P11.82.a targeting the glioblastoma master regulator c/ebpß: a pharmacokinetic and pharmacodynamic neoadjuvant study of st101
Neuro-oncology(2023)
Abstract
BACKGROUND The vast amounts of genomics, epigenomics and transcriptomics data in glioblastoma (GBM) have yet to translate into better outcomes to most patients. One of the main challenges is to how to best integrate these diverse layers of omics to personalize and improve the treatment of glioblastomas. Cancer master regulators are often transcription factors (TFs), which control the expression of many genes and considered promising antitumor targets. CCAAT/enhancer-binding protein β (C/EBPβ) is an abundantly-expressed transcription factor (Zahnow 2009). C/EBPβ was previously described as a master regulator in GBM (Carro 2010). ST101 is a first-in-class cell-penetrating peptide antagonist of C/EBPβ with known ability to cross the blood-brain barrier. We have demonstrated potent anti-tumor activity with ST101 in multiple in vivo models including glioblastoma. Based on early efficacy data on the initial clinical study including objective responses in GBM, we designed this surgical study to further understand the antitumor mechanisms of ST101. METHODS we will recruit total of 12 newly diagnosed GBM and 6 recurrent patients. Recurrent GBM patients who are deemed surgical candidates will be treated with ST101 at the RP2D of 500 mg IV weekly for 2 to 4 weeks and then undergo standard of care surgical resection. After recovery from surgery, patients will continue ST101 until there is significant toxicity or tumor progression. 12 patients with newly diagnosed GBM who had undergone a prior biopsy or partial resection, and that upon further neurosurgical evaluation have an indication for additional debulking surgery will be eligible for this study. Patients will be treated with ST101 at the recommended phase 2 dose for 2 weeks and then undergo standard of care surgical resection. Patients will undergo standard of care treatment with radiation and temozolomide and continue ST101 after recovery from surgery. ST101 plasma concentration will be correlated with ST101 drug levels in enhancing and non-enhancing tumor tissue of recurrent and newly diagnosed patients. We will compare the molecular abnormalities in the post-treatment tissue through deep bulk whole-exome sequencing and mRNAseq against the intra-patient baseline tissue. Pharmacodynamics evaluation will focus on the expression of genes regulated by the transcription factor CEBPβ, such as BCL2, cyclins and cyclin-dependent kinases and inhibition of differentiation genes. Due to the diversity of cell types in the tumor microenvironment and the early data that ST101 can also reprogram M2 macrophages to M1 in addition to its direct antitumor effects, we will perform single nucleus RNAseq on these surgical specimens. Enrollment has started in January 2023 and 6 recurrent and 2 newly diagnosed patients have been accrued.
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Key words
pharmacodynamic neoadjuvant study,pharmacokinetic
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