Brain Tumors: New Hope?

What You Need to Know: Targeted therapies are a growing and groundbreaking field in cancer care in which drugs or other substances are designed to interfere with genes or molecules that control the growth and survival of cancer cells. Now, scientists have identified a novel interaction between a microRNA and a gene that could lead to new therapies for the most common and deadly form of brain tumor, malignant glioma.

Background: Scientists at Virginia Commonwealth University (USA) have identified a novel interaction between a microRNA and a gene that could lead to new therapies for the most common and deadly form of brain tumor, malignant glioma.

Details, details: Investigators provided the first evidence of an important link between a specific microRNA, miR-184, and a cancer promoting gene, SND1, in the regulation of malignant glioma. miR-184 is known to suppress tumor development by regulating a variety of genes involved in cancer growth, while SND1 has been shown to play a significant role in the development of breast, colon, prostate and liver cancers. Through a variety of preclinical experiments, the team demonstrated that increasing the expression of miR-184 slows the growth and invasive characteristics of glioma cells through direct regulation of SND1. Additionally, they showed that reduced levels of SND1 led to reduced levels of STAT3, a gene that has been shown to promote the most lethal characteristics of brain cancer.

“Patients suffering from brain tumors are in desperate need of improved therapies,” says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM. “We’re hopeful that this new understanding of the relationship between miR-184 and SND1 ultimately will lead to the development of new drugs that reduce SND1 expression and improve patient outcomes.”

Prior studies have shown that levels of miR-184 are unusually low in tissue samples from patients with malignant gliomas. Using advanced computer analysis techniques designed to study and process biological data, the researchers identified SND1 among a handful of other genes that miR-184 helps regulate. Knowing SND1 is implicated in a variety of cancers and having previously defined its role in liver cancer, Emdad, Fisher and their colleagues explored this relationship further. They confirmed low levels of miR-184 expression in human glioma tissue samples and cultured cell lines as well as an increase in the expression of SND1 compared to normal brain tissue. Using data from a large public brain tumor database called REMBRANDT, the researchers confirmed that patients with lower levels of SND1 survived longer than those with elevated SND1 expression.

“We still have a long way to go and many challenges to overcome before we will have therapies that are ready for clinical use, but this is a significant first step in the process,” says Emdad, member of the Cancer Molecular Genetics research program at Massey, assistant professor in the VCU Department of Human and Molecular Genetics and member of the VIMM. “Future studies will aim to explore the relationship between SND1 and STAT3, identify additional microRNAs that may be relevant to malignant glioma and explore the effects of drugs that block SND1 expression in more advanced preclinical models.”

I’m Dr. Michael Hunter.

Journal Reference:
L. Emdad, A. Janjic, M. A. Alzubi, B. Hu, P. K. Santhekadur, M. E. Menezes, X.-N. Shen, S. K. Das, D. Sarkar, P. B. Fisher. Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness. Neuro-Oncology, 2014; DOI: 10.1093/neuonc/nou220

Virginia Commonwealth University. “Important gene interaction defined that drives aggressive brain cancer.” ScienceDaily. ScienceDaily, 11 December 2014. <www.sciencedaily.com/releases/2014/12/141211162501.htm>.

Different Brain Tumors Have the Same Origin

What You Need to Know: Glioma is a common name for serious brain tumors. Different types of glioma are usually diagnosed as separate diseases and have been considered to arise from different cell types in the brain. Now researchers at Uppsala University, together with American colleagues, have shown that one and the same cell of origin can give rise to different types of glioma. This is important for the basic understanding of how these tumors are formed and can contribute to the development of more efficient and specific glioma therapies.

The most common primary, malignant brain tumors in adults, called glioma, are formed from cells in the brain that are not nerve cells. These are serious tumors that lack highly effective treatment, and relapses are common. There are different types of glioma, classified according to an established system based on which cell type the tumor arises from. The most common gliomas are astrocytoma, which have their name from astrocytes, and oligodendroglioma, which are believed to arise from oligodendrocytes. Patients with astrocytoma have a poorer prognosis than oligodendroglioma patients, and the two tumor types are considered separate clinical diagnoses.

“Since the tumor types look different and have different prognoses it has been assumed that they arise from different cells of origin in the brain, but the fact is that the exact cell of origin has not been determined for any glioma. We have for a long time been interested in finding out more about the origin of gliomas and how it is associated with the genetic alterations that cause the tumor,” says lead researcher Lene Uhrbom.

In collaboration with colleagues in the United States, Uhrbom’s research group has studied glioma development in mice. Using tumor models for both astrocytoma and oligodendroglioma, which are very similar to human tumors, they showed that one and the same cell type, called oligodendrocyte precursor cells, could give rise to both tumor forms.

The researchers discovered that it is not the cell of origin but rather the genetic aberrations that control which tumor type is formed. By analysing gene activity in a large number of human astrocytoma and oligodendroglioma they could also conclude that the tumors are more similar to one another than was previously believed. This supports their finding that the glioma diagnoses can have the same origin.

“We saw that the same kind of more differentiated cell of origin, which has previously only been shown to give rise to oligodendroglioma, also can give rise to astrocytoma. New findings such as these increase our understanding of the basic mechanisms that cause glioma,” says Lene Uhrbom.

I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad: Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Uppsala University. “Different brain tumors have the same origin, new findings show.” ScienceDaily. ScienceDaily, 28 October 2014. <www.sciencedaily.com/releases/2014/10/141028214055.htm>.

A Trojan Horse for the Deadly Brain Tumor Glioblastoma?

brain tumor cancer Johns Hopkins researchers say they have successfully used stem cells derived from human body fat to deliver biological treatments directly to the brains of mice with the most common and aggressive form of brain tumor, significantly extending their lives. The experiments advance the possibility, the researchers say, that the technique could work in people after surgical removal of brain cancers called glioblastomas to find and destroy any remaining cancer cells in difficult-to-reach areas of the brain. Glioblastoma cells are particularly nimble; they are able to migrate across the entire brain, hide out and establish new tumors. Cure rates for the tumor are notoriously low as a result.

In the mouse experiments, the Johns Hopkins investigators used mesenchymal stem cells (MSCs) — which have an unexplained ability to seek out cancer and other damaged cells — that they harvested from human fat tissue. They modified the MSCs to secrete bone morphogenetic protein 4 (BMP4), a small protein involved in regulating embryonic development and known to have some tumor suppression function. The researchers, who had already given a group of mice glioblastoma cells several weeks earlier, injected stem cells armed with BMP4 into their brains. In a report published in the May 1 issue of Clinical Cancer Research, the investigators say the mice treated this way had less tumor growth and spread, and their cancers were overall less aggressive and had fewer migratory cancer cells compared to mice that didn’t get the treatment. Meanwhile, the mice that received stem cells with BMP4 survived significantly longer, living an average of 76 days, as compared to 52 days in the untreated mice.

“These modified mesenchymal stem cells are like a Trojan horse, in that they successfully make it to the tumor without being detected and then release their therapeutic contents to attack the cancer cells,” says study leader Alfredo Quinones-Hinojosa, M.D., a professor of neurosurgery, oncology and neuroscience at the Johns Hopkins University School of Medicine.

Standard treatments for glioblastoma include chemotherapy, radiation and surgery, but even a combination of all three rarely leads to more than 5 years of survival after diagnosis. Finding a way to get biologic therapy to mop up what other treatments can’t get is a long-sought goal, says Quinones-Hinojosa, who cautions that years of additional studies are needed before human trials of fat-derived MSC therapies could begin.

Quinones-Hinojosa, who treats brain cancer patients at Johns Hopkins Kimmel Cancer Center, says his team was heartened by the fact that the stem cells let loose into the brain in his experiments did not transform themselves into new tumors. The latest findings build on research published in March 2013 by Quinones-Hinojosa and his team in the journal PLOS ONE, which showed that harvesting MSCs from fat was much less invasive and less expensive than getting them from bone marrow, a more commonly studied method. Ideally, he says, if MSCs work, a patient with a glioblastoma would have some adipose tissue (fat) removed from any number of locations in the body a short time before surgery. The MSCs in the fat would be drawn out and manipulated in the lab to secrete BMP4. Then, after surgeons removed the brain tumor, they could deposit these treatment-armed cells into the brain in the hopes that they would seek out and destroy the cancer cells.

I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad: Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

References: Q. Li, O. Wijesekera, S. J. Salas, J. Y. Wang, M. Zhu, C. Aprhys, K. L. Chaichana, D. A. Chesler, H. Zhang, C. L. Smith, H. Guerrero-Cazares, A. Levchenko, A. Quinones-Hinojosa. Mesenchymal Stem Cells from Human Fat Engineered to Secrete BMP4 Are Nononcogenic, Suppress Brain Cancer, and Prolong Survival. Clinical Cancer Research, 2014; 20 (9): 2375 DOI: 10.1158/1078-0432.CCR-13-1415; Johns Hopkins Medicine. “Human fat: Trojan horse to fight brain cancer?.” ScienceDaily. ScienceDaily, 1 May 2014. <www.sciencedaily.com/releases/2014/05/140501075055.htm>.

Aspirin May Stop Growth of Tumors That Cause Hearing Loss

ear hearing pinna

Researchers from Massachusetts Eye and Ear, Harvard Medical School, Massachusetts Institute of Technology and Massachusetts General Hospital have demonstrated, for the first time, that aspirin intake correlates with halted growth of vestibular schwannomas (also known as acoustic neuromas), a sometimes lethal intracranial tumor that typically causes hearing loss and tinnitus.

“Currently, there are no FDA-approved drug therapies to treat these tumors, which are the most common tumors of the cerebellopontine angle and the fourth most common intracranial tumors,” explains Konstantina Stankovic, M.D., Ph.D., who led the study. “Current options for management of growing vestibular schwannomas include surgery (via craniotomy) or radiation therapy, both of which are associated with potentially serious complications.”

The Study: The findings, which are described in the February issue of the journal Otology and Neurotology, were based on a retrospective series of 689 people, 347 of whom were followed with multiple magnetic resonance imaging (MRI) scans (50%). The main outcome measures were patient use of aspirin and rate of vestibular schwannoma growth measured by changes in the largest tumor dimension as noted on serial MRIs. A significant inverse association was found among aspirin users and vestibular schwannoma growth (odds ratio: 0.50, 95 percent confidence interval: 0.29-0.85), which was not confounded by age or gender.

“Our results suggest a potential therapeutic role of aspirin in inhibiting vestibular schwannoma growth,” said Dr. Stankovic, who is an otologic surgeon and researcher at Mass. Eye and Ear, Assistant Professor of Otology and Laryngology, Harvard Medical School (HMS), and member of the faculty of Harvard’s program in Speech and Hearing Bioscience and Technology.

My Take: While retrospective analysis does not provide a high level of evidence (not high enough to recommend aspirin with confidence), the findings are nevertheless thought-provoking, and hopefully will lead to clinical trials investing the use of aspirin. I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Massachusetts Eye and Ear Infirmary. “Aspirin intake may stop growth of tumors that cause hearing loss.” ScienceDaily. ScienceDaily, 24 January 2014. <www.sciencedaily.com/releases/2014/01/140124110705.htm>.

 Journal Reference: Tjeerd Muurling, Konstantina M. Stankovic. Metabolomic and Network Analysis of Pharmacotherapies for Sensorineural Hearing LossOtology & Neurotology, 2014; 35 (1): 1 DOI: 10.1097/MAO.0000000000000254

Deadly Brain Tumor: Gross Total Resection Prolongs Survival

English: TAC_Brain_tumor_glioblastoma-Transver...
English: TAC_Brain_tumor_glioblastoma-Transverse_plane Italiano: Immagine TAC della zona cerebrale, indicante un tumore di tipo glioblastoma. Piano Trasverso (Photo credit: Wikipedia)

Gross total resection of glioblastoma may prolong survival with modern radiation therapy and chemotherapy, according to new research from the German Glioma Network. However, incomplete resection appears no better than a biopsy.

“There is no linearity such as ‘70% resection is better than 50%,'” said Dr. Joerg-Christian Tonn from University of Munich LMU, who led the new work. “The goal must be (if anatomically and clinically feasible) to resect all the solid tumor mass — this makes the difference.”

Among the 222 patients (64.2%) who underwent radiotherapy plus chemotherapy, median overall survival was significantly longer after gross total resection (21.0 months) than after incomplete resection (15.2 months) or biopsy (15.7 months). In multivariate Cox regression analyses, independent predictors of better overall survival included gross total resection, age 60 years or less, Karnofsky performance score of 80 or higher, MGMT promoter methylation, and radiotherapy plus chemotherapy. Incomplete resection was no better than biopsy.

for those unable to have a complete resection, Dr. Samuel Ryu from Gachon University Gil Hospital in Inchon, Korea, made a case for incomplete resection, even if it has no survival benefits: “The role of surgical resection also includes removal or reduction of mass effect,” he told Reuters Health by email. “Although there is no survival benefit, there can be some neurological benefit by reducing the pressure to the adjacent brain parenchyma.”

And there is this eloquent criticism of the paper, too:

Dr. Sonia Tejada from Universidad de Navarra in Spain, questioned whether there are meaningful conclusions to be drawn from the new work. “I am surprised that this article that does not give any new data in the field has been published in this journal,” she said. “Nowadays,” Dr. Tejada noted, “a paper about resection in glioblastoma without volumetric analysis is incomplete and should not have been published. Indeed, the data about overall survival in the group of incomplete resection was 11.7 (10.0-13.5) months and in the group of biopsy was 8.7 (6.3-11.2) months. Although not statistically significant, there is a difference; the absence of significance does not mean an absence of difference.”

I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: http://www.medscape.com/viewarticle/814079; Annals of Oncology 2013

Progress on Deadly Brain Cancer?

English: Gliobastoma (astrocytoma) WHO grade I...
English: Gliobastoma (astrocytoma) WHO grade IV – MRI sagittal view, post contrast. 15 year old boy. Deutsch: Glioblastom (Astrozytom) WHO Grad IV – MRT sagittale Schnittführung, nach Kontrastmittel. 15 Jahre alter Junge. (Photo credit: Wikipedia)

Eight of 16 patients participating in a study of an experimental immune system therapy directed against the most aggressive malignant brain tumors — glioblastoma multiforme — survived longer than five years after diagnosis, according to Cedars-Sinai researchers, who presented findings Nov. 23 at the Fourth Quadrennial Meeting of the World Federation of Neuro-Oncology.

Seven of the 16 participants still are living, with length of survival ranging from 60.7 to 82.7 months after diagnosis. Six of the patients also were “progression free” for more than five years, meaning the tumors did not return or require more treatment during that time. Four participants still remain free of disease with good quality of life at lengths ranging from 65.1 to 82.7 months following diagnosis. One patient who remained free of brain cancer for five years died of leukemia. The original clinical trial — a Phase I study designed to evaluate safety — included 16 patients with glioblastoma multiforme enrolled between May 2007 and January 2010 by researchers at Cedars-Sinai’s Johnnie L. Cochran, Jr. Brain Tumor Center.

Results published in January at the end of the study showed median overall survival of 38.4 months. Typically, when tumor-removal surgery is followed by standard care, which includes radiation and chemotherapy, median length of survival is about 15 months. Median progression-free survival — the time from treatment to tumor recurrence — was 16.9 months at study’s end. With standard care, the median is about seven months.

The experimental treatment consists of a vaccine, ICT-107, intended to alert the immune system to the existence of cancer cells and activate a tumor-killing response. It targets six antigens involved in the development of glioblastoma cells.

According to information presented at the scientific meetings, all eight long-term survivors had tumors with at least five antigens, 75 percent had tumors with all six, and 100 percent had tumors with at least four antigens associated with cancer stem cells — cancer-originating cells that appear to enable tumors to resist radiation and chemotherapy and even regenerate after treatment.

“Our findings suggest that targeting antigens that are highly expressed by cancer stem cells may be a viable strategy for treating patients who have glioblastomas. Long-term remission of disease in this group of patients was correlated with the expression of cancer stem cell tumor-associated antigens,” said Surasak Phuphanich, MD, director of the Neuro-Oncology Program at the Cochran Brain Tumor Center and professor of neurology with Cedars-Sinai’s Department of Neurosurgery and Department of Neurology.

Based on results of the Phase I study, the ICT-107 vaccine entered a Phase II multicenter, randomized, placebo-controlled trial in 2011.

The vaccine is based on dendritic cells, the immune system’s most powerful antigen-presenting cells — those responsible for helping the immune system recognize invaders. They are derived from white blood cells taken from each participating patient in a routine blood draw. In the laboratory, the cells are cultured with synthetic peptides of the six antigens — essentially training the dendritic cells to recognize the tumor antigens as targets. When the “new” dendritic cells in the vaccine are injected under the patient’s skin, they are intended to seek and destroy lingering tumor cells. Vaccine is administered three times at two-week intervals after standard radiation and chemotherapy.

My Take: While the results are promising, they are preliminary (? selection bias). Still, vaccines are an innovative approach, and we really need to have an approach to glioblastoma that is paradigm-shifting.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Cedars-Sinai Medical Center (2013, November 24). Update: 50 percent of patients in new brain cancer study alive after five years. ScienceDaily. Retrieved November 24, 2013, from http://www.sciencedaily.com­/releases/2013/11/131124093517.htm

Genes Driving Brain Cancer Revealed

This image shows the coding region in a segmen...
This image shows the coding region in a segment of eukaryotic DNA. (Photo credit: Wikipedia)

Researchers at Columbia University (New York City, USA) have identified 18 genes responsible for driving glioblastoma multiforme (GBM), one of the most common (and deadly) forms of brain cancer.

Background: Cancers rely on driver genes to remain cancer. These driver genes are potential targets for therapy. If we can shut the pathway down through this means, the cancer may collapse.

The Research: The investigators from Columbia University (New York City, USA) believe that they have identified the vast majority of drivers for the delay form of brain tumors, glioblastoma multiforme (GBM). The team identified 15 driver genes that had already been discovered in other studies, and 18 new driver genes that had never been implicated in glioblastoma.

My take: This creates a list of the most important targets for GBM drug development. And then? Personalized management of brain cancer. About 15% of glioblastomas are driven by genes that can be targeted with drugs available in the USA today. We need clinical trials to enroll these patients. Of course, given tumors are powered by varying driver genes, a complicated analysis is required before personalized treatment can be offered. Imagine if we could isolate the most aggressive cells from a tumor, identify the driver gene responsible for its growth, and test drugs on the isolate cells to find the optimal therapy. Some of these genes are in cancer stem cells, the tumor’s most aggressive cells.

For the 15% of patients whose tumors are driven by certain gene fusions, there are drugs approved for use in the USA. Half of these patients have tumors driven by a fusion between the gene EGFR and several other genes. This makes EGFR (epidermal growth factor receptor, a growth factor for some cancers) hyperactive. Other patients have a fusion of the genes FGFR (fibroblast growth factor receptor) and TACC (transforming acidic coiled-coil), first reported in 2012 by the COlumbia University team.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minuteable now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

References: Nature Genetics (05 August 2013)