Phase II Trial of Ritonavir/lopinavir in Patients with Progressive or Recurrent High-grade Gliomas

Overview

Journal J Neurooncol

Publisher Springer

Date 2010 Aug 5

PMID 20683757

Citations 18

Authors

Manmeet S Ahluwalia

Carol Patton

Glen Stevens

Tanya Tekautz

Lilyana Angelov

Michael A Vogelbaum

Robert J Weil

Sam Chao

Paul Elson

John H Suh

Gene H Barnett

David M Peereboom

Affiliations

Soon will be listed here.

Abstract

Current therapies for recurrent or progressive high-grade gliomas (HGG, WHO grade 3-4) produce a 6-month progression-free survival of only 10-25%. Migration and invasion by HGG is mediated in part by matrix metalloproteases (MMPs) which promote remodeling of the extracellular matrix. Several HIV protease inhibitors (HIVPI) decrease the expression of MMPs in astrocytes and microglia. Given these mechanisms of antitumor activity of HIVPI, we evaluated the efficacy of ritonavir/lopinavir, a combination HIVPI, in patients with progressive or recurrent HGG in an open label phase II trial. Nineteen patients were treated in this study. Patients received ritonavir/lopinavir (400 mg/100 mg) orally twice daily. All patients were treated until progression of disease or unacceptable toxicity. A complete response was seen in one patient (5%). Three patients (16%) had stable disease as the best response. Fifteen patients (79%) had progressive disease. The 6-month progression free survival (PFS(6)) was 11% (2 of 19 patients). Ritonavir/lopinavir was well tolerated in patients with heavily pretreated refractory HGG, and no grade 3 or 4 toxicity was seen. The activity at the dose and schedule used in this study, however, was modest and the study did not meet its efficacy endpoint.

Citing Articles

Antiretroviral Drug Repositioning for Glioblastoma.

Rivas S, Valdez M, Chandar J, Desgraves J, Lu V, Ampie L Cancers (Basel). 2024; 16(9).

PMID: 38730705 PMC: 11083594. DOI: 10.3390/cancers16091754.

Small molecule inhibitors for cancer metabolism: promising prospects to be explored.

Liu D, Wang H, Li X, Liu J, Zhang Y, Hu J J Cancer Res Clin Oncol. 2023; 149(10):8051-8076.

PMID: 37002510 DOI: 10.1007/s00432-022-04501-4.

The Interleukin-11/IL-11 Receptor Promotes Glioblastoma Survival and Invasion under Glucose-Starved Conditions through Enhanced Glutaminolysis.

Stuart S, Bezawork-Geleta A, Areeb Z, Gomez J, Tsui V, Zulkifli A Int J Mol Sci. 2023; 24(4).

PMID: 36834778 PMC: 9960532. DOI: 10.3390/ijms24043356.

Interactions between HIV protease inhibitor ritonavir and human DNA repair enzyme ALKBH2: a molecular dynamics simulation study.

Shaji U, Tuti N, Das S, Anindya R, Mohan M Mol Divers. 2022; 27(2):931-938.

PMID: 35543797 DOI: 10.1007/s11030-022-10444-2.

High myosin binding protein H expression predicts poor prognosis in glioma patients.

Zhang J, Guo Q, Zhang G, Cao X, Chen W, Li Y Sci Rep. 2022; 12(1):1525.

PMID: 35087137 PMC: 8795254. DOI: 10.1038/s41598-022-05512-4.

References

Wong E, Hess K, Gleason M, Jaeckle K, Kyritsis A, PRADOS M . Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999; 17(8):2572-8. DOI: 10.1200/JCO.1999.17.8.2572. View

Friedman H, Prados M, Wen P, Mikkelsen T, Schiff D, Abrey L . Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009; 27(28):4733-40. DOI: 10.1200/JCO.2008.19.8721. View

Burger P, Dubois P, Schold Jr S, SMITH Jr K, ODOM G, Crafts D . Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg. 1983; 58(2):159-69. DOI: 10.3171/jns.1983.58.2.0159. View

Liuzzi G, Mastroianni C, Latronico T, Mengoni F, Fasano A, Lichtner M . Anti-HIV drugs decrease the expression of matrix metalloproteinases in astrocytes and microglia. Brain. 2003; 127(Pt 2):398-407. DOI: 10.1093/brain/awh049. View

Gupta A, Cerniglia G, Mick R, McKenna W, Muschel R . HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res. 2005; 65(18):8256-65. DOI: 10.1158/0008-5472.CAN-05-1220. View

Kumar G, Jayanti V, Johnson M, Uchic J, Thomas S, Lee R . Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans. Pharm Res. 2004; 21(9):1622-30. DOI: 10.1023/b:pham.0000041457.64638.8d. View

Anderson J, McFarland B, Gladson C . New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med. 2008; 10:e23. PMC: 2646508. DOI: 10.1017/S1462399408000768. View

Pore N, Gupta A, Cerniglia G, Maity A . HIV protease inhibitors decrease VEGF/HIF-1alpha expression and angiogenesis in glioblastoma cells. Neoplasia. 2006; 8(11):889-95. PMC: 1716015. DOI: 10.1593/neo.06535. View

Pajonk F, Himmelsbach J, Riess K, Sommer A, McBride W . The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res. 2002; 62(18):5230-5. View

10.

Walker D, Lavin M . The molecular genetics of astrocytomas: current understanding and future applications. J Clin Neurosci. 1997; 4(2):114-21. DOI: 10.1016/s0967-5868(97)90060-6. View

11.

Du R, Petritsch C, Lu K, Liu P, Haller A, Ganss R . Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM. Neuro Oncol. 2008; 10(3):254-64. PMC: 2563048. DOI: 10.1215/15228517-2008-001. View

12.

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View

13.

Bussemakers M, Schalken J . The role of cell adhesion molecules and proteases in tumor invasion and metastasis. World J Urol. 1996; 14(3):151-6. DOI: 10.1007/BF00186894. View

14.

Macdonald D, Cascino T, Schold Jr S, Cairncross J . Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990; 8(7):1277-80. DOI: 10.1200/JCO.1990.8.7.1277. View

15.

van Waterschoot R, Ter Heine R, Wagenaar E, van der Kruijssen C, Rooswinkel R, Huitema A . Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br J Pharmacol. 2010; 160(5):1224-33. PMC: 2936030. DOI: 10.1111/j.1476-5381.2010.00759.x. View

16.

Pati S, Pelser C, Dufraine J, Bryant J, Reitz Jr M, Weichold F . Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood. 2002; 99(10):3771-9. DOI: 10.1182/blood.v99.10.3771. View

17.

Cvetkovic R, Goa K . Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003; 63(8):769-802. DOI: 10.2165/00003495-200363080-00004. View

18.

Gaedicke S, Constantiniu O, Lucchiari-Hartz M, Freudenberg M, Galanos C, Niedermann G . Antitumor effect of the human immunodeficiency virus protease inhibitor ritonavir: induction of tumor-cell apoptosis associated with perturbation of proteasomal proteolysis. Cancer Res. 2002; 62(23):6901-8. View

19.

Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S . HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med. 2002; 8(3):225-32. DOI: 10.1038/nm0302-225. View

20.

Lamborn K, Yung W, Chang S, Wen P, Cloughesy T, DeAngelis L . Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008; 10(2):162-70. PMC: 2613818. DOI: 10.1215/15228517-2007-062. View