Glioblastoma

What Causes Glioblastoma?

The root cause of a brain tumor is a mutation or damage in the genes that control the growth of affected cells. In healthy cells, these genes prevent the cell from growing or reproducing too rapidly, and the genes can also determine the cell’s normal lifespan. In a tumor’s cells, the damage to the genes causes the cells to grow and reproduce rapidly, and the cells may live longer than usual. As this rapid growth and reproduction continues, the cells grow into an abnormal mass. In some cases, the tumor produces chemicals that stop the body’s immune system from fighting the cancer, and the tumor cells may also trigger an increase in blood supply to support their growth.

The specific cause of the gene damage that triggers a tumor’s formation is usually not identifiable. In rare cases, glioblastomas appear to be associated with certain genetic disorders, including:

• Neurofibromatosis type 1
• Turcot syndrome
• Li Fraumeni syndrome

Is Glioblastoma Hereditary?

Most glioblastomas do not appear to be linked to inherited traits. Instead, researchers believe most gene changes that cause tumors come from external environmental factors or changes within cells that occur randomly and with no external trigger.

However, the specific genetic syndromes sometimes associated with glioblastomas run in families. These syndromes are inherited in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

How Is Glioblastoma Detected?

Because glioblastomas tend to grow rapidly, symptoms often come on suddenly. When symptoms do present, they may vary depending on the location of the tumor and its growth rate. Some symptoms, such as headaches or nausea, are likely caused by pressure created as the tumor presses on surrounding brain tissue. Neurological symptoms, such as vision problems or weakness, may result from the specific areas of the brain affected by the tumor’s growth.

Some common warning signs of glioblastomas include:

• Headaches, especially when the patient has no history of headaches or the pattern or severity of headaches changes
• Nausea or vomiting that doesn’t have another apparent cause
• Problems with balance
• Blurred vision, double vision, or loss of peripheral vision
• Loss of strength on one side of the body
• Seizures

How Is Glioblastoma Diagnosed?

Doctors may take several different diagnostic steps when they suspect that a patient may have a glioblastoma.

• Neurological exam. A basic neurological exam will test a patient’s reflexes, balance, coordination, strength, vision, and hearing. The results of this exam may prompt a doctor to look further for a tumor’s presence, and it may give a clue to the affected part of the brain, if any.
• Imaging. Imaging technologies are non-invasive ways to look at brain tissue and possibly detect a tumor’s presence. They may also be used to judge the tumor’s size, location, and growth. Magnetic resonance imaging (MRI) uses a strong magnetic field to produce images of the brain and central nervous system. Computerized tomography (CT) scan may also be used to look for tumors.
• Biopsy. Doctors may require a biopsy, in which a sample of the tumor is removed and analyzed by a pathologist. The biopsy might be conducted with surgery or, if the tumor is in a particularly hard-to-reach area, using a needle guided by imaging technology. A pathologist’s examination of the tissue sample can help suggest the best treatment course.

How Is Glioblastoma Treated?

Glioblastoma is generally not curable, and treatments aim to control the tumor’s growth for as long as possible. Surgery to remove the tumor is typically the first step, but the cancer’s growth into healthy brain tissue usually makes it impossible to completely remove all the cancer cells. Because of this, follow-up treatments with radiation and/or chemotherapy are necessary.

Surgery

The most direct way to treat a brain tumor is to remove as much of it as possible with surgical intervention. Typically, the surgery involves opening the skull and removing the tumor while being careful not to damage the surrounding healthy tissue. However, when a tumor is located in an especially sensitive area or has infiltrated a critical part of the brain, the surgeon may not be able to remove all of the tumor, and other subsequent treatment options may be necessary.

Radiation Therapy

Radiation therapies involve using high-energy x-rays to target and kill tumor cells directly. The radiation beams are typically focused on the tumor so they do not damage healthy cells. Radiation therapy is often used when the tumor can’t be entirely removed with surgery.

Side effects of radiation therapy may include headaches, memory loss, fatigue, and scalp reactions.

Chemotherapy

Chemotherapy uses chemicals that intentionally damage the body’s cells with the expectation that healthy cells can more easily recover from the damage than tumor cells can. Chemotherapy can effectively treat some tumors, but its success rate is not high in treating most brain tumors. One obstacle is the body’s blood-brain barrier, a border of cells that protects the brain by blocking the transmission of many substances from the circulatory system into the vulnerable brain tissue. The blood-brain barrier may prevent chemotherapy drugs from reaching the tumor.

Other Therapies

Some other therapies may help to slow the growth of glioblastomas.

• Tumor treating fields (TTF) use electric fields administered through electrodes on the scalp. The electric fields can interfere with the cancer cells’ ability to reproduce.  
• Targeted drug therapies use medications to attack vulnerabilities unique to the tumor cells, leaving healthy cells alone.

How Does Glioblastoma Progress?

Because of the rapid growth rate of the tumor and treatment difficulties, the long-term outlook for people with glioblastoma is generally poor. Many people with this type of cancer do not survive for more than a year after diagnosis.

However, some factors can increase the possibility of a better outcome or a longer life expectancy. These factors include:

• Age at diagnosis. Younger people tend to have a better prognosis.
• Relatively low level of impairment at diagnosis using a measurement called the Karnofsky Performance Status Scale
• Prompt treatment with radiation and/or chemotherapy
• Successful surgery to remove the tumor

How Is Glioblastoma Prevented?

There is no clear way to prevent a glioblastoma from occurring. Even the lifestyle changes that can decrease the risk of many other types of cancer, such as quitting smoking or maintaining a healthy weight, may not reduce the chance of developing a brain tumor.

The only widely accepted preventative measure for brain tumors is the avoidance of high doses of radiation to the head.

Glioblastoma Caregiver Tips

Caring for someone with a brain tumor can be even more challenging than the already high demands of caring for someone with any other type of serious, progressive illness. Along with the physical changes that make other cancers and serious illnesses so physically and emotionally exhausting to deal with, brain tumors also often produce psychological and cognitive changes in the patient that can threaten the caregiver’s well-being, too.

As you care for your loved one through the progressive stages of their illness, keep these tips in mind:

• Learn as much as possible about the potential effects of your loved one’s specific type of brain tumor. This will allow you to understand how the illness affects the sufferer’s behavior.
• Get help from your friends and family. Caring for a brain tumor patient is a huge task, and you shouldn’t try to do it alone.
• Take time whenever possible to step away from the patient and the illness and find time for yourself. Acknowledge that it is normal and acceptable to need occasional relief from caregiving burdens.
• Find a support group. It can be beneficial to learn that you are not alone and that other people understand what you are going through.

Many people with glioblastomas also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with these tumors:

• People with brain tumors often experience depression or anxiety.
• Personality changes resembling bipolar disorder are sometimes an indication of a brain tumor.

Glioblastoma Brain Science

Researchers are currently working on projects to increase our understanding of brain tumors and improve patients’ prognoses. Research is ongoing in areas ranging from risk factor identification to early diagnosis and more effective treatment.

Some currently active areas of research include:

• Gene research. Scientists are working to understand who is at risk for developing glioblastomas and find ways to prevent the development of the tumors.
• Blood-brain barrier research. Scientists are also trying to find ways to temporarily and safely disrupt the blood-brain barrier so that drug treatments can more effectively be delivered to the site of tumors.
• Targeted drugs and viral therapies. Research is ongoing into drugs and viral agents that can precisely and effectively attack cancer cells without damaging healthy cells.
• Imaging technologies. New imaging technologies are being developed that may detect tumors at earlier stages or monitor the effects of treatment on existing tumors more closely.

Glioblastoma Research

Title: Longitudinal Assessment of Marrow and Blood in Patients With Glioblastoma (LAMB-G)

Stage: Recruiting

Principal investigator: Peter Fecci, MD, PhD

Duke University Medical Center

Durham, NC

The investigators’ recent studies show that large numbers of T cells in patients and mice with intracranial tumors are sequestered in the bone marrow. This phenomenon mysteriously confines a pool of functional, naïve T cells with anti-tumor capacity to a compartment where they are unable to access the tumor, eliciting a mode of T cell dysfunction categorized as “ignorance.” The investigators have uncovered that loss of the sphingosine-1-phosphate receptor 1 (S1P1) from the surface of T cells mediates their sequestration in bone marrow while blocking internalization of S1P1 facilitates stabilization of the receptor on T cells and frees them for anti-tumor activities. As the investigators look to design interventions targeting β-arrestin mediated S1P1 internalization as a novel anti-tumor strategy, they need to better understand variations in sequestration across patients, over time, and with treatment. Assessing these variations and biomarkers that may accompany them will help establish a target treatment population and the optimal timing for intervention.

Primary Objectives:

• Assess variations in blood and bone marrow T cell counts as they relate to treatment time-points in patients with glioblastoma (GBM).
• Assess variations in S1P1 levels and their correlation with blood and bone marrow T cell counts over the course of treatment in patients with GBM

Exploratory Objectives:

• Assess the associations between tumor size and degree of lymphopenia and bone marrow T cell sequestration observed.
• Compare The Cancer Genome Atlas (TCGA) subclasses concerning the degree of lymphopenia and bone marrow T cell sequestration observed at diagnosis.
• Examine patient plasma, tumor supernatant, and tumor ribonucleic acid (RNA) for markers associated with lymphopenia, T cell S1P1 levels, and bone marrow T cell sequestration. Initial candidates will include transforming growth factor-β (TGFβ) 1/2, tumor necrosis factor (TNF), interleukin (IL)-33, IL-6, catecholamines, signal transducer, and activator of transcription 3 (STAT3) RNA, and Kruppel-like factor 2 (KLF2) RNA.
• Compare T cell phenotypes in the blood and bone marrow of patients exhibiting versus not exhibiting T cell lymphopenia or sequestration.
• Compare differences in tumor-infiltrating lymphocyte numbers and phenotypes between patients with and without lymphopenia/sequestration at diagnosis.
• Establish baseline β-arrestin 1 and 2 expression in patients and assess variation across individuals.
• Archive samples for subsequent assessment of β-arrestin recruitment to the cytoplasmic component of T cell S1P1 and the capacity to inhibit such recruitment in vitro with candidate small molecules.

Title: AB154 Combined With AB122 for Recurrent Glioblastoma

Stage: Recruiting

Principal investigator: Antonio Omuro, MD

Yale University

New Haven, CT

This is a phase 0/I exploratory study. Patients at the first or second recurrence of glioblastoma will be enrolled. The study will be divided into two cohorts: Cohort A (safety cohort) and Cohort B (surgical patient cohort).

Cohort A: Eligible patients will be sequentially enrolled to receive intravenous AB154 combined with AB122 (N=6). AB154 will be given at a dose of 10 mg/kg, and AB122 will be given at a dose of 240 mg (flat).

Cohort B: Expansion surgical cohort. The purpose of cohort B is to provide an additional safety evaluation of AB154 + AB122 as well as tissue and blood for exploratory ancillary studies investigating the effects of AB154 + AB122 in the tumor and tumor microenvironment. A total of 40 patients will be enrolled in this cohort.

Title: Paxalisib With a High Fat, Low Carb Diet, and Metformin for Glioblastoma

Stage: Not Yet Recruiting

Principal investigator: Howard Fine, MD

Weill Cornell Medicine

New York, NY

This study is for patients with newly diagnosed glioblastoma and patients who have recurring glioblastoma. Subjects will be given daily paxalisib and metformin while also maintaining a ketogenic diet.

The purpose of this study is to assess the safety of paxalisib while maintaining a ketogenic diet (a high fat, low carbohydrate diet) and metformin (a drug approved by the Food and Drug Administration to treat type 2 diabetes) and to see what effects it has on glioblastoma.

This is a two-stage, two cohort phase 2 trial of a new blood-brain penetrant PI3K/mTOR inhibitor (paxalisib) combined with a ketogenic diet plus metformin in patients with either newly diagnosed MGMT unmethylated glioblastoma or patients with recurrent glioblastoma regardless of MGMT promoter methylation status.