Study provides clues to the role of PRMT5 in glioblastoma


Recent research on glioblastoma

A collaborative team of researchers from the Massachusetts Institute of Technology (MIT) and Harvard Medical School has identified a vulnerability in an aggressive brain tumor, known as glioblastoma[1].

Findings of the study were published in Cancer Cell on 28 September 2017. The co-first authors of the study include Christian Braun, Monica Stanciu, and Paul Boutz, all of whom are from MIT.

Glioblastoma prognosis is generally bleak. The median survival following diagnosis is 12-18 months, and long-term survival is quite rare. More effective therapies are in desperate need.

Why are brain tumors like glioblastoma so difficult to treat? One important reason is that the blood-brain barrier, which protects the brain by preventing harmful substances from entering the brain, also blocks many drugs from reaching the brain tumor. So some scientists are focusing on developing drugs that can cross the blood-brain barrier.

The team previously performed a shRNA screen to search genes implicated in glioblastoma. The screen pointed to the PRMT5 gene, whose inactivation stopped tumor growth.

The PRMT5 gene encodes an enzyme that belongs to the methyltransferase family. This enzyme acts on many different proteins and plays a role in several cellular processes, including transcriptional regulation. Dysregulation of PRMT5 activity is associated with many cancers. However, the precise role of PRMT5 in cancer development is not fully elucidated.

The team also found that a striking number of human mRNAs still have introns. As a result, these mRNAs cannot leave the nucleus and cannot be translated.

In the current study, the team demonstrated that PRMT5 inhibition disrupts the removal of detained introns and exerts potent anti-tumor activity. Blocking PRMT5 caused tumor cells to enter a nondividing state.

Furthermore, PRMT5 inhibitors successfully suppressed the growth of glioblastoma tumors transplanted under the skin of mice. But PRMT5 inhibitors did not work on tumors transplanted into the brains of mice. An obvious reason for such failure is that these inhibitors are unable to penetrate the blood-brain barrier.

In conclusion, the study reveals a role of PRMT5 in intron splicing. Further investigation is needed to better understand its association with various cancers.

Overview of glioblastoma

Glioblastoma, or glioblastoma multiforme (GBM), is an aggressive brain cancer, which is classified as a grade IV astrocytoma by the WHO[2]. Glioblastoma is a type of astrocytoma, a cancer that forms from star-shaped cells in the brain called astrocytes. It can grow fast and spread quickly, causing damage to normal brain tissue. There is no known cure for this disease, and its prognosis remains poor, and current treatment can only ease symptoms. It's uncommon in children and usually affects adults. It's the most common type of malignant brain tumor among adults.

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].

Fig. 1 Annual Incidence

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.

Fig. 2 Survival Rate

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).
 

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