candidates for high-dose chemotherapy (HDT) and autologous stem-cell transplantation (SCT) were not enrolled. However, patients who progressed 3 months after HDT/SCT were eligible for this trial. Patients could not have received more than three prior treatment regimens, and must have discontinued all prior therapies for at least 30 days before study entry. Rituximab, when used alone or in combination with cytotoxic chemotherapy, was not considered a separate prior regimen.

Other entry criteria included bidimensionally measurable disease; an estimated life expectancy of at least 12 weeks; an Eastern Cooperative Oncology Group performance status of 0 to 2; and adequate organ function including total bilirubin 1.5x upper limit of normal (ULN), ALT, and AST 2.5 x ULN, and serum creatinine 2 x ULN.

Patients were excluded if they had known CNS or leptomeningeal involvement; HIV-associated lymphoma; serious concomitant disorder (such as active bacterial, fungal, or viral infection); ECG abnormalities, including prolonged QTc interval (> 450 msecs for males or > 470 msecs for females), or other clinically significant cardiac abnormalities; or an inability to swallow tablets.

The protocol was approved by the institutional review board of each participating institution. Written informed consent was obtained from each patient before study enrollment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practices and applicable laws and regulations.

Treatment Plan
Patients received oral enzastaurin once daily during each 28-day cycle of therapy, with a planned duration of up to six treatment cycles. After completing the planned six cycles of therapy, responding patients had the option of continuing on-study with the agreement of the investigator and sponsor. Enzastaurin was discontinued if patients developed progressive disease or unacceptable toxicity.

Enzastaurin was initially given as 525-mg capsules. In March 2004, the capsules were replaced with 500-mg tablets, which had equivalent pharmacokinetics and increased ease of administration. Since enzastaurin levels are two-fold higher when the drug is administered after eating (L. Musib, personal communication, June 2006), patients were instructed to take enzastaurin within 30 minutes of completing a meal (preferably breakfast). No other chemotherapy, immunotherapy, anticancer hormone therapy, experimental medications, or radiation therapy was permitted while patients were on study. The use of erythropoietin was not precluded. Routine or prophylactic use of granulocyte colony-stimulating factors was not permitted during this study. Granulocyte colony-stimulating factors were used only for patients who had an absolute granulocyte count less than 0.5 x 10⁹/L for at least 5 days, neutropenic fever, or documented infections while neutropenic, and were discontinued at least 24 hours before the start of the next cycle of chemotherapy.

If a patient experienced any of the following events that were considered possibly related to study drug, enzastaurin was omitted until the event resolved: an absolute neutrophil count less than 0.5 x 10⁹/L for longer than 7 days, an absolute neutrophil count less than 1.0 x 10⁹/L with fever (temperature of 101°F/38.3°C), or a platelet count less than 10 x 10⁹/L; National Cancer Institute Common Toxicity Criteria grade 3 or 4 nonhematologic toxicity; or prolongation of QTc by more than 50 msecs. If the event resolved to grade 1 or the patient's baseline, therapy was restarted at a dose of 400 mg per day. If, after restarting therapy, the patient did not have recurrence of the event after 28 days of therapy, the patient was re-escalated to the full dose (500 mg) at the discretion of the investigator. If the event did not resolve after omission of the equivalent of one cycle (28 days), the patient was discontinued from study drug therapy.

Baseline and Treatment Assessments
Baseline patient assessments were performed no more than 4 weeks before enrollment. These included unilateral bone marrow aspirate and/or biopsy (for patients with a history of marrow involvement by lymphoma) and assessment of prior lymphoma history and tumor-related symptoms. Disease status was evaluated before every cycle for palpable or visible lesions or after every fourth cycle for measurable tumors using mandatory chest and abdominal/pelvic computed tomography (CT) scans and optional magnetic resonance imaging, gallium, and positron emission topography (PET) scans. Before enrollment and before each cycle, medical and physical examinations, performance status evaluation, serum chemistry and hematology laboratory tests, and ECG were performed. A slit lamp ocular exam was performed at baseline and during every other cycle of therapy.

Response was assessed using the revised International Working Group criteria.²³ The primary end point of freedom from progression was defined as complete response (CR), partial response, or stable disease for two cycles. Complete or partial responses were confirmed with scans performed at least 4 weeks after the initial response. Thirty days after discontinuation, performance status evaluation, tumor measurements, and imaging studies were repeated. Any patient with an ongoing response or stable disease at the 30-day poststudy evaluation visit was followed at 4- to 8-week intervals with tumor measurements and imaging studies until disease progression, death, or another therapy was initiated. Patients with prolonged progression-free survival (> 12 months) were evaluated with PET scans 1 month before this report (June 2006). In these patients with prolonged freedom from progression (FFP), CRs were defined as the absence of PET scan and CT scan abnormalities or the presence of only PET-negative residual CT abnormalities.²³

All enrolled patients were assessed before each cycle for treatment-related toxicity using National Cancer Institute Common Toxicity Criteria version 2.0.

Pharmacokinetic Assessment
Plasma samples were obtained for pharmacokinetic evaluation at three different occasions: 1 to 4 hours postdose on day 1 of cycle 1; predose on day 28 of cycle 1; and postdose on day 28 of cycle 1, with at least an hour difference between the predose and the postdose sample. Samples were assayed for enzastaurin and its metabolites using high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS) as previously described. A population pharmacokinetic approach was used for the pooled plasma concentration time data of all patients and analyzed using nonlinear mixed effect modeling. The pharmacokinetic model was developed using intensive and sparse PK data from studies (L. Musib, personal communication, June 2006). The sparse data from this study was combined with the pharmacokinetic data from reference studies (L. Musib, personal communication, June 2006) for posthoc estimation of enzastaurin clearance and area under the curve at steady-state (AUC_0-24,ss) of enzastaurin and LY326020.

Immunohistochemical Analysis of PKCß Expression
Available tumor samples from initial diagnosis and/or relapse were obtained from patients for immunohistochemical staining of PKCß expression. An additional pilot series of 11 relapsed DLBCL biopsy specimens was obtained from Brigham and Women's Hospital Hematopathology Archives (Boston, MA) for PKCß immunohistochemistry. Immunohistochemical staining was performed as previously described³ with a murine monoclonal antibody specific for PKCß (Serotec, Oxford, United Kingdom) and a secondary goat antimouse horseradish-peroxidase-conjugated antibody (Envision Detection Kit; DAKO, Carpinteria, CA). The intensity of staining was graded from 0 (no staining) to 3 (maximal staining), as previously described.³

	RESULTS

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Patient Characteristics
Fifty-five patients, (28 females and 27 males) with a median age of 68 years (range, 31 to 87 years), were enrolled onto the study (Table 1). Forty-seven patients (85%) had an ECOG performance status of 1, and 28 patients (51%) had elevated lactate dehydrogenase levels at baseline (Table 1). Patients received a median of two prior therapies (range, one to five), including HDT/SCT in six patients (Table 1).

View larger version (151K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Immunohistochemical analysis of protein kinase C beta expression. (A and B) Two representative tumors from a pilot series of relapsed diffuse large B-cell lymphoma. (C and D) Paired diagnostic and relapsed tumor specimens from the same disease site in a trial patient. All original magnifications at x400 with hematoxylin counterstain.

Study Drug Administration
All 55 patients enrolled received at least one dose of enzastaurin. Fifteen patients completed less than one cycle of therapy, which is noteworthy because enzastaurin must be administered for at least 14 days to achieve therapeutic levels.¹⁸ In all of these 15 patients, protocol therapy was discontinued due to progressive disease. Six patients completed six cycles of therapy and four of these patients have completed 20 treatment courses.

Clinical Toxicities
All 55 enrolled patients were evaluated for safety (Table 2). There were 12 dose omissions due to toxicities, two of which were possibly related to study drug (fatigue and edema). The most common toxicities reported were fatigue (eight patients), diarrhea (seven patients), and nausea or vomiting (five patients). Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities were fatigue in two patients, and edema, headache, hyperkalemia, motor neuropathy, and thrombocytopenia each in one patient (Table 2). No grade 3 or 4 anemia or neutropenia occurred (Table 2), and there were no treatment-related deaths.

	DISCUSSION

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Current pharmacokinetic data are consistent with that obtained in a recent phase I study in which the mean steady-state concentration for total enzastaurin analytes, at the dose of 525 mg, was 1,950 nmol/L.¹⁸ In in vitro kinase screens, 1,000 nmol/L enzastaurin inhibited PKCß and additional PKC isoforms without affecting multiple other analyzed kinases.¹⁹ PKCß is the major PKC isoform expressed in both healthy and malignant B cells, suggesting that enzastaurin is working, at least in part, via its effects on PKCß.

Because a small subset of four patients with relapsed/refractory DLBCL obtained long-term responses to enzastaurin, the basis for differential sensitivity to this targeted agent is of particular interest. Steady-state enzastaurin levels were similar in long-term responders and the remaining patients. Therefore, achievable drug levels are unlikely to explain these differences in response to therapy.

Immunohistochemical analyses of PKCß expression in a small pilot series suggested that the enzyme was near uniformly expressed in relapsed DLBCLs. Available relapsed DLBCLs from current enzastaurin trial patients were similarly positive for PKCß expression. In patients with available paired diagnostic and relapsed DLBCL biopsies, PKCß expression was increased at relapse, supporting the hypothesis that the enzyme is more abundant in chemotherapy-resistant DLBCL.³ If the majority of relapsed DLBCLs express PKCß, it is unlikely that enzyme levels, per se, explain the heterogeneity in response to therapy in the current phase II trial. In future studies, it will be useful to evaluate PKCß activity, as well as PKCß protein expression, in DLBCLs.

The ease of administration of this oral agent, the favorable toxicity profile, and the evidence of activity and long-term responses in relapsed/refractory DLBCL suggest that enzastaurin should be evaluated further in this disease. For these reasons, a large phase III trial of standard induction therapy (CHOP/rituximab) with or without enzastaurin consolidation has been initiated in patients with newly diagnosed, high-intermediate/high-risk DLBCL.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Luna Musib, Eli Lilly; Christelle Darstein, Eli Lilly; Nathan Enas, Eli Lilly; Donald Thornton, Eli Lilly; Christopher A. Slapak, Eli Lilly Leadership: N/A Consultant: Brad S. Kahl, Eli Lilly; Margaret A. Shipp, Eli Lilly Stock: Michael J. Robertson, Eli Lilly; Nathan Enas, Eli Lilly; Donald Thornton, Eli Lilly; Christopher A. Slapak, Eli Lilly Honoraria: Jon C. Aster, Cell Signaling, Merck; Margaret A. Shipp, Eli Lilly Research Funds: Brad S. Kahl, Eli Lilly; Julie M. Vose, Eli Lilly; Stuart L. Goldberg, Eli Lilly; Jon C. Aster, Merck; Margaret A. Shipp, Eli Lilly Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Michael J. Robertson, Brad S. Kahl, Julie M. Vose, Donna Neuberg, Kerry J. Savage, Donald Thornton, Christopher A. Slapak, Margaret A. Shipp

Provision of study materials or patients: Michael J. Robertson, Brad S. Kahl, Julie M. Vose, Sven de Vos, Mary Laughlin, Patrick J. Flynn, Kendrith Rowland, Jose C. Cruz, Stuart L. Goldberg, Kerry J. Savage, Ann LaCasce, Margaret A. Shipp

Collection and assembly of data: Julie M. Vose, Jose C. Cruz, Stuart L. Goldberg, Jeffery L. Kutok, Jon C. Aster, Margaret A. Shipp

Data analysis and interpretation: Michael J. Robertson, Julie M. Vose, Luna Musib, Christelle Darstein, Nathan Enas, Jeffery L. Kutok, Jon C. Aster, Kerry J. Savage, Donald Thornton, Christopher A. Slapak, Margaret A. Shipp

Manuscript writing: Michael J. Robertson, Brad S. Kahl, Julie M. Vose, Mary Laughlin, Stuart L. Goldberg, Luna Musib, Christelle Darstein, Nathan Enas, Donna Neuberg, Kerry J. Savage, Donald Thornton, Margaret A. Shipp

Final approval of manuscript: Michael J. Robertson, Brad S. Kahl, Julie M. Vose, Sven de Vos, Mary Laughlin, Patrick J. Flynn, Kendrith Rowland, Jose C. Cruz, Stuart L. Goldberg, Luna Musib, Christelle Darstein, Nathan Enas, Jeffery L. Kutok, Jon C. Aster, Donna Neuberg, Kerry J. Savage, Ann LaCasce, Donald Thornton, Christopher A. Slapak, Margaret A. Shipp

	ACKNOWLEDGMENTS

 
We wish to thank Parag Garhyan for pharmacokinetic analysis and Asavari Wagle and Noelle Gasco for editorial and technical assistance.

	NOTES

 
published online ahead of print at www.jco.org on March 26, 2007.

Supported in part by National Institutes of Health Grant No. RR00750-27S3 (M.J.R.). This study was sponsored by Eli Lilly and Company (study code H6Q-MC-JCAI).

Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Morton LM, Wang SS, Devesa SS, et al: Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 107:265-276, 2006[Abstract/Free Full Text]

2. Abramson J, Shipp M: Advances in the biology and therapy of diffuse large B-cell lymphoma–moving towards a molecularly targeted approach. Blood 106:1164-1174, 2005[Abstract/Free Full Text]

3. Shipp MA, Ross KN, Tamayo P, et al: Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8:68-74, 2002[CrossRef][Medline]

4. Monti S, Savage KJ, Kutok JL, et al: Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 105:1851-1861, 2005[Abstract/Free Full Text]

5. Rosenwald A, Wright G, Chan WC, et al: The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma. N Engl J Med 346:1937-1947, 2002[Abstract/Free Full Text]

6. Hans CP, Weisenburger DD, Greiner TC, et al: Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Modern Pathol 2005

7. Su TT, Guo B, Kawakami Y, et al: PKC-beta controls IkappaB kinase lipid raft recruitment and activation in response to BCR signaling. Nature Immunol 3:780-786, 2002[Medline]

8. Saijo K, Mecklenbrauker I, Santana A, et al: Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha. J Exp Med 195:1647-1652, 2002[Abstract/Free Full Text]

9. Shinohara H, Yasuda T, Aiba Y, et al: PCKbeta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J Exp Med 202:1423-1431, 2005[Abstract/Free Full Text]

10. Sommer K, Guo B, Pomerantz JL, et al: Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity 23:561-574, 2005[CrossRef][Medline]

11. Rueda D, Thome M: Phosphorylation of CARMA1: The link(er) to NF-kappaB activation. Immunity 23:551-555, 2005[CrossRef][Medline]

12. Yoshiji H, Kuriyama S, Ways D, et al: Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis. Cancer Res 59:4413-4418, 1999[Abstract/Free Full Text]

13. Teicher BA, Menon K, Alvarez E, et al: Antiangiogenic and antitumor effects of a protein kinase C beta inhibitor in murine lewis lung carcinoma and human Calu-6 non-small-cell lung carcinoma xenografts. Cancer Chemother Pharmacol 48:473-480, 2001[CrossRef][Medline]

14. Suzuma K, Takahara N, Suzuma I, et al: Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization. Proc Natl Acad Sci U S A 99:721-726, 2002[Abstract/Free Full Text]

15. Salven P, Terenhovi L, Joensuu H: A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin's lymphoma. Blood 90:3167-3172, 1997[Abstract/Free Full Text]

16. Bertolini F, Paolucci M, Peccatori F, et al: Angiogenic growth factors and endostatin in non-Hodgkin's lymphoma. Br J Haematol 106:504-509, 1999[CrossRef][Medline]

17. Sauma S, Yan Z, Ohno S, et al: Protein kinase C beta 1 and protein kinase beta 2 activate p57 mitogen-activated protein kinase and block differentiation in colon carcinoma cells. Cell Growth Differ 7:587-594, 1996[Abstract]

18. Carducci MA, Musib L, Kies MS, et al: Enzastaurin (LY317615), an oral PKCbeta (PKCbeta) inhibitor, in patients with advanced cancer: A phase I dose escalation and pharmacokinetic study. J Clin Oncol 24:4092-4099, 2006[Abstract/Free Full Text]

19. Graff JR, McNulty AM, Hanna KR, et al: The protein kinase Cbeta-selective inhibitor, enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 65:7462-7469, 2005[Abstract/Free Full Text]

20. Wu E, Aguiar R, Savage K, et al: PKCbeta: A rational therapeutic target in diffuse large B-cell lymphoma. Blood 100:202a, 2002

21. Rossi RM, Henn AD, Conkling R, et al: The PKCbeta selective inhibitor, enzastaurin (LY317615), inhibits growth of human lymphoma cells. Blood 106:427a, 2005

22. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 17:3835-3849, 1999[Abstract/Free Full Text]

23. Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579-586, 2007[Abstract/Free Full Text]

Submitted September 25, 2006; accepted February 1, 2007.

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