In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5231-5231
Abstract:
Background: Standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide (TMZ). Nearly all tumors recur and 5-year survival is less than 3%. Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance. Second-line treatment with bevacizumab has failed to improve survival and GBMs escape treatment by inducing intratumor hypoxia. VAL-083 is a bi-functional DNA-targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. VAL-083 induces DNA interstrand crosslinks at N7-guanine, leading to double-strand breaks and cancer cell-death in GBM cells, independent of MGMT. VAL-083 is currently in Phase II clinical trial for the treatment of MGMT promoter unmethylated GBM, both recurrent and treatment-naïve (NCT02717962, NCT03050736), and it remains to be seen if it shows enhanced anti-tumor effect compared to TMZ. Based on its unique monosaccharide backbone structure, VAL-083 may also benefit from bevacizumab-induced GLUT transporter upregulation leading to enhanced uptake and anti-tumor activity. Methods: The cytotoxic effect of VAL-083 and TMZ was verified in 3D GBM organoids derived from 18 patient-derived orthotopic xenograft (PDOX) GBM models of different (epi)genetic background. Cell responses to drugs were calculated as the area under the curve (AUC). We further evaluated VAL-083 ability to decrease tumor growth in vivo in a MGMT-unmethylated, temozolomide-resistant recurrent GBM PDOX model. Mice were grouped into control, bevacizumab, VAL-083, and VAL-083+bevacizmab. Tumor progression was measured by MRI and histopathological assessment. Results: GBM organoids showed only partial response to TMZ. As expected, MGMT- methylated GBMs were less resistant in comparison to MGMT-unmethylated GBMs. VAL-083 was generally more effective than TMZ and response to VAL-083 was not dependent on MGMT promoter methylation status. Responses to TMZ and VAL-083 were comparable between treatment-naïve PDOXs and PDOXs derived from patients previously treated with TMZ and radiation. VAL-083 led to dramatic reduction of tumor growth in vivo (-83% for VAL-083 group, -90% for VAL-083 + bevacizumab). The analysis of tumor growth in time showed further reduction of tumor progression upon combined treatment. Histological assessment showed increased DNA damage (H2AX-P) in tumor cells. H2AX-P was only slightly increased in certain zones of the normal brain, close to meninges and subventricular zone, to a much lower extend in comparison to tumor cell, which was in line with the low toxicity of VAL-083. Citation Format: Anna Golebiewska, Anaïs Oudin, Virginie Baus, Ann-Christin Hau, Eliane Klein, Anne Steino, Jeffrey A. Bacha, Simone P. Niclou, Dennis M. Brown. Dianhydrogalactitol (VAL-083) exhibits strong efficacy in GBM tumors with different (epi)genetic background and treatment history [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5231.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-5231
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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