# Translocon-regulated ER proteostasis in glioblastoma

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $452,925

## Abstract

Abstract
Glioblastoma multiforme (GBM) remains refractory to current standard-of-care treatment and is
associated with a bleak prognosis and poor quality of life in the final months. Endoplasmic
reticulum (ER) stress, and consequently a constitutive activation of the unfolded protein response
(UPR), is a common feature of GBM and has been linked to increased aggressiveness and
therapeutic resistance. The Sec61 translocon is a protein-conducing channel which spans the ER
membrane and is essential for cotranslocational translocation of client proteins. Sec61 subunits
are also upregulated by ER stress in GBM and the gene encoding the gamma subunit (SEC61G)
is considered a GBM proto-oncogene. We now present evidence that Sec61 is directly implicated
in ER stress/UPR signaling in GBM cancer stem cells (GSCs). Overall, our results suggest that
pharmacological inactivation of Sec61 results in depletion of BiP mRNA levels and prevents pro-
survival UPR signaling particularly through the UPR sensor inositol-requiring enzyme 1 (IRE1).
Our central hypothesis is that Sec61 translocon is an essential regulator of UPR signaling and
proteostasis in GBM. We will test this hypothesis through the following specific aims: 1) Define
the role of Sec61 in UPR signaling in GBM. 2) Evaluate the therapeutic potential of
pharmacological targeting Sec61 in orthotopic GSCs mouse models. This multidimensional
approach will reveal the tumor-supportive properties of Sec61 translocon in GBM and GSCs and
explore the feasibility of safely targeting Sec61 for therapeutic advantage while avoiding toxicities
due to non-specific inhibition of secretory protein biosynthesis. This early stage pre-clinical
research is expected to inform the future advancement of newly designed synthetic Sec61
inhibitors for the treatment of GBM and other aggressive human cancers characterized by high
levels of adaptive ER stress.

## Key facts

- **NIH application ID:** 10301296
- **Project number:** 1R21NS119959-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Christian Elias Badr
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,925
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301296

## Citation

> US National Institutes of Health, RePORTER application 10301296, Translocon-regulated ER proteostasis in glioblastoma (1R21NS119959-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10301296. Licensed CC0.

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