Brain Tumor & Glioblastoma Multiforme (GBM)

Glioblastoma Multiforme (GBM)

GBM (Glioblastoma Multiforme) is typically challenging to cure, and there are currently no approved treatment modalities, resulting in a short life expectancy. Even with the best available treatments, most patients cannot survive beyond two years.

  • Glioblastoma Multiforme (GBM) is the most prevalent type of primary malignant brain tumor, known for its lethal and highly complex nature. In the United States, it is estimated that in 2023, there were 94,390 new diagnoses of primary brain tumors, of which 26,940 were malignant. GBM is a highly malignant, diffuse astrocytoma (Grade IV), accounting for 14.2% of all central nervous system tumors and 49% of all malignant brain tumors, making it the most common primary malignant brain tumor in the U.S., with an incidence rate of 3 cases per 100,000 people. The five-year survival rate for GBM patients is merely 6.9%, with an average overall survival period of 8 months.
  • GBM, the acronym for Glioblastoma Multiforme, is also known as malignant polymorphic neuroglioblastoma. It has a poor prognosis and is prone to recurrence. This brain tumor is one of the most common and aggressive forms, typically occurring in adults and the elderly. Due to the rapid growth and spread of GBM, the chances of survival at the time of diagnosis are typically very low. The average life expectancy for glioblastoma patients who undergo treatment is 12 to 15 months, whereas those who do not receive treatment have an average life expectancy of only 4 months. The life expectancy of GBM patients can be influenced by various factors, including the patient’s age, overall health, the location and size of the tumor, and the extent of tumor resection.
  • GBM originates from the glial cells in the brain, which support and maintain neurons. Symptoms of GBM include headaches, seizures, cognitive impairments, speech and motor difficulties, and more. These symptoms severely impact the patients’ quality of life, and due to its highly malignant nature, treatment is extremely challenging. Early signs of brain cancer may include limping, loss of balance while walking, drowsiness, lethargy, headaches, seizures, blurred vision, double vision, vision loss, and memory decline. If any of these symptoms are present, it is best to seek medical evaluation immediately.
  • The treatment and research of GBM remain focal issues in neurology and oncology. Many institutions and research teams are dedicated to finding more effective treatments and improving survival rates. Current treatment methods include surgical resection, radiotherapy, and chemotherapy. However, due to the aggressive and recurrent nature of GBM, existing treatments have limited effectiveness. Ongoing development of new treatment methods and clinical research aims to provide better prognosis and quality of life for GBM patients.

Background of Glioblastoma Multiforme (GBM)

  • Lack of effective treatment: According to statistics from the American Cancer Society (ACS) and the Central Brain Tumor Registry of the United States (CBTRUS), an estimated 20,000 new brain tumor cases are diagnosed each year, with approximately 400 new cases of malignant gliomas in Taiwan annually. The current conventional therapies for treating malignant brain tumors, including surgical treatment, radiation therapy, and chemotherapy, have very limited efficacy. Furthermore, due to the protection of the blood-brain barrier in the affected area, there are currently no truly curative drugs available, necessitating the development of new-generation therapies.
  • Rapid recurrence and low survival rates: Glioblastoma Multiforme (GBM) can grow up to 16 times its size within one month and is a rapidly worsening primary brain tumor. The recurrence rate after surgery is also very high, often requiring patients to repeatedly undergo hospital treatments. Patients diagnosed with stage IV GBM have an average survival time of only 12 to 18 months. Malignant brain tumors spread rapidly and are challenging to eradicate. Once diagnosed, they are usually in advanced stages, and the average survival period is often around one year. The current standard treatment for malignant brain tumors involves a combination of surgery, radiation therapy, and chemotherapy, all of which have limited effectiveness.
  • Several celebrities have encountered this unfortunate condition: Prominent individuals both domestically and internationally have died from incurable GBM, including U.S. Senators John Sidney McCain and Edward M. Kennedy, British politician Tessa Jowell, and New York Times journalist Tom Wicker.
  • Diagnosis: The most common early symptom of brain tumors is headaches. Clinical symptoms may include headaches, increased intracranial pressure, double vision, and difficulty articulating thoughts, all of which may indicate a possible brain tumor. These symptoms are usually due to the tumor’s growth causing compression and edema in the brain tissues. Therefore, it is essential to be vigilant about any unusual bodily changes. If the above symptoms occur and worsen progressively, they may be related to GBM, making early detection challenging. In 2018, a woman named Mrs. Guo from Tzu Chi Hospital was diagnosed with GBM after experiencing sudden paralysis and collapsing due to dizziness.

Tears of the Queen: Conquering Malignant Brain Tumor - The Real-World Quest for the Holy Grail

The recent popular Korean drama “Queen of Tears” has sparked widespread discussion, with its finale achieving remarkable viewership ratings, making it the highest-rated series on TVN.

In the series, the lead character Hong Hae-rin, portrayed by actress Kim Ji-won, is diagnosed with a severe form of brain cancer (Glioblastoma), with a life expectancy of only three months. This type of brain tumor spreads throughout the brain like mist, with symptoms including headaches, eye blinking, dizziness, and memory loss. The medical condition depicted in the storyline closely resembles glioblastoma multiforme (GBM), a malignant and rapidly progressing primary brain tumor with a high recurrence rate after surgical removal and currently lacking effective treatment options. While the lead character in the drama was fortunate to undergo CAR-T (Chimeric Antigen Receptor T-cell) therapy in Germany and achieve recovery, in real life, as of the end of 2023, there are approximately 15 clinical trials underway for CAR-T therapy in treating brain cancer. These trials still await validation before potentially benefiting patients. Additionally, even with optimal treatment, patients diagnosed with high grade GBM may struggle to attain a survival period exceeding one and a half years.

On the path to developing new therapies for brain cancer, concerted efforts from scientists are essential. Hopefully, in the near future, we will discover the holy grail to conquer malignant brain tumors, enabling real-world patients to experience the same fortune as the protagonist in the drama.

Current Treatment Approaches for GBM

  • Surgical Resection

Surgical resection is the preferred method for treating GBM. The goal of surgery is to remove the tumor as much as possible, reducing the burden of diseased cells and improving patient symptoms and quality of life. However, complete resection is challenging due to the invasive nature of GBM, and usually, only partial tumor removal is feasible. Surgical procedures carry high risks and may result in side effects and neurological damage.

  • Radiation Therapy

Radiation therapy involves using high-energy gamma rays or other forms of radiation to destroy GBM tumor cells. External radiation is delivered from outside the body through machines that emit radiation beams directed at the affected area. The goal is to kill tumor cells effectively. Radiation therapy is a common approach for treating GBM, often used in combination with surgery. It may cause certain side effects, such as fatigue, nausea, vomiting, headaches, and skin redness.

  • Chemotherapy

Chemotherapy involves using chemical drugs to destroy GBM tumor cells. It can be administered alone or in combination with surgical resection and radiation therapy. Chemotherapy can be taken orally or intravenously, entering the bloodstream and reaching tumor cells to kill them. However, chemotherapy may also have toxic side effects on the body, such as hair loss, nausea, vomiting, and decreased immunity.

  • Immunotherapy

The core concept of immunotherapy is to harness the body’s immune system to attack and destroy brain tumor cells. Patients may receive certain medications that help rebuild or enhance their immune system, enabling it to more effectively target brain tumor cells.

  • Electrical Field Therapy (Medical Device, Non-pharmaceutical)

The FDA has approved a medical device named Optune GIO for use in adults aged 22 and above. It has recently been approved for marketing by the Taiwan Ministry of Health and Welfare for use in adults aged 18 and above. This tumor electrical field therapy is a form of cancer physical therapy that utilizes alternating electric fields adjusted to specific frequencies. Through various mechanisms, it selectively targets and destroys tumor cells.

Brain Cancer Classification

Brain cancer is a complex and diverse disease that can be subdivided into different types based on cytological and molecular characteristics. Accurate classification of brain cancer is crucial for selecting appropriate treatment strategies. Understanding the molecular and biological features of brain cancer can help physicians choose the most suitable treatment for patients, thereby improving treatment efficacy and survival rates.

The main classification schemes for brain cancer are as follows:

1. IDH (Isocitrate Dehydrogenase) Gene Mutation Status

IDH gene mutation is a key factor influencing brain cancer classification and prognosis, and confers differential sensitivity to specific treatments. Based on IDH mutation status, brain cancer can be divided into two major categories:

  • IDH-wildtype: In this type, the IDH gene is not mutated. Patients with IDH-wildtype brain cancer generally have a poorer prognosis and respond worse to chemotherapy and radiation therapy. Common IDH-wildtype brain cancers include glioblastoma (GBM) and small cell glioblastoma (scGBM).
  • IDH-mutant: This type harbors mutations in the IDH1 or IDH2 genes. IDH-mutant brain cancers typically have a better prognosis and respond better to standard treatments. Common IDH-mutant brain cancers include oligodendroglioma (ODG) and astrocytoma (AC).

2. Histopathological Classification

In addition to IDH mutation status, brain cancer can also be classified based on histopathological features, primarily including the following types:

  • Glioma: Gliomas originate from glial cells in the brain and are the most common type of brain cancer. Based on the degree of cellular differentiation, they can be graded from I to IV, with grade IV being glioblastoma (GBM), which has the worst prognosis, and grades I-III being lower-grade gliomas.
  • Medulloblastoma: Medulloblastoma is a common malignant brain cancer in children, primarily occurring in the cerebellum.
  • Meningioma: Meningiomas arise from meningeal cells and are mostly benign tumors, although some are malignant.
  • Pituitary Tumor: Pituitary tumors occur in the pituitary gland and can be classified as functional or non-functional.

3. Molecular Subtype Classification:

In addition to IDH mutation status, brain cancers can also be classified based on other molecular subtypes, such as MGMT methylation status, 1p/19q chromosomal deletions, etc. These molecular subtypes can help physicians more accurately predict patient responses to treatment and prognosis.

Current Treatment Reference Drugs

Treating glioblastoma multiforme (GBM), a particularly challenging form of brain cancer, presents numerous obstacles.

Gliadel® Wafer (Carmustine Implant)
  • Gliadel® Wafer is an implantable treatment for GBM (Glioblastoma Multiforme). It is a biodegradable polymer-based circular wafer containing the chemotherapy drug Carmustine. Each wafer has a diameter of approximately 1.45 mm and a thickness of about 1 mm.

  • Gliadel® Wafer is used during brain tumor resection surgery. After the surgical procedure, the surgeon places the wafers at the site of tumor removal, with a maximum of 8 wafers allowed. Carmustine is released from the wafers and forms a high-concentration region around the remaining tumor, effectively killing the residual tumor cells, thereby extending the survival of GBM patients. (One of the most direct ways to breach the blood-brain barrier)

  • Clinical trials of Gliadel® Wafer have shown that the median overall survival for newly diagnosed patients was 13.8 months compared to 11.6 months in the placebo group. For recurrent patients, the median overall survival was 7.4 months with Gliadel Wafer compared to 5.5 months in the placebo group. (Source: Investigator’s Brochure)

  • Possible side effects may include seizures, brain edema, abnormal wound healing, and infections. Patients using Gliadel® Wafer need to be closely monitored for possible side effects.

Avastin® (bevacizumab)
  • Avastin® is a biopharmaceutical that contains the monoclonal antibody bevacizumab and is used for the treatment of brain tumors, including GBM.

  • The mechanism of action of Avastin® involves the inhibition of tumor angiogenesis, thereby slowing down or blocking tumor growth. It is used for the treatment of recurrent malignant gliomas (WHO Grade 4) – glioblastoma multiforme (GBM) in adult patients who have previously received standard radiation therapy and chemotherapy, including temozolomide, but the treatment has failed. (Source: Investigator’s Brochure)

  • Avastin® is administered intravenously, typically once every two weeks, until disease progression occurs. Common side effects of Avastin® include hypertension and bleeding.

  • Based on clinical trial data, the median overall survival for recurrent patients using Avastin® was 9.3 months, which is longer than the placebo group with 8.8 months. (life expectancy after avastin treatment)

TEMODAL (Temozolomide)
  • TEMODAL has antitumor activity and is an alkylating agent containing the imidazotetrazine ring. In the systemic circulation, it rapidly undergoes chemical transformation to form the active compound MTIC (Monomethyl triazeno imidazole carboxamide) under physiological pH conditions. The theoretical cytotoxicity of MTIC is mainly attributed to its alkylation of the sixth oxygen atom of guanine, and it also undergoes minor additional alkylation at the seventh nitrogen atom of guanine, leading to subsequent cytotoxicity believed to be associated with these aberrantly repaired methylated compounds. (Source: Investigator’s Brochure)

  • TEMODAL is administered orally and is combined with radiation therapy. The treatment duration depends on the patient’s condition and may continue up to 2 years, typically ranging from 6 to 12 months. Side effects may include nausea, vomiting, and others.

  • Clinical trial data shows that the median overall survival for recurrent patients using TEMODAL was 5.8 months.

 

Current Treatment Medical Devices

Optune GioTM
  • Tumor Treating Fields (TTFields) is a portable physical therapy for cancer that utilizes alternating electric fields adjusted to specific frequencies. Through various mechanisms, it selectively targets and destroys tumor cells. The key mechanisms include:

  1. Interference with mitosis
  2. Downregulation of DNA damage repair
  3. Enhancement of downstream anti-tumor immunity
  4. Interference with tumor cell migration
  • It can be used in newly diagnosed or recurrent adult glioblastoma patients who have undergone surgery, radiation therapy, and targeted drug therapy.

  • When used in conjunction with chemotherapy (TMZ), the most common side effects include decreased platelet count, nausea, constipation, vomiting, fatigue, scalp irritation caused by the device, headache, seizures, and depression. When used alone, the most common side effects of Optune Gio are scalp irritation (redness and itching) and headache. Other side effects include malaise, muscle twitching, falls, and skin ulcers.

  • Approved by the Taiwan Ministry of Health and Welfare in May 2023, it falls under self-pay, with an approximate monthly cost of $10,000 USD.

(Note: The image is for illustrative purposes only and does not represent the appearance of Optune Helmet.)

Investigational Drug

CEREBRACA® WAFER
CEREBRACA® WAFER <Phase IIa>  >>more
  • Cerebraca® Wafer developed by Everfront Biotech Inc. is a therapeutic drug wafer that can be used to treat highly malignant glioblastoma (malignant brain cancer). It can be directly implanted into the brain and slowly releases drugs at a high concentration, high penetration, and long duration for about 1 month, exerting a multi-target effect (EF-API-001) that helps to treat cancer and make cancer cells more susceptible to chemotherapy or immune cell killing.
  • Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor that can grow up to 16 times its original size within a month. It has a high rate of recurrence after surgical resection, and there are currently no effective treatment options available.
  • EF-API-001the small molecule active pharmarceutical ingredient  in Cerebraca® Wafer, has the following characteristics:
    • Targeting Axl-1 receptor tyrosine kinase: effectively inhibits the growth and metastasis of brain tumor stem cells.
    • Inhibiting the PD-L1 immune checkpoint: reduces the immune suppressive nature of the tumor microenvironment, thus preserving the activity of immune cells to kill tumor cells. 
    • Inhibition of MGMT DNA repair enzyme: overcomes resistance to Temozolomide (chemotherapy drug) and enables cancer cells to be killed again by chemotherapy.
  • Cerebraca® Wafer, its small molecule active ingredient and biodegradable polymer are all manufactured by internationally renowned PIC/S GMP pharmaceutical companies in Taiwan to ensure high quality and reliable aseptic manufacturing processes.
 
AMG-193 <Phase II>
  • AMG-193 is under clinical development by Amgen and currently in Phase II for Brain Tumor.
  • AMG 193 is an MTA-cooperative PRMT5i that preferentially targets the MTA-bound state of PRMT5 that is enriched in MTAP-null tumors and represents a novel strategy to increase the therapeutic margin of this class of inhibitors.
PF-07799544 (ARRY-134)  <Phase I>
  • PF-07799544 (ARRY-134) is under development for the treatment of solid tumors by Pfizer including primary brain tumor and metastatic melanoma.
  • It is administered through oral route in the form of tablet.

GBM Recovery: Living Care and Precautions

Adequate Rest

During the GBM recovery period, it is essential to have sufficient rest and sleep to aid in cell repair, enhance the immune system, and reduce fatigue. If in the advanced stages of brain cancer, as the tumor continues to grow, symptoms like headaches, dizziness, memory loss, weakness, and seizures may arise, making adequate rest even more crucial to maintain physical strength.

Balanced Diet

A well-balanced diet can assist in body restoration and improve physical strength. It is advisable to consume fresh vegetables and fruits while reducing the intake of high-fat, high-sugar, and processed foods. It is essential to follow the physician’s advice for a balanced diet.

Moderate Exercise

Engaging in light exercises such as walking, yoga, or tai chi during the recovery period can help in physical rehabilitation, alleviate fatigue, and boost immunity.

Adherence to Medication and Prescription Instructions

Proper and timely administration of medication, as instructed by the doctor, is crucial in treating GBM. During medication therapy, regular follow-ups and check-ups are necessary to enable doctors to make timely adjustments to the treatment plan.

Psychological or Spiritual Therapy

Both GBM patients and their family members often experience significant emotional stress and pressure. Psychological or spiritual therapy can help relieve stress, enabling patients and families to face the disease more positively and maintain a better quality of life.

Safety Precautions

Patients undergoing hospital or home-based GBM recovery must pay special attention to safety measures and precautions. Monitoring the living environment and taking steps to prevent falls and other accidents are essential for patient safety.

Reference

Brain Cancer Support Website

This article is provided for informational purposes only regarding industry information. The development of new drugs involves lengthy timelines, high financial investments, and is not guaranteed to be successful. These factors may expose investors to risks, and therefore, investors should exercise caution and prudence when making investment decisions.

Development Pipeline