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Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status

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Abstract

Introduction

Pleomorphic xanthoastrocytoma (PXA) is a rare Grade II and III glioma. Surgical resection is the mainstay of treatment, however, adjuvant therapy is sometimes necessary. Given the rarity of PXA, chemotherapeutic efficacy data is limited. The importance of the BRAF V600E mutation in the context of MAP kinase pathway inhibition is unknown. The purpose of this study was to perform an in vivo screen of a variety to agents to determine efficacy against both V600E mutant and non-mutant PXA.

Methods

The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n = 5–10 mice). Select agents were also assessed in an intracranial model of D2363 PXA (n = 6–9). Subcutaneous tumor growth and survival were the endpoints.

Results

Temozolomide, bevacizumab, CPT 11, and sorafenib significantly inhibited subcutaneous tumor growth in both V600E-mutant and V600E-non-mutant models (P < 0.05). MEK inhibition (cobimetinib) but not BRAF inhibition (vemurafenib) also inhibited tumor growth regardless of V600E mutation (P < 0.05). Temozolomide, CPT 11, and bevacizumab also prolonged survival in a V600E-non-mutant intracranial model (median overall survival (OS) 68.5, 62.5, and 42.5 days, respectively) in contrast to controls (31.5 days, P < 0.001).

Conclusions

These findings suggest that when adjuvant treatment is clinically indicated for PXA, temozolomide, CPT 11, or bevacizumab may be considered. Additionally, a trial of a MEK inhibitor or tyrosine kinase inhibitor could be considered for PXA regardless of V600E mutation status.

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References

  1. Rao AA, Laack NN, Giannini C, Wetmore C (2010) Pleomorphic xanthoastrocytoma in children and adolescents. Pediatr Blood Cancer 55(2):290–294. https://doi.org/10.1002/pbc.22490

    Article  PubMed  Google Scholar 

  2. Antonelli M, Badiali M, Moi L, Buttarelli FR, Baldi C, Massimino M, Sanson M, Giangaspero F (2015) KIAA1549:BRAF fusion gene in pediatric brain tumors of various histogenesis. Pediatr Blood Cancer 62(4):724–727. https://doi.org/10.1002/pbc.25272

    Article  CAS  PubMed  Google Scholar 

  3. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121(3):397–405. https://doi.org/10.1007/s00401-011-0802-6

    Article  CAS  PubMed  Google Scholar 

  4. Tabouret E, Bequet C, Denicolai E, Barrie M, Nanni I, Metellus P, Dufour H, Chinot O, Figarella-Branger D (2015) BRAF mutation and anaplasia may be predictive factors of progression-free survival in adult pleomorphic xanthoastrocytoma. Eur J Surg Oncol 41(12):1685–1690. https://doi.org/10.1016/j.ejso.2015.09.012

    Article  CAS  PubMed  Google Scholar 

  5. Schmidt Y, Kleinschmidt-DeMasters BK, Aisner DL, Lillehei KO, Damek D (2013) Anaplastic PXA in adults: case series with clinicopathologic and molecular features. J Neurooncol 111(1):59–69. https://doi.org/10.1007/s11060-012-0991-4

    Article  CAS  PubMed  Google Scholar 

  6. Dias-Santagata D, Lam Q, Vernovsky K, Vena N, Lennerz JK, Borger DR, Batchelor TT, Ligon KL, Iafrate AJ, Ligon AH, Louis DN, Santagata S (2011) BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS ONE 6(3):e17948. https://doi.org/10.1371/journal.pone.0017948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gallo P, Cecchi PC, Locatelli F, Rizzo P, Ghimenton C, Gerosa M, Pinna G (2013) Pleomorphic xanthoastrocytoma: long-term results of surgical treatment and analysis of prognostic factors. Br J Neurosurg 27(6):759–764. https://doi.org/10.3109/02688697.2013.776666

    Article  PubMed  Google Scholar 

  8. Perkins SM, Mitra N, Fei W, Shinohara ET (2012) Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis. J Neurooncol 110(1):99–104. https://doi.org/10.1007/s11060-012-0939-8

    Article  PubMed  Google Scholar 

  9. Ida CM, Rodriguez FJ, Burger PC, Caron AA, Jenkins SM, Spears GM, Aranguren DL, Lachance DH, Giannini C (2015) Pleomorphic xanthoastrocytoma: natural history and long-term follow-up. Brain Pathol 25(5):575–586. https://doi.org/10.1111/bpa.12217

    Article  CAS  PubMed  Google Scholar 

  10. Thompson EM, Brown M, Dobrikova E, Ramaswamy V, Taylor MD, McLendon R, Sanks J, Chandramohan V, Bigner D, Gromeier M (2018) Poliovirus receptor (CD155) expression in pediatric brain tumors mediates oncolysis of medulloblastoma and pleomorphic xanthoastrocytoma. J Neuropathol Exp Neurol 77(8):696–702. https://doi.org/10.1093/jnen/nly045

    Article  PubMed  PubMed Central  Google Scholar 

  11. Friedman HS, Colvin OM, Skapek SX, Ludeman SM, Elion GB, Schold SC Jr, Jacobsen PF, Muhlbaier LH, Bigner DD (1988) Experimental chemotherapy of human medulloblastoma cell lines and transplantable xenografts with bifunctional alkylating agents. Cancer Res 48(15):4189–4195

    CAS  PubMed  Google Scholar 

  12. Carlson BL, Pokorny JL, Schroeder MA, Sarkaria JN (2011) Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery. Curr Protoc Pharmacol 52:14–16. https://doi.org/10.1002/0471141755.ph1416s52

    Article  Google Scholar 

  13. Pollack IF, Bredel M, Erff M, Hamilton AD, Sebti SM (1999) Inhibition of Ras and related guanosine triphosphate-dependent proteins as a therapeutic strategy for blocking malignant glioma growth: II–preclinical studies in a nude mouse model. Neurosurgery 45(5):1208–1214 (Discussion 1214–1205)

    Article  CAS  PubMed  Google Scholar 

  14. Kaloshi G, Brace G, Rroji A, Bushati T, Roci E, Hoxha M, Fejzo G, Petrela M (2013) Bevacizumab alone at 5 mg/kg in an every-3-week schedule for patients with recurrent glioblastomas: a single center experience. Tumori J 99(5):601–603. https://doi.org/10.1700/1377.15309

    Article  CAS  Google Scholar 

  15. Weathers SP, Han X, Liu DD, Conrad CA, Gilbert MR, Loghin ME, O’Brien BJ, Penas-Prado M, Puduvalli VK, Tremont-Lukats I, Colen RR, Yung WKA, de Groot JF (2016) A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma. J Neurooncol 129(3):487–494. https://doi.org/10.1007/s11060-016-2195-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Muller PJ, Tator CH (1978) The effect of amphotericin B on the survival of brain-tumor-bearing mice treated with CCNU. J Neurosurg 49(4):579–588. https://doi.org/10.3171/jns.1978.49.4.0579

    Article  CAS  PubMed  Google Scholar 

  17. Adkins CE, Nounou MI, Hye T, Mohammad AS, Terrell-Hall T, Mohan NK, Eldon MA, Hoch U, Lockman PR (2015) NKTR-102 efficacy versus irinotecan in a mouse model of brain metastases of breast cancer. BMC Cancer 15:685. https://doi.org/10.1186/s12885-015-1672-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thompson EM, Dosa E, Kraemer DF, Neuwelt EA (2010) Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery 67(1):87–93. https://doi.org/10.1227/01.NEU.0000370918.51053.BC

    Article  PubMed  PubMed Central  Google Scholar 

  19. Iorio AL, da Ros M, Genitori L, Lucchesi M, Colelli F, Signorino G, Cardile F, Laffi G, de Martino M, Pisano C, Sardi I (2017) Tumor response of temozolomide in combination with morphine in a xenograft model of human glioblastoma. Oncotarget 8(52):89595–89606. https://doi.org/10.18632/oncotarget.19875

    Article  PubMed  PubMed Central  Google Scholar 

  20. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, Chow P, Ong HS, Chung A, Soo KC (2009) Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med 13(8B):2673–2683. https://doi.org/10.1111/j.1582-4934.2009.00692.x

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kawaguchi K, Igarashi K, Murakami T, Kiyuna T, Lwin TM, Hwang HK, Delong JC, Clary BM, Bouvet M, Unno M, Hoffman RM (2017) MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX). Oncotarget 8(29):47490–47496. https://doi.org/10.18632/oncotarget.17667

    Article  PubMed  PubMed Central  Google Scholar 

  22. Koya RC, Mok S, Otte N, Blacketor KJ, Comin-Anduix B, Tumeh PC, Minasyan A, Graham NA, Graeber TG, Chodon T, Ribas A (2012) BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res 72(16):3928–3937. https://doi.org/10.1158/0008-5472.CAN-11-2837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bagriacik EU, Baykaner MK, Yaman M, Sivrikaya G, Durdag E, Emmez H, Fincan GO, Borcek AO, Secen AE, Ercan S (2012) Establishment of a primary pleomorphic xanthoastrocytoma cell line: in vitro responsiveness to some chemotherapeutics. Neurosurgery 70(1):188–197. https://doi.org/10.1227/NEU.0b013e3182262c5b

    Article  PubMed  Google Scholar 

  24. Marucci G, Morandi L (2011) Assessment of MGMT promoter methylation status in pleomorphic xanthoastrocytoma. J Neurooncol 105(2):397–400. https://doi.org/10.1007/s11060-011-0605-6

    Article  CAS  PubMed  Google Scholar 

  25. Yang F, Van Meter TE, Buettner R, Hedvat M, Liang W, Kowolik CM, Mepani N, Mirosevich J, Nam S, Chen MY, Tye G, Kirschbaum M, Jove R (2008) Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas. Mol Cancer Ther 7(11):3519–3526. https://doi.org/10.1158/1535-7163.MCT-08-0138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66(24):11851–11858. https://doi.org/10.1158/0008-5472.CAN-06-1377

    Article  CAS  Google Scholar 

  27. Karajannis MA, Legault G, Fisher MJ, Milla SS, Cohen KJ, Wisoff JH, Harter DH, Goldberg JD, Hochman T, Merkelson A, Bloom MC, Sievert AJ, Resnick AC, Dhall G, Jones DT, Korshunov A, Pfister SM, Eberhart CG, Zagzag D, Allen JC (2014) Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol 16(10):1408–1416. https://doi.org/10.1093/neuonc/nou059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee EQ, Kuhn J, Lamborn KR, Abrey L, DeAngelis LM, Lieberman F, Robins HI, Chang SM, Yung WK, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados MD, Cloughesy TF, Gilbert MR, Wen PY (2012) Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05–02. Neuro Oncol 14(12):1511–1518. https://doi.org/10.1093/neuonc/nos264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sievert AJ, Lang SS, Boucher KL, Madsen PJ, Slaunwhite E, Choudhari N, Kellet M, Storm PB, Resnick AC (2013) Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci USA 110(15):5957–5962. https://doi.org/10.1073/pnas.1219232110

    Article  CAS  PubMed  Google Scholar 

  30. Chamberlain MC (2013) Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J Neurooncol 114(2):237–240. https://doi.org/10.1007/s11060-013-1176-5

    Article  CAS  PubMed  Google Scholar 

  31. Amayiri N, Swaidan M, Al-Hussaini M, Halalsheh H, Al-Nassan A, Musharbash A, Tabori U, Hawkins C, Bouffet E (2017) Sustained response to targeted therapy in a patient with disseminated anaplastic pleomorphic xanthoastrocytoma. J Pediatr Hematol Oncol. https://doi.org/10.1097/MPH.0000000000001032

    Article  Google Scholar 

  32. Levy JM, Thompson JC, Griesinger AM, Amani V, Donson AM, Birks DK, Morgan MJ, Mirsky DM, Handler MH, Foreman NK, Thorburn A (2014) Autophagy inhibition improves chemosensitivity in BRAF(V600E) brain tumors. Cancer Discov 4(7):773–780. https://doi.org/10.1158/2159-8290.CD-14-0049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brown NF, Carter T, Kitchen N, Mulholland P (2017) Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol 6(4):291–296. https://doi.org/10.2217/cns-2017-0006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Migliorini D, Aguiar D, Vargas MI, Lobrinus A, Dietrich PY (2017) BRAF/MEK double blockade in refractory anaplastic pleomorphic xanthoastrocytoma. Neurology 88(13):1291–1293. https://doi.org/10.1212/WNL.0000000000003767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Johanns TM, Ferguson CJ, Grierson PM, Dahiya S, Ansstas G (2018) Rapid clinical and radiographic response with combined dabrafenib and trametinib in adults with BRAF-mutated high-grade glioma. J Natl Compr Cancer Netw 16(1):4–10. https://doi.org/10.6004/jnccn.2017.7032

    Article  Google Scholar 

  36. Medicine USNLo (2018) Phase II pediatric study with dabrafenib in combination with trametinib in patients with HGG and LGG. https://clinicaltrials.gov/ct2/show/NCT02684058. Accessed 8 Jul 2018

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Funding

This study was funded by a donation from the Moyle Family.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Duke University, Durham, NC, USA

    Eric M. Thompson, Daniel Landi, David Ashley, Stephen T. Keir & Darell Bigner

  2. Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA

    Eric M. Thompson, Daniel Landi, David Ashley, Stephen T. Keir & Darell Bigner

  3. Department of Pediatrics, Duke University, Durham, NC, USA

    Daniel Landi

  4. Duke University Medical Center, Box 3272, Durham, NC, 27710, USA

    Eric M. Thompson

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  1. Eric M. Thompson
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Correspondence to Eric M. Thompson.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Thompson, E.M., Landi, D., Ashley, D. et al. Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status. J Neurooncol 140, 261–268 (2018). https://doi.org/10.1007/s11060-018-2975-5

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  • DOI: https://doi.org/10.1007/s11060-018-2975-5

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