Targeting cellular stress response to overcome chemoresistance in glioblastoma

Preclinical evaluation of ER stress modulation as a promising therapeutic rationale to overcome chemoresistance in cancer cells.
Published in Cancer
Targeting cellular stress response to overcome chemoresistance in glioblastoma
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Background

Glioblastoma is one of the deadliest tumours that inevitably recurs. Treatment failures are commonly due to the development of de novo or acquired chemoresistance. The presence of the blood-brain barrier also represents a major challenge to finding effective therapies for brain tumours. However, there is no consensus regarding the best treatment options for patients with recurrent glioblastoma, especially those who are resistant to chemotherapies.

Based on our previous studies, endoplasmic reticulum (ER) stress and the associated unfolded protein response (UPR) play an important role in therapeutic resistance and tumour relapse following long-term temozolomide (TMZ) treatment. ER is the major site for protein synthesis, and ER chaperones function to ensure proper folding of newly synthesized proteins. Cancer cells with an adaptive ER stress response and upregulation of the ER chaperone have been found to better tolerate chemotherapies.

Cancer cells per se harbour a state of chronically active ER stress that sets them apart from normal cells. It provides an opportunity for therapeutic intervention, as ER stress-engaged tumour cells may be specifically targeted, either by alleviating ER stress (to downregulate protective UPR) or by aggravating ER stress to overwhelming levels (to promote pro-apoptotic UPR).

Overcoming the hindrances

Here, we have developed a novel treatment modality to overcome chemoresistance by using albumin-encapsulated nanoparticles targeting the chaperone protein: protein disulphide isomerase (PDI). Nanoparticles were used as a drug delivery carrier with TMZ to minimize side effects and enhance treatment efficacy. This is particularly useful for brain cancer, where drug delivery is often compromised by the blood-brain barrier.

Key findings

We investigated a new formulation of albumin nanoparticles loaded with a PDI inhibitor (CCF642) as a drug delivery carrier in a chemoresistant glioblastoma model. Following the preparation of albumin-encapsulated nanoparticles (with an average size of 245.4 ± 6.514 nm), we asked whether inhibition of PDI would sensitise TMZ-resistant tumour cells in a mice model and whether these new nanoformulations would be better in terms of effectiveness, tolerability, and safety profile.

We found that PDI inhibition (CCF642 without any formulation) alone did not exert any anti-tumour effect in TMZ-resistant tumour (U87-R), whereas the nanoformation of PDI inhibitor (CCF642-NP) shrank the tumour compared to the vehicle control, suggesting that PDI inhibitor itself might have failed to reach the target site due to low solubility and poor drug delivery. Moreover, when given in conjunction with TMZ, CCF642-NP further suppressed tumour growth, either at a low or high dose.

The CCF642 suspension alone remained ineffective in enhancing TMZ cytotoxicity. This further demonstrated a better drug delivery system when it was given in nanoformulation, as well as the therapeutic potential of CCF642-NP as a TMZ adjunct. To investigate the associated ER changes after treatment, it was found that prolonged PDI inhibition induced by CCF642 not only suppressed PERK signalling, but also activated ATF6 and resulted in UPR-mediated cell death.

Take-home message

Temozolomide is the standard chemotherapeutic treatment, and it has demonstrated survival benefits for newly diagnosed glioblastomas. To overcome chemoresistance, one strategy is to induce acute UPR toward a death-triggering pathway that is “beyond repair” by targeting the ER stress response. Such concomitant use of ER stress modulator sensitised TMZ to enhance cell death. The rationale underpinning our approach could also be extended to the treatment of other cancers susceptible to the acquisition of chemoresistance following chemotherapy exposure.

Anti-cancer effects being outnumbered by side effects from toxicity or limited by low availability at the target site are commonly seen in chemotherapy clinical trials. However, these hindrances can be addressed by the use of a biocompatible drug delivery carrier, human-serum albumin (HSA), which is particularly useful for hydrophobic drugs with low water solubility. Drugs can be encapsulated in the inner core of HSA as albumin nanoparticles; such a formulation has been shown to greatly increase solubility and enhance tissue targetability.

References

  1. Markouli M, Strepkos D, Papavassiliou AG, Piperi C: Targeting of endoplasmic reticulum (ER) stress in gliomas. Pharmacol Res 2020, 157:104823.
  2. Liu Y, Ji W, Shergalis A, Xu J, Delaney AM, Calcaterra A, Pal A, Ljungman M, Neamati N, Rehemtulla A: Activation of the Unfolded Protein Response via Inhibition of Protein Disulfide Isomerase Decreases the Capacity for DNA Repair to Sensitize Glioblastoma to Radiotherapy. Cancer Res 2019, 79(11):2923-2932.
  3. Luo B, Lee AS: The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 2013, 32(7):805-818.
  4. Sisinni L, Pietrafesa M, Lepore S, Maddalena F, Condelli V, Esposito F, Landriscina M: Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance. Int J Mol Sci 2019, 20(4).
  5. Happold C, Roth P, Wick W, Schmidt N, Florea AM, Silginer M, Reifenberger G, Weller M: Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. J Neurochem 2012, 122(2):444-455.
  6. Vatolin S, Phillips JG, Jha BK, Govindgari S, Hu J, Grabowski D, Parker Y, Lindner DJ, Zhong F, Distelhorst CW et al: Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma. Cancer Res 2016, 76(11):3340-3350.

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