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  • Combined Multimodality Treatment With Hypoxia-activated Prodrug TH-302 And XRT Results In Enhanced Antitumor Efficacy In Preclinical Malignant Meningioma Mouse Model.

    Final Number:
    51

    Authors:
    Asif Maknojia MD; Vaibhav M. Patel MD; Michael Garcia; Dave Cavazos; Courtney Bosse; Aleksandra Gruslova; Niko Papanikolaou; Andrew Brenner MD; John Robert Floyd MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: Meningioma account for 36% of intracranial tumors and 4.7% to 7.2% of these demonstrate aggressive clinical behavior and are categorized as malignant meningioma. Currently treatments of these lesions are limited to surgery and radiation. In this article we investigate TH302, a hypoxia activated prodrug with hypoxia dependent cytotoxicity in a mouse model of malignant meningioma

    Methods: Human meningioma tissue obtained intraoperatively was implanted into nude mice subcutaneously in the flank at a size of 1 mm3 . The tumors were then allowed to grow for 80 days and then randomized into groups based on tumor volume 1) XRT only (n=4) 2) XRT and TH302 (n=4) and 3) Control (n=1). Mice were focally radiated on a LINAC system in five fractions of 3 Gy given daily to a total of 15 Gy. Treatment in the TH302+ XRT was started on day 3 of radiation with a dosing of 50 mg/kg given for a total of 9 doses. Tumor volume was measured using calipers.

    Results: Tumor grew in the control mice from 1199 mm3 to 19246 mm3 over 91 days. In the same time the tumors in the XRT only group increased from 890 mm3 to 4220 mm3 compared to the XRT+ TH302 only group where tumor increased from 890 mm3 to 1159 mm3 only.These results were statistically significant (p<0.001). Additionally it took only 29 days since initiation of treatment for the control group to reach a size of 4000 mm3 (primary endpoint) as opposed to XRT group which took 91 days and the XRT+ TH302 group which did not reach that tumor volume at 150 days.

    Conclusions: Mice with meningioma treated with XRT and TH302 showed a slower growth in tumor volume in comparison to XRT only group. These results confirm TH 302 as a viable chemotherapeutic agent for malignant meningioma..

    Patient Care: Patients with malignant meningioma are limited in treatment to surgery and radiation only. Unfortunately these modalities fail to control the growth of these tumors with a high rate of recurrence in this patient population. Our work identifies a possible chemotherepeutic that could help delay the recurrence of these tumors allowing for a longer progression free survival.

    Learning Objectives: By the conclusion of this session, participants should be able to 1) Understand the mechanism by which TH302 induces DNA damage in a hypoxic specific way; 2) Identify it as a viable chemotherepeutic for malignant meningioma.

    References:

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