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ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449

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Abstract

Purpose

Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal.

Methods

ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal.

Results

Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9–11.1%). Median PFS was 2.3 months (95% CI 1.9–2.6) and mOS was 7.8 months (95% CI 5.4–10.1).

Conclusions

GDC-0449 was well tolerated, reached tumor, and inhibited CD133+ neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.

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Data availability statement

All data refered to in this manuscript is available for review.

References

  1. Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828

    CAS  Google Scholar 

  2. Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401. https://doi.org/10.1038/nature03128

    Article  CAS  Google Scholar 

  3. Yuan X, Curtin J, Xiong Y et al (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23(58):9392–9400. https://doi.org/10.1038/sj.onc.1208311

    Article  CAS  Google Scholar 

  4. Dirks PB (2008) Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol 26(17):2916–2924. https://doi.org/10.1200/JCO.2008.17.6792

    Article  Google Scholar 

  5. Liu G, Yuan X, Zeng Z et al (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 2(5):67. https://doi.org/10.1186/1476-4598-5-67

    Article  CAS  Google Scholar 

  6. Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432(7015):324–331. https://doi.org/10.1038/nature03100

    Article  CAS  Google Scholar 

  7. Bar EE, Chaudhry A, Lin A et al (2007) Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25(10):2524–2533. https://doi.org/10.1634/stemcells.2007-0166

    Article  CAS  Google Scholar 

  8. Clement V, Sanchez P, de Tribolet N, Radovanovic I, RuiziAltaba A (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17(2):165–172. https://doi.org/10.1016/j.cub.2006.11.033

    Article  CAS  Google Scholar 

  9. Von Hoff DD, LoRusso PM, Rudin CM et al (2009) Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361(12):1164–1172. https://doi.org/10.1056/NEJMoa0905360

    Article  Google Scholar 

  10. Rudin CM, Hann CL, Laterra J et al (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 361(12):1173–1178. https://doi.org/10.1056/NEJMoa0902903

    Article  CAS  Google Scholar 

  11. Graham RA, Lum BL, Cheeti S et al (2011) Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin Cancer Res 17(8):2512–2520. https://doi.org/10.1158/1078-0432.CCR-10-2736

    Article  CAS  Google Scholar 

  12. Hjelmeland AB, WuQ HJ et al (2011) Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ 18(5):529–540

    Article  Google Scholar 

  13. Guryanova OA, Wu Q, Cheng L et al (2011) Nonreceptor tyrosine kinease BMX maintains self-renewal, and tumorigenic potential of gliomblastoma stem cells by activating STAT3. Cancer Cell 19(4):498–511

    Article  CAS  Google Scholar 

  14. Eyler CE, Wu W, Yan K et al (2011) Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell 146(1):53–66

    Article  CAS  Google Scholar 

  15. Heddleston JM, Wu Q, Rivera M et al (2012) Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ 19:428–439. https://doi.org/10.1038/cdd.2011.109

    Article  CAS  Google Scholar 

  16. Kaur H, Phillips-Mason PJ, Burden-Gulley SM et al (2012) Cadherin-11, a marker of the mesenchymal phenotype, regulates glioblastoma cell migration and survival in vivo. Mol Cancer Res 10(3):293–304

    Article  CAS  Google Scholar 

  17. Huang P, Sandhya R, Ahluwalia MS et al (2012) Tumor necrosis factor receptor I expression on tumor-associated endothelial cells in glioblastomas provides a pro-apoptotic signal that is negatively regulated by integrin a681. Cancer Res 72(6):1428–1437

    Article  CAS  Google Scholar 

  18. Lathia J, Li M, Hall PE et al (2012) Laminin alpha 2 enables glioblastoma stem cell growth. Ann Neurol 72(5):766–778. https://doi.org/10.1002/ana.23674

    Article  CAS  Google Scholar 

  19. Jin X, Kim JLY, Wu A et al (2017) Targeting glioma stem cells through combined BMI1 and EZH2 inhibition. Nat Med 23:1352–1361. https://doi.org/10.1038/nm.4415

    Article  CAS  Google Scholar 

  20. Li Z, Bao S, Wu Q et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15(6):501–513

    Article  CAS  Google Scholar 

  21. Wang J, Wang H, Li Z et al (2008) c-Myc is required for maintenance of glioma cancer stem cells. PLoS ONE 3(11):e3769

    Article  Google Scholar 

  22. Lathia JD, Gallagher J, Heddleston JM et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6(5):421–432

    Article  CAS  Google Scholar 

  23. Esteller M, Hamilton SR, Burger PC et al (1999) Inactivation of the DNA repair gene 06-methylguanineDNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    CAS  Google Scholar 

  24. Verhaak RGW, Hoadley KA, Purdom E et al (2010) An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell 17(1):98–110

    Article  CAS  Google Scholar 

  25. Phillips HS, Kharbanda S, Chen R et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression and resemble stages in neurogenesis. Cancer Cell 9:157–173

    Article  CAS  Google Scholar 

  26. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280

    Article  CAS  Google Scholar 

  27. Wong H, Alicke B, West KA et al (2011) Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation. Clin Cancer Res 17(14):4682–4692. https://doi.org/10.1158/1078-0432.CCR-11-0975

    Article  CAS  Google Scholar 

  28. LoRusso PM, Rudin CM, Reddy JC et al (2011) Phase I trial of Hedgehog pathway inhibitor GDC-0449 (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 17(8):2052–2511

    Article  Google Scholar 

  29. Chen J, Li Y, Yu TS et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488(7412):522–526. https://doi.org/10.1038/nature11287

    Article  CAS  Google Scholar 

  30. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V et al (2012) Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell 22(3):373–388. https://doi.org/10.1016/j.ccr.2012.07.016

    Article  CAS  Google Scholar 

  31. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. https://doi.org/10.1056/NEJMoa043330

    Article  CAS  Google Scholar 

  32. Nabors LB, Fiveash J (2005) Treatment of adults with recurrent malignant glioma. Expert Rev Neurother 5(4):509–514. https://doi.org/10.1586/14737175.5.4.509

    Article  CAS  Google Scholar 

  33. Pitz MW, Desai A, Grossman SA, Blakeley JO (2011) Tissue concentration of systemically administered antineoplastic agents in human brain tumors. J Neuroncol 104(3):629–638. https://doi.org/10.1007/s11060-011-0564-y

    Article  CAS  Google Scholar 

  34. Hoashi T, Kanda N, Saeki H (2022) Molecular mechanisms and targeted therapies of advanced basal cell carcinoma. Int J Mol Sci 23(19):11968. https://doi.org/10.3390/ijms231911968

    Article  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge the contributions of the patients who participated in this study and their families. We thank Lisa Rogers, DO, formerly from the Seidman Cancer Center, John Pink, Ph.D., and Erin Hohler of the Translational Research Core of the Case Comprehensive Cancer Center (CCCC) for coordinating the biomarker studies, as well as Megan Sims, of ABTC for clinical coordination.

Funding

National Institutes of Health [CA 137443-ARRA]; The Adult Brain Tumor Consortium (ABTC; PI, S.G.; Co-I, A.E.S); The Peter D. Cristal Chair; The Kimble Foundation; The Ferry Family Foundation; The Kaufman Fund (to A.E.S.).

Author information

Authors and Affiliations

  1. Chief of Neuroscience, Piedmont Healthcare, Atlanta, USA

    Andrew E. Sloan & Amber Kerstetter-Fogle

  2. Department of Medicine, UH-Seidman Cancer Center and Case Comprehensive Cancer Center, Cleveland, OH, USA

    Charles J. Nock

  3. Adult Brain Tumor Consortium, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Xiaobu Ye, Joy Fisher, Serena Desideri & Stuart Grossman

  4. Department of Neurology, UH-Seidman Cancer Center and Case Comprehensive Cancer Center, Cleveland, OH, USA

    Robert Buerki

  5. Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA

    Susan Chang & Michael Prados

  6. Department of Radiation Oncology, Wake Forest University, Wake Forest, NC, USA

    Glenn Lesser

  7. Department of Medicine, Dana Farber Cancer Institute, Boston, MA, USA

    Andrew Norden

  8. Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA

    Timothy Cloughesy

  9. Department of Neurosurgery, Emory University, Atlanta, GA, USA

    Jeffrey Olson

  10. Department of Neurology and Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Jeremy Rich

  11. National Cancer Institute, Clinical Investigations Branch, National Institutes of Health, Bethesda, MD, USA

    Naoko Takebe & William Timmer

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  1. Andrew E. Sloan
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Contributions

Study conception and design: SG, AES, MP, NT, WT. Clinical Protocol: AES, CJN, and SG. Development of Biomarker Studies: AES. Surgical Training of investigators: AES. Statistical design of study: Lamborn, XY. Conduct of clinical studies: CJN, AES, SG, MP. Performance of PK and PD studies: Graham, Supko. Performance of neurosphere assays, PCR, and microscopy: AES, AK-F. Analysis and interpretation of data: AES, CJN, Barnholtz-Sloan, AK-F, XY, Rich, SG, Prados. Drafting the article: AES, MP, Nock, Rich, SG. Critically revising the article: all authors. Patient care: AES, CJN, SG, MP.

Corresponding author

Correspondence to Andrew E. Sloan.

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Sloan, A.E., Nock, C.J., Ye, X. et al. ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449. J Neurooncol 161, 33–43 (2023). https://doi.org/10.1007/s11060-022-04193-3

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