Study provides clues to the role of PRMT5 in glioblastoma

Incidence of glioblastoma

Glioblastoma is the most common primary brain tumor, accounting for half of all primary brain tumors. It has an annual incidence of 3.1 per 100,000, which is low compared to cancers arising from other organs such as breast (171.20 per 100,000) or prostate (201.40 per 100,000)^[3].


Pathogenesis of glioblastoma

Despite numerous effects to elucidate the biology and pathogenesis of glioblastoma, the cause of glioblastoma is usually unclear, and risk factors other than age are poorly defined. Possible risk factors may include:

1. Age
Glioblastoma is mainly diagnosed in the elderly. The median age of diagnosis (the age at which half of cancer patients were older and half were younger) is 64 years. The incidence continues to rise with increasing age, peaks at 75–84 years of age and drops after 85 years

2. Being male
Gender is also a factor that influences the development of glioblastoma. Men have a higher risk of developing glioblastoma compared with women. Specifically, the incidence rate of glioblastoma is 1.6 times higher in men as compared to women.

3. Race
Whites have the highest incidence rates for glioblastoma, followed by blacks, Asian/Pacific Islanders and American Indian/Alaska Native.

4. Others
These Factors may increase glioblastoma risk:
*Prior therapeutic radiation
*Decreased susceptibility to allergy
*Certain immune factors
*Some variations in the genes CDKN2B and RTEL1
*High socio-economic status (SES)
*Taller height

These Factors may decrease glioblastoma risk:
*Allergies or atopic diseases (e.g. asthma, eczema, psoriasis)
*Short term (< 10 years) use of anti-inflammatory medications^[4]

Treatment of glioblastoma

Glioblastoma is generally hard to treat, though there are several treatment options available, such as surgery, radiotherapy, chemotherapy, and antiangiogenic therapy.

This is, first of all, because at the cellular and molecular levels, glioblastoma tumors can be quite different. Two individuals who receive the same diagnosis of glioblastoma may carry different mutations in their DNA that drive tumor growth. This means that a therapeutic strategy works for one patient will not necessarily work for another patient. It's difficult to develop a therapy that is universally effective.

The second important reason is the invasive nature of glioblastoma. Glioblastoma tumor cells grow fast and often crawl away from the main tumor mass and spread to normal tissues in the brain. Surgery, which is the first stage of treatment for patients with glioblastoma may remove the main central tumor mass of a glioblastoma tumor but fail to get rid of malignancy cells embedded deep in other areas of the brain.

Radiotherapy is an important approach to killing cancer cells. However, high-dose of radiation delivered to the brain to target cancer cells may also cause damage to normal brain tissues, which can lead to mild-to-severe brain damage. Newer radiation therapy techniques can limit these side effects but may not always eliminate them.

Chemotherapy drugs such as temozolomide are an additional treatment option, but drug resistance may occur. It's estimated that at least 50% of temozolomide treated patients with glioblastoma do not respond to the drug^[5].

Due to the presence of the blood-brain barrier, many therapeutic agents cannot effectively get into the brain to make an effect.

Treatment of glioblastoma is challenging but there are still promises. For instance, immunotherapy, which uses the patient's own immune system to attack cancer cells, has emerged as a therapy with potential; Electric field therapy offers an approach to target cells in the tumor while not hurting normal cells and has been reported to improve survival when used in combination with temozolomide^[6].
Prognosis of glioblastoma

The prognosis for glioblastoma patients is bleak. only a small proportion of patients live beyond 2.5 years after diagnosis and less than 5% of patients survive 5 years post diagnosis, as shown in Fig. 2. In the first year after diagnosis, the relative survival rate is only 35% and it falls in the second year post diagnosis (13.7%) and thereafter.


If left untreated, the disease is extremely fatal, with a median survival of only 3 months. A combination of surgery, radiotherapy, and chemotherapy can help extend patients' survival.

Reference:
[1] Christian J. Braun, Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma, Cancer Cell (2017).
[2] David N. Louis et al, The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary, Acta Neuropathologica (2016).
[3] Hans-Georg Wirsching et al, Chapter 23 - Glioblastoma, Handbook of Clinical Neurology (2016).
[4] Jigisha P. Thakkar et al, Epidemiologic and Molecular Prognostic Review of Glioblastoma, Cancer Epidemiology, Biomarkers & Prevention (2014).
[5] Sang Y. Lee et al, Temozolomide resistance in glioblastoma multiforme, Genes & Diseases (2016).
[6] Roger Stupp et al, Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial, JAMA (2017).