Gene Targeting In Improving Brain Cancer Response To Therapy


Glioblastoma is the most common and malignant primary brain tumour in adults. Currently, standards of care include maximal surgical removal of the tumours followed by treatment with a chemotherapy drug called temozolomide (TMZ) and ionising radiation (IR). However glioblastoma is the most aggressive cancerous brain tumour in adults due to its resistance to therapy, and so in spite of these treatment efforts, in the majority of cases the tumour cells reoccur and therapeutic resistance leave patients with a median survival rate of less than 18 months after diagnosis.

More information on glioblastoma.
Source: John McCain’s cancer: What is glioblastoma?

Within glioblastoma tumours are rare brain tumour stem cells (BTSCs) that can undergo self-renewal to replenish themselves, or give rise to all the cellular subpopulations within a tumour to repeat the various functions of a tumour during growth; BTSCs are what are responsible for therapeutic resistance and tumour regrowth. Proliferation of BTSCs and glioblastoma tumorigenesis is regulated by the cytokine receptor for oncostatin M (OSMR). Oncostatin M (OSM) is a protein that is encoded by the OSM gene in humans and is the ligand for OSMR (the receptor). The protein OSM is reported to regulate different hallmarks of cancer and is shown to increase tumour growth and metastasis of prostate and breast cancer. The receptor OSMR is a member of the interleukin-6 receptor family that carries out a diverse range of cellular function, including regulation of homeostasis, cell growth and differentiation. It is expressed in many tumour cell types, including glioma, sarcoma, melanoma, breast and prostate carcinoma. OSMR is what strengthens mitochondria by interacting with them in order to force them to generate more energy for cancer cells, and thus fortifying cancer stem cells’ resistance to therapy.

Here the researchers used CRISPR (a technology that can be used to edit genes), along with other similar methods, in multiple patient-derived human BTSCs to induce OSMR knockdown (KD; where expression of the OSMR gene is significantly reduced in the cell). And so, the mice used in the experiment either received OSMR KD BTSCs or control BTSCs. The mice receiving the control BTSCs formed malignant tumours three weeks following injection while the mice receiving OSMR KD BTSCs, had significantly smaller tumours.

How gene targeting is carried out.
Source: Gene Targeting.

The researchers also assessed whether IR therapy in mice receiving OSMR KD BTSCs improves the lifespan of the animals. At 17 days following surgery, mice receiving control BTSCs formed malignant brain tumours in the absence of IR and were at endpoints as assessed by major weight loss and neurological signs. Whereas mice exposed to IR or mice receiving OSMR KD BTSCs were at endpoint at 23 and 26 days, respectively. Strikingly, mice receiving a combination of OSMR KD BTSCs and IR survived past 40 days.

This research paper presents evidence that deletion of OSMR initiates a series of events and signalling networks that ultimately induces cell death. Importantly, the researchers established that loss of OSMR is sufficient to sensitise the response of glioblastoma tumours to IR therapy and to prolong lifespan. And so it is suggested that OSMR targeting in combination with IR provides a promising therapeutic approach for better treatment of glioblastoma tumours. OSM/OSMR targeted therapies are promising in eliminating IR-resistant BTSCs in the tumour mass, impairing mitochondrial function, and improving response to IR.

A Sharanek, A Burban, M Laaper, E Heckel, J-S Joyal, V D. Soleimani and A Jahani-Asl. (2020). “OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation.” Nature. 11, Article 4116 .


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