Novel structural-related analogs of PFI-3 (SRAPs) that target the BRG1 catalytic subunit of the SWI/SNF complex increase the activity of temozolomide in glioblastoma cells

Lawrence Pfeffer,Yali He,Duane Miller,Chuanhe Yang,Joshua Sacher,Michelle Sims,Yinan Wang

doi:10.3390/ecmc2021-11610

Lawrence Pfeffer, Yali He + Show 5 more

Open Access

https://doi.org/10.3390/ecmc2021-11610

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Abstract

Glioblastoma (GBM) is the most aggressive and treatment-refractory malignant adult brain cancer. After standard of care therapy, the overall median survival for GBM is only ~6 months with a 5-year survival <10%. Although some patients initially respond to the DNA alkylating agent temozolomide (TMZ), unfortunately most patients become resistant to therapy and brain tumors eventually recur. We previously found that knockout of BRG1 or treatment with PFI-3, a small molecule inhibitor of the BRG1 bromodomain, enhances sensitivity of GBM cells to temozolomide in vitro and in vivo GBM animal models. Those results demonstrated that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex appears to play a critical role in regulating TMZ-sensitivity. In the present study we designed and synthesized Structurally Related Analogs of PFI-3 (SRAPs) and tested their bioactivity in vitro. Among of the SRAPs, 9f and 11d show better efficacy than PFI-3 in sensitizing GBM cells to the antiproliferative and cell death inducing effects of temozolomide in vitro, as well as enhancing the inhibitor effect of temozolomide on the growth of subcutaneous GBM tumors.

Highlights

Clinical characteristics of GBM Glioblastoma (GBM) is the most common and most aggressive form of primary brain cancer in adults Median overall survival is 12-14 months from diagnosis. Standard of care is surgery with adjuvant radiotherapy and treatment with temozolomide (TMZ), a DNA alkylating agent
Some patients initially respond to the DNA alkylating agent temozolomide (TMZ), most patients become resistant to therapy and brain tumors eventually recur
We previously found that knockout of BRG1 or treatment with PFI-3, a small molecule inhibitor of the BRG1 bromodomain, enhances sensitivity of GBM cells to temozolomide in vitro and in vivo GBM animal models

Summary

Introduction

The BRG1 subunit of the SWI/SNF complex in tumorigenesis:. The BRG1 (SMARCA4) catalytic subunit of the SWI/SNF complex regulates gene expressio differentiation, DNA repair and development. The BRG1 subunit of the SWI/SNF complex in tumorigenesis:. OUR HYPOTHESIS: The BRG1 subunit of the SWI/SNF complex promotes tumorigenesis in GBM. GBM patient samples were queried for EGFR, PTEN, BRM and BRG1 mutations, deletions and amplifications using the cBioPortal tool. A. BRG1 expression in non-tumor tissue and GBM patient samples in Rembrandt database was compared. B. RNA was extracted from de-identified patient biopsies from GBM, LGG or normal brain tissue (55, 44 and 12 samples, respectively), and BRG1 expression was determined by qPCR (n = 3) and normalized to actin expression. After tumors were identified by bioluminescence (~10 days after tumor cell injection), mice were intraperitoneally injected thrice weekly with TMZ (60 mg/Kg body weight) or PFI-3 (10 mg/Kg body weight) alone, or in combination. Kaplan-Meier analysis of the survival data (8 mice/group) was performed

Results and discussion

Conclusions