Current Research Efforts:

Research for brain cancer is underfunded and exceedingly complex due to the need to mitigate cognitive side effects with the desire to slow tumor growth. Unfortunately, progress in the research lab seldom translates into progress in real world patients. Recent research has shown some promise in lengthening remission time, but a cure has yet to be discovered. The present standard of care for brain tumors is surgery, which due to the diffuse nature of the tumor cannot remove all of the malignant cells, followed by radiation treatment and chemotherapy, usually temozolomide (brand name Temador). While this treatment lengthens and possibly doubles the life expectancy of brain cancer patients, the tumor eventually returns, usually in a more aggressive and chemo-resistant form.

Despite this grim state of affairs, there is still room for hope. Researchers are working on new possibilities: examining the possible role viruses play in tumor growth; creating vaccines that are tailored to the specific makeup of individual tumors; examining methods of starving the tumors by restricting their blood supply; and considering the effectiveness of multipronged approaches, such as attacking tumor with radiation and chemotherapy simultaneously or combining chemotherapy treatment.

Update November 28, 2011:

Will Power Research Fund donated funding to support a laboratory technician to assist with the Phase 1 clinical trial run by Dr. Juan Fueyo and his wife, Dr. Candelaria Gomez-Manzano. The preliminary results, which Dr. Fueyo generously shared with us, are extremely promising and we have decided to make another gift of $25,000 to support this exciting research. Stay tuned for more information when the results of the trial are finalized! Here is a desription of the trail from Dr. Fueyo:

"Delta-24 a replication-competent tumor-selective adenovirus holds promise as a novel anti-glioma treatment. In an ongoing Phase I clinical trial at M.D. Anderson over 20 patients with recurrent malignant gliomas have been treated to date. Delta-24 was injected intratumorally and was generally well-tolerated. Although preliminary, current results demonstrate the potential of this treatment platform."

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Delta-24-RGD is being studied by Dr. Juan Fueyo and his wife, Dr. Candelaria Gomez-Manzano. It is an andenovirus, the kind that causes the common cold, which has been modified to attack glioma cells (brain cancer cells), but not healthy human cells. Like many cancer cells, glioma cells lack retinoblastoma protein (pRb), a protein that prevents unrestrained cell division. The absence of pRb is one of the reasons cancer cells develop into deadly tumors. Delta-24-RGD is designed to attack only cells that lack this protein, so unlike chemotherapy and radiation, it does not harm healthy cells. When the virus attacks a cancer cell, it takes control of the cell’s replication machinery and forces the cell to produce more viruses. These newly generated viruses can then attack even more cancer cells

Studies using mice infected with human glioblastoma tumors have been very promising. Survivability was significantly increased, with 60% of the mice apparently cured. While studies with mice are quite preliminary, this is an especially encouraging result because Delta-24-RGD managed to destroy the glioma’s brain stem cells via autophagy (self-cannibalism). The virus forced both the “adult” glioma cells and the cancer’s brain stem cells to self-cannibalize. The ability to eliminate the cancer’s stem cells is crucial for curing brain cancer because these stem cells tend to be less susceptible to chemotherapy and radiation, which is theorized to be a primary cause for the recurrence of brain cancer.

Delta-24-RGD also holds promise because it might make glioma cells more vulnerable to other treatments. For example, a study published in 2007 suggested that Delta-24-RGD may have a synergistic effect when combined with temodar(temozolomide). Temozolomide is the present gold standard chemotherapy treatment for gliomas. Temozolomide works by hindering the glioma cell’s ability to replicate its DNA. Unfortunately, some of the cancer cells retain the ability to repair their genome, so they can renew replication of their DNA, allowing the tumor to eventually return.

This resistance limits temozolomide’s efficacy in many patients. When the Delta-24-RGD virus infects a host cell it must mitigate the host cell’s DNA repair mechanism in order to successfully take control of the cell’s transcription machinery. Thus, when Delta-24-RGD attacks a glioma cell, it has the added affect of making the glioma cell more vulnerable to temozolomide, because it takes control of the mechanism that the cell uses to restore its ability to transcribe DNA. So the virus acts like a double-edged sword increasing temozolomide’s efficacy with one slice while simultaneously destroying glioma cells with another slice.

In addition, because viruses force cells to express their genes, Drs. Fueyo and Gomez-Manzano are looking into using Delta-24-RGD to make gliomas more susceptible to vaccines like CDX-110, the vaccine in development at Duke University (see in Brain Cancer News Oct. 2009). These vaccines work by training the patient’s immune system to attack cells expressing particular protein receptors predominant in glioma cells, epithelial growth factor receptor variant III (EGFRvIII) in CDX-110’s case. Unfortunately, these types of receptors are not expressed by all gliomas, rendering the vaccines ineffective in these patients. Delta-24-RGD can, possibly, combat this by forcing the infected glioma cells to transcribe the requisite receptor proteins, making them susceptible to the vaccine.

At present, a phase I clinical trial is being conducted on humans. In this trial, Delta-24 will be injected into brain tumors through a surgically implanted catheter. After a couple of weeks, the tumors will be removed and examined. Later, however, researchers hope to use mesenchymal stem cells, as a Trojan horse to deliver the virus to the tumor. These stem cells are attracted to tumors, even when the tumor is garrisoned behind the blood-brain barrier. By hiding the virus inside the stem cells, it could be delivered directly to the tumor without detection by the patient’s immune system and, once inside, destroy it.

While research on Delta-24-RGD is still in the preliminary stages, it is the kind of research we are interested in because it entails looking at a cure for brain cancer using a fresh approach and it encourages seeking multipronged treatments for gliomas. We believe this kind of innovative research is the most hopeful.

For a report from MD Anderson Cancer Center commenting on this research:

http://www2.mdanderson.org/depts/oncolog/articles/07/11-nov/11-07-1.html

From the Journal of the National Cancer Institute

Modified Adenovirus Offers New Approach to Treating Aggressive Brain Tumors

Will Power Research Fund recently gave $10,000 to a pilot study run by UCSF that attempts to quantify the cognitive and emotional effects of brain cancer treatment.

I met with the lead researchers (Dr. Chang and Dr. Racine pictured below) of this study on the Thursday after my most recent MRI in order to learn more about their proposed goals and methods. I was impressed, and after discussing the merits of their pilot study with my family, we decided to make a donation to help support their work.

The main impetus for this study comes the improved prognosis for recurrence and survivability for brain cancer patients due to more effective treatments. This has made patient’s quality of life more important. Traditional cancer treatments “Slash/Burn/Poison” (surgery/radiation/chemotherapy) are notorious for causing side effects that can, at times, seem worse than the disease. In fact, many of the symptoms usually associated with cancer (hair loss, nausea, fatigue) are actually side-effects from treatment. The added complications of using these treatments in the brain can lead to severe neurocognitive deficits, including memory loss, reduced fine motor skills, speech impediments, attention deficits, and other faculties. However, these long-term effects are only beginning to concern patients, because improvements in treatment are allowing them to live long enough for side-effects to become a concern. I have actually noticed a personal memory deficit in comparison with my pre-treatment self, particularly regarding my vocabulary and concentration ability.

According to the group at UCSF, cognitive effects of brain cancer treatment are currently measured and considered, but the measurements are much too coarse and rely on tests that are comically simple and heavily skewed towards the low end of the mental spectrum. In other words, a “high-functioning” individual may be noticeably duller (so to speak) post-treatment, but still be given a top score by the test because he/she is still a fully functioning adult. This is only a minor consolation to the individual since their personal quality of life is still significantly diminished. Unfortunately, more elaborate tests that would provide greater resolution of neurocognitive ability are impractically time consuming and costly to administer. As patients and physicians become increasingly concerned about the long-term quality of life consequences of brain cancer and its treatment, the need for an efficient mechanism for measuring cognitive changes in patients is emerging rapidly.

The main goal of the UCSF study is to use advanced cognitive tests and high-resolution MRI images to find correlations between the physical and mental effects of cancer treatment. Quite a bit of research is available regarding the effect of traumatic brain injuries on cognition, but radiation damage is different in a number of ways. Most significantly, brains show some capacity to heal or adapt following a traumatic injury, but little to none following radiation damage. This may be a result of the extreme novelty of high dosage radiation applied to the brain in human evolution. The hope is that MRI images could replace the intense neurocognitive testing process. For (a rather coarse) example, indications of damage to the left temporal lobe would likely be an accurate indicator of a speech deficit. Mental side-effects of treatment options could be evaluated quantitatively using imaging studies, creating a reliable metric for monitoring neurocognitive side-effects and (hopefully) lead to treatment evaluations that more effectively consider quality of life. The MRI studies potentially also allow for the development of a “susceptibility map” of the brain, identifying the areas most vulnerable to radiation. This information would be invaluable for patients and doctors to more accurately evaluate the costs and benefits of treatment.