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 11

QST is a brain-penetrant HDACi that sensitizes GBM cells to radiation treatment.

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QST is a brain-penetrant HDACi that sensitizes GBM cells to radiation tr...
Summary of the major findings in this study. Through a careful PK-PD–guided approach, we determined that QST can cross the BBB and exert its intended PD effect (increase in histone acetylation) in normal brain tissue as well as GBM cells. A second-generation HDACi, QST has high subnanomolar isoform selectivity for HDAC1 and HDAC2, which are class I HDAC isoforms that are primarily responsible for mediating histone deacetylation. Free (non–protein bound) QST inhibit the function of HDAC1 and HDAC2, resulting in widespread histone hyperacetylation in GBM cells. QST treatment alone in GBM cells also results in increased levels of DNA damage and oxidative stress. When QST is combined with IR treatment, genes involved in DNA damage repair pathways and cell division are downregulated, whereas genes that regulate neuronal development and function are significantly upregulated. These findings suggest that combination therapy of QST and IR provides therapeutic benefit through decreased cell proliferation, dampening of pathways involved in the DNA damage repair response, and a shift toward a neuron-like cell fate. ROS, reactive oxygen species.