Inhibition of intracellular Ca2+ channels as a strategy to control glioma
Ca2GB
COFAC/ILIND/CBIOS/4/2024
2025-07-01
2026-12-31
Ongoing
Tumours of the brain and nervous system (BNS) represent a particular diagnosis and therapeutical challenge. The estimated cumulative risk of mortality associated with BNS cancers is particularly high in countries such as Portugal and Brazil. BNS cancers rank 8th and 9th in the list of cancers with higher mortality in Portugal and Brazil, respectively. The poor survival rate of glioma patients is mostly attributed to the high genetic heterogeneity and invasive properties of the tumour. Inevitably, this leads to invasion of adjacent tissues and resistance to the therapies. Tumour invasion is a key hallmark of high-grade gliomas such as glioblastoma (GB) and a determinant for patient outcome. The current therapies rarely result in remission or meaningful improvement of life expectancy. Therefore, the development of alternative therapeutic approaches against gliomas is urgent. Despite this, no approved drugs target cell invasion.
Calcium ion (Ca2+) signalling dynamics and subcellular localization are tightly regulated. The dysregulation of Ca2+ homeostasis is crucial in cancer initiation and progression. Cancer cells can establish cancer hallmark features, by manipulating the expression or activity of Ca2+ modulators, including pumps, channels, and exchangers. Thus, our main goal is to explore the modulation of intracellular Ca2+ fluxes as a therapeutic strategy to inhibit glioma progression.
As an innovative approach, we propose to reprogram Ca2+ intracellular fluxes/homeostasis by inhibiting specific endoplasmic reticulum (ER) or Golgi apparatus (GA) Ca2+ channels to control glioma progression. Ca2+ release to the cytoplasm can control processes essential for glioma progression. Increasing evidence associates intracellular Ca2+, redox and thiol homeostases with glioma progression. The mechanisms linking these key aspects of glioma cell biology and how they impact cell invasion or proliferation are unclear and no approved glioma therapeutics target these processes. We propose to modulate the activity of specific intracellular ER and GA Ca2+ channels to control glioma progression.
As proof of principle, we demonstrated that manipulating the GA Ca2+ channel TMBIM4 expression impacts glioma cell invasion and in vivo tumour growth. We herein propose to identify other ER and GA Ca2+ channels that affect glioma progression and to find pharmacological inhibitors to TMBIM4.
To identify the first inhibitors of the GA Ca2+ channel TMBIM4, a virtual screening will be conducted from libraries of compounds that will include natural compounds and derivatives. The impact of the identified molecules on GB 3D invasion and redox status will be evaluated in vitro.
The search for additional ER and GA Ca2+ channels that may constitute therapeutic targets will start with a bioinformatic approach based on glioma gene expression and patient survival data, to identify those associated with glioma patient outcome. The effects of expression manipulation of identified channels on cell viability, proliferation, invasion, and redox status will be analysed. To survive in adverse conditions, cancer cells undergo deep metabolic reprogramming. Here, thiol homeostasis the availability of cysteine are central for glioma progression. Searching for additional mechanistic clues, we propose to identify the subset of ER and GA Ca2+ channels that act on glioma cell phenotype in a cysteine-dependent manner. Here, our findings will break the ground on the combined effects of Ca2+ intracellular fluxes deregulation and cysteine availability in glioma.
This project will allow the identification of drug-like copounds able to inhibit TMBIM4, which could constitute potential drugs and mechanistic tools for cell biology studies, and the identification and validation of additional ER or GA Ca2+ channels that affect glioma progression. The data generated will pave the way for subsequent lines of research in pharmacology and drug delivery systems against glioma invasion.
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