Glutaminase inhibition in renal cell carcinoma therapy

Abstract

Receptor tyrosine kinase inhibitors have been a standard first-line therapy for renal cell carcinoma (RCC) for over a decade. Although they stabilize the disease, they are unable to remove all tumor cells, leading to relapse. Moreover, both intrinsic and acquired resistance to therapy are a significant health burden. In order to overcome resistance, several combination therapies have been recently approved by the FDA. Another approach takes advantage of altered metabolism in tumor cells, which switch to alternative metabolic pathways to sustain their rapid growth and proliferation. CB-839 is a small molecule inhibitor of kidney type glutaminase (GLS). GLS is often upregulated in glutamine addicted cancers, enhancing glutamine metabolism for the production of energy and the biosynthesis of various cellular building blocks. CB-839 is currently in clinical trials for several tumors, including clear cell (cc)RCC, both as monotherapy and in combination with the approved therapeutic agents everolimus, cabozantinib and nivolumab. Early results of Phase 1/2 clinical trials look promising, especially for CB-839 plus cabozantinib, and all combinations seem to be well tolerated. However, cancer cells can activate compensatory pathways to overcome glutaminolysis inhibition. Therefore, genetic and metabolomic studies are crucial for the successful implementation of CB-839 alone or in combination in subgroups of ccRCC patients.

Keywords

Glutamine addiction / renal cell carcinoma / combination therapy / metabolism

References

[1] Ferlay J,Bray F,Mathers C.Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008..Int J Cancer2010;127:2893-917

[2] Gupta K,Li JZ,Charbonneau C.Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review..Cancer Treat Rev2008;34:193-205

[3] Ljungberg B,Cho HY,Lee JE.The epidemiology of renal cell carcinoma..Eur Urol2011;60:615-21

[4] Krabbe L-M,Margulis V.Surgical management of renal cell carcinoma..Semin Intervent Radiol2014;31:27-32 PMCID:PMC3930656

[5] Kalra S,Matrana MR,Wood CG.Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases..BJU Int2016;117:761-5 PMCID:PMC4666814

[6] Gerlinger M,Horswell S,Larkin J.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing..N Engl J Med2012;366:883-92 PMCID:PMC4878653

[7] Lim SH,Ji JH,Yi JH.Intrinsic resistance to sunitinib in patients with metastatic renal cell carcinoma..Asia Pac J Clin Oncol2017;13:61-7

[8] Rini BI.Resistance to targeted therapy in renal-cell carcinoma..Lancet Oncol2009;10:992-1000

[9] Busch J,Weikert S,Kempkensteffen C.Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma..BMC Cancer2011;11:295 PMCID:PMC3154177

[10] Motzer RJ,Bukowski RM,Gerorge DJ.Sunitinib in patients with metastatic renal cell carcinoma..JAMA2006;295:2516-24

[11] Motzer RJ,Tomczak P,Bukowski RM.Sunitinib versus Interferon alfa in metastatic renal-cell carcinoma..N Engl J Med2007;356:115-24

[12] Zarrabi K,Wu S.New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy..J Hematol Oncol2017;10:38 PMCID:PMC5288948

[13] Motzer RJ,Oudard S,Porta C.Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial..Lancet2008;372:449-56

[14] Voss MH,Motzer RJ.mTOR inhibitors in advanced renal cell carcinoma..Hematol Oncol Clin North Am2011;25:835-52 PMCID:PMC3587783

[15] Weinstock M.Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma..Ther Adv Urol2015;7:365-77 PMCID:PMC4647139

[16] Frei E,Levin RH,Taylor RJ.The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia..Blood1965;26:642-56

[17] Komarova EA.Chemoprotection from p53-dependent apoptosis: potential clinical applications of the p53 inhibitors..Biochem Pharmacol2001;62:657-67

[18] Chong CR.New uses for old drugs..Nature2007;448:645-6

[19] Motzer RJ,Glen H,Molina A.Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial..Lancet Oncol2015;16:1473-82

[20] Escudier B,Koralewski P,Bracarda S.Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial..Lancet2007;370:2103-11

[21] Escudier B,Négrier S,Melichar B.Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final Analysis of Overall Survival..J Clin Oncol2010;28:2144-50

[22] Motzer RJ,McDermott DF,Melichar B.Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma..N Engl J Med2018;378:1277-90 PMCID:PMC5972549

[23] FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. Available from: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm604685.htm. [Last accessed on 24 Apr 2019].

[24] Motzer RJ,Atkins MB,McDermott DF.IMmotion151: a randomized phase iii study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC)..J Clin Oncol2018;36:578

[25] Lee CH,Rasco D,Stepan D.Lenvatinib + pembrolizumab in patients with renal cell carcinoma: updated results..J Clin Oncol2018;36:4560

[26] Apolo A,Stein M,Nadal R.A phase I study of cabozantinib plus nivolumab (CaboNivo) and cabonivo plus ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic (m) urothelial carcinoma (UC) and other genitourinary (GU) tumors..J Clin Oncol2017;35:4562

[27] Nadal R,Stein M,Davarpanah N.Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies..J Clin Oncol2018;36:515

[28] Escudier B,Ravaud A,Needle M.Tivozanib combined with nivolumab: Phase Ib/II study in metastatic renal cell carcinoma (mRCC)..J Clin Oncol2018;36:618

[29] Hanahan D.Hallmarks of Cancer: The Next Generation..Cell2011;144:646-74

[30] Vander Heiden M,Thompson C.Understanding the warburg effect: the metabolic requirements of cell proliferation..Science2009;324:1029-33 PMCID:PMC2849637

[31] Carr E,Wu G,Senkevitch E.Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation..J Immunol2010;185:1037-44 PMCID:PMC2897897

[32] Lukey MJ,Cerione RA.Therapeutic strategies impacting cancer cell glutamine metabolism..Future Med Chem2013;5:1685-700 PMCID:PMC4154374

[33] Ahluwalia GS,Hao Z.Metabolism and action of amino acid analog anti-cancer agents..Pharmacol Ther1990;46:243-71

[34] Ovejera A,Catane R,Muggia F.Efficacy of 6-Diazo-5-oxo-l-norleucine and N-[N-γ-Glutamyl-6-diazo-5-oxo-norleucinyl]-6-diazo-5-oxo-norleucine against experimental tumors in conventional and nude mice..Cancer Res1979;39:3220-4

[35] Mueller C,Jaeger E,Bausch M.A phase IIa study of PEGylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-L-norleucine (DON) in patients with advanced refractory solid tumors..J Clin Oncol2008;26:2533

[36] DeLaBarre B,Fang C,Jha A.Full-length human glutaminase in complex with an allosteric inhibitor..Biochemistry2011;50:10764-70

[37] Robinson M,Tsukamoto T,Ferraris D.Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES)..Biochem J2007;406:407-14 PMCID:PMC2049044

[38] Le A,Hamaker M,Gouw A.Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells..Cell metabolism2012;15:110-21 PMCID:PMC3345194

[39] Shukla K,Thomas AG,Duvall B.Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors..J Med Chem2012;55:10551-63 PMCID:PMC3539823

[40] Matre P,Jacamo R,Su X.Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes..Oncotarget2016;7:79722-35 PMCID:PMC5340236

[41] Parlati F,Janes J,MacKinnon A.Glutaminase Inhibitor CB-839 Synergizes with Pomalidomide in Preclinical Multiple Myeloma Models..Blood.2014;124:4720

[42] Gross MI,Dennison JB,Chernov-Rogan T.Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer..Mol Cancer Ther2014;13:890-901

[43] Lampa M,He T,Reeves J.Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition..PLoS One2017;12:e0185092 PMCID:PMC5614427

[44] Parlati F. CB-839, a selective glutaminase inhibitor, synergizes with signaling pathway inhibitors to produce an anti-tumor effect in cell lines and tumor xenografts. Available from: https://www.calithera.com/wp-content/uploads/2017/12/AACR-2015-final.pdf. [Last accessed on 24 Apr 2019]

[45] Gameiro PA,Metelo AM,Baker R.In virto HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation..Cell Metabolism17:372-85 PMCID:PMC4003458

[46] Study of the Glutaminase Inhibitor CB-839 in Solid Tumors. Available from: https://clinicaltrials.gov/ct2/show/NCT02071862. [Last accessed on 24 Apr 2019]

[47] Harding J,Munster P,Molineaux C.Safety and tolerability of increasing doses of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase, in solid tumors..J Clin Oncol2015;33:2512

[48] Meric-Bernstam F,Mier J,Telli M.Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), alone and in combination with everolimus (E) in patients (pts) with renal cell cancer (RCC)..J Clin Oncol2016;34:4568

[49] Guo H,Bai S,Guo W.The PI3K/AKT pathway and renal cell carcinoma..J Genet Genomics2015;42:343-53 PMCID:PMC4624215

[50] Bernardi R,Jin D,Alimonti A.PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR..Nature2006;442:779

[51] Brodaczewska K,Fiedorowicz M,Czarnecka A.Choosing the right cell line for renal cell cancer research..Mol Cancer2016;15:83 PMCID:PMC5168717

[52] Tannir N,Lee R,Iliopoulos O.Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus (E) or cabozantinib (Cabo) in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell cancer (mRCC)..J Clin Oncol2018;36:603

[53] Meric-Bernstam F,Harding J,Mier J.Phase 1 study of CB-839, a small molecule inhibitor of glutaminase, in combination with everolimus in patients (pts) with clear cell and papillary renal cell cancer (RCC)..Eur J Cancer2016;69:S12-S3

[54] Guo L,Chen B.Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor..J Cancer2017;8:410-6 PMCID:PMC5332892

[55] Gross M,Englert J,Leone R.Abstract 2329: glutaminase inhibition with CB-839 enhances anti-tumor activity of PD-1 and PD-L1 antibodies by overcoming a metabolic checkpoint blocking T cell activation..Cancer Research2016;76:2329

[56] Study CB-839 in combination with nivolumab in patients with melanoma, ccRCC and NSCLC. Available from: https://clinicaltrials.gov/ct2/show/NCT02771626. [Last accessed on 24 Apr 2019]

[57] Emberley E, Bennett M, Chen J, Gross M, Huang T, et al. CB-839, a selective glutaminase inhibitor, has anti-tumor activity in renal cell carcinoma and synergizes with cabozantinib and everolimus. Available from: https://www.calithera.com/wp-content/uploads/2017/12/03.2017-Keystone-poster-Emberley-2017.pdf. [Last accessed on 24 Apr 2019]

[58] Tannir N,Agarwal N,Whiting S.CANTATA: a randomized phase 2 study of CB-839 in combination with cabozantinib vs. placebo with cabozantinib in patients with advanced/metastatic renal cell carcinoma..J Clin Oncol2018;36:TPS4601

[59] Halama A,Dib SS,Siveen KS.Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis..Cancer Lett2018;430:133-47