Science
Glioblastoma Multiforme is an incurable and devastating brain cancer
When it comes to cancer most stories focus on survivors and miracles. People want to hear uplifting accounts filled with hope, positivity, and war metaphors to describe what the cancer patient went through. Most stories tell of fighting and battling cancer, suggesting that cancer can be defeated if one just fights hard enough. That is not always so. Sometimes cancer can not be defeated, no matter how hard the patient and the doctors “fight”. Cancer is an illness. A disease that sadly kills people every day. Cancer killed my mother. By some luck of the draw she got one of the most, if not the deadliest of tumors — Glioblastoma Multiforme. There is very little fighting that one can do when faced with glioblastoma.
Glioblastoma (GMB) is the most aggressive and fatal form of primary brain tumors — that originate in the tissues of the brain (namely neurons and glial cells). No cure is available. Even with optimal treatment, this devastating brain cancer typically results in death in the first 15 months after diagnosis. It is estimated that 240,000 people are diagnosed with GBM per year, worldwide. My mother was diagnosed with glioblastoma multiforme grade IV. She underwent surgery to remove the tumor, followed by radiation and chemotherapy. I like to believe that these treatments gave her more time, but cancer grew back rapidly and seemed not deterred by radiation and chemotherapy. She survived only 8 months after the diagnosis.
Why is glioblastoma so hard to treat?
The conventional treatment for glioblastoma is surgical excision of the tumor, followed by radiation therapy and chemotherapy. The most advanced chemotherapy drug used in GBM is temozolomide (TMZ).
However, this conventional treatment is met with a number of challenges; Firstly complete removal of the tumor is difficult. GBM tumors have tentacles that infiltrate and extend into surrounding normal brain tissue. This means they can recur and grow back (and they almost always do). This is where radiation and chemotherapy come in. These treatments are used to try and limit the growth of any tumor that remains after surgery. They are well proven to slow the progression of the disease, but glioblastomas are rapidly growing tumors. They are spidery, they change and morph and they almost always outpace these treatments and develop radiotherapy and chemoresistance. Another big hurdle comes from the fact that this biologically aggressive tumor is localized in the brain, and the brain has a limited capacity to repair itself. All these factors combine to make for very poor patient outcomes.
Is there any hope for a better prognosis?
Various research has focused on a few novel approaches to try and address the overwhelmingly poor treatment results for patients currently diagnosed with glioblastoma. There is a need to overcome the chemoresistance and inhibit recurrence of the tumor growth after surgical removal. The following is a brief look at two of the most promising scientific studies on GBM and efforts to find treatments that can improve the outcome for patients.
Lumefantrine- an anti-malarial drug may improve the success rate of radiation and chemotherapy in GBM
Lumefantrine, already approved by the Food and Drug Administration to combat malaria, can enhance the effectiveness of the primary drug used to treat GBM.
Proteins called Heat Shock proteins have been shown to contribute to the development of radio/temozolomide-resistant GBM. Heat shock proteins are stress proteins that protect cells exposed to harmful conditions. They play an important role in inducing cancer cell resistance to anticancer chemotherapy drugs. There is an elevated expression of the heat shock protein called HSPB1 in GMB and in radiation-resistant/temozolomide-resistant GBM. A protein, identified as Friend Leukemia Integrated 1 (FLi-1) transcriptionally regulates the HSPB1 gene. FLi-1 has subsequently been linked to oncogenic transformation in radiation and temozolomide-resistant GBM. The overexpression of FLi-1 in GBM promotes resistance. If FLi-1 is inhibited, resistance is suppressed, making FLI-1 a potential therapeutic target for combating radiation and temozolomide-resistant GBM. This link led to the search for targeted molecules that inhibit Fli-1. Screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor.
Lumefantrine has been shown to inhibit the growth of the tumor by targeting the Fli-/HSPB1 signaling pathway. These studies are preclinical but show lumefantrine as a potential drug for the management of glioblastoma, which may help improve the success rate of radiation and chemotherapy treatments.
Although the safety profile of lumefantrine is appropriate for clinical use, further studies are needed to determine the efficiency of this new anti-glioblastoma drug to pass the blood-brain barrier.
The blood–brain barrier (BBB) is a selective network of blood vessels and tissue that allows vital nutrients to reach the brain but keeps harmful substances from crossing into the brain. While it is very effective at preventing unwanted substances from accessing the brain, it means that potential drug treatments for mental and neurological disorders and diseases such as GBM can not readily cross the barrier either.
The BBB presents a stumbling block to the delivery of drug therapies to the brain. Targeted approaches are necessary to ensure drugs can reach tumors in the brain.
Synthetic protein nanoparticles
The second approach which could greatly improve GBM outcomes involves an engineered synthetic nanoparticle capable of passing the nearly impermeable BBB in mice. It is made using a protein called human serum albumin, which is one of a few molecules that can cross the BBB. The nanoparticle carries a STAT3 inhibitor. STAT3 is a signal that is activated in many cancers and plays a role in tumor growth and metastasis. It controls cellular proliferation and invasion, allowing cancer to grow unabated within the brain. This synthetic nanoparticle has been successfully delivered to GBM tumors in mice. Researchers showed that, in combination with radiation therapy, the injection of the nanoparticles led to long-term survival in mice, and no recurrence of cancer’s growth.
The study demonstrates that synthetic protein nanoparticles are an effective vehicle for the delivery of biological therapeutics.
These advances in scientific research present promising opportunities to broaden the effectiveness of current treatments for glioblastoma. Other substantial efforts involve immunotherapies and trials to deliver drugs directly into the tumor.
It is clear that there is a strong desire to change the inevitable outcome of a glioblastoma diagnosis. There is no doubt that one or more of these therapies or innovations will provide the ultimate game-changer, and give rise to increases in survival, and a new sense of hope that hasn’t always been the case with this devastating disease.
