Quisinostat is a brain-penetrant radiosensitizer in glioblastoma
Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna-Melendez, James B. McNamara, Connor I. White, William Knight, Saisrinidhi Ganta, Zorana Opachich, Claudia Cantoni, Wonsuk Yoo, Nader Sanai, Artak Tovmasyan, Shwetal Mehta
Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna-Melendez, James B. McNamara, Connor I. White, William Knight, Saisrinidhi Ganta, Zorana Opachich, Claudia Cantoni, Wonsuk Yoo, Nader Sanai, Artak Tovmasyan, Shwetal Mehta
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Research Article Oncology Therapeutics

Quisinostat is a brain-penetrant radiosensitizer in glioblastoma

Abstract

Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDAC inhibitors have failed to provide substantial clinical benefit to patients with glioblastoma (GBM) to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. Although no isoform-specific HDAC inhibitors are currently available, the second-generation hydroxamic acid–based HDAC inhibitor quisinostat possesses subnanomolar specificity for class I HDAC isoforms, particularly HDAC1 and HDAC2. It has been shown that HDAC1 is the essential HDAC in GBM. This study analyzed the neuropharmacokinetic, pharmacodynamic, and radiation-sensitizing properties of quisinostat in preclinical models of GBM. It was found that quisinostat is a well-tolerated and brain-penetrant molecule that extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.

Authors

Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna-Melendez, James B. McNamara, Connor I. White, William Knight, Saisrinidhi Ganta, Zorana Opachich, Claudia Cantoni, Wonsuk Yoo, Nader Sanai, Artak Tovmasyan, Shwetal Mehta

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Figure 8

QST is a potent radiosensitizer in an orthotopic PDX model of GBM.

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QST is a potent radiosensitizer in an orthotopic PDX model of GBM. (A) S...
(A) Schematic illustrating the experimental design of the treatment study in an orthotopic PDX model of GBM (GB126) to assess survival benefit across all treatment cohorts. Mice received IR only in the first week of treatment. Mice continued to receive QST treatment alone until they displayed neurological symptoms (the survival PK and PD endpoint). QST and IR were administered MWF. (B) Representative heatmap images of bioluminescence intensity across all treatment cohorts 22 days after treatment initiation. (C) Mean photon flux (p/s) measured through bioluminescence imaging across all cohorts throughout the entire duration of the treatment. Error bars indicate SEM. (D) Kaplan-Meier survival analysis of mice treated with vehicle, QST (10 mg/kg), IR (6 Gy), or QST+IR (6 Gy IR and 10 mg/kg QST) mice. Total (E) and unbound (F) levels of QST in tumor tissue and brain tissue contralateral to the tumor in mice treated with QST and QST+IR (n = 4 or 5 mice per cohort). Circles and squares indicate values, bars indicate mean values, and error bars indicate SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001 by unpaired, 2-tailed Student’s t test (C) or Kaplan-Meier method with the Mantel-Cox log-rank test (D).