Research and Clinical Trials News

Research and Clinical Trials News

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Study reveals genes that drive brain cancer

  • Monday, 05 August 2013 23:47

Columbia researchers find that about 15 percent of glioblastoma patients could receive personalized treatment with drugs currently used in other cancers

IMAGE: An analysis of all gene mutations in nearly 140 brain tumors has uncovered most of the genes responsible for driving glioblastoma. The analysis found 18 new driver genes (labeled red),...

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NEW YORK, NY (August 5, 2013) — A team of researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center has identified 18 new genes responsible for driving Glioblastoma Multiforme, the most common—and most aggressive—form of brain cancer in adults. The study was published August 5, 2013, in Nature Genetics.

"Cancers rely on driver genes to remain cancers, and driver genes are the best targets for therapy," said Antonio Iavarone, MD, professor of pathology and neurology at Columbia University Medical Center and a principal author of the study.

"Once you know the driver in a particular Tumor and you hit it, the cancer collapses. We think our study has identified the vast majority of drivers in glioblastoma, and therefore a list of the most important targets for glioblastoma drug development and the basis for personalized treatment of brain cancer."

Personalized treatment could be a reality soon for about 15 percent of glioblastoma patients, said Anna Lasorella, MD, associate professor of pediatrics and of pathology & cell biology at CUMC.

"This study—together with our study from last year, Research May Lead to New Treatment for Type of Brain Cancer—shows that about 15 percent of glioblastomas are driven by genes that could be targeted with currently available FDA-approved drugs," she said. "There is no reason why these patients couldn't receive these drugs now in clinical trials."

New Bioinformatics Technique Distinguishes Driver Genes from Other Mutations

In any single tumor, hundreds of genes may be mutated, but distinguishing the mutations that drive cancer from mutations that have no effect has been a longstanding problem for researchers.

The Columbia team used a combination of high throughput DNA sequencing and a new method of statistical analysis to generate a short list of driver candidates. The massive study of nearly 140 brain tumors sequenced the DNA and RNA of every gene in the tumors to identify all the mutations in each tumor. A statistical algorithm designed by co-author Raul Rabadan, PhD, assistant professor of biomedical informatics and systems biology, was then used to identify the mutations most likely to be driver mutations. The algorithm differs from other techniques to distinguish drivers from other mutations in that it considers not only how often the gene is mutated in different tumors, but also the manner in which it is mutated.

"If one copy of the gene in a tumor is mutated at a single point and the second copy is mutated in a different way, there's a higher probability that the gene is a driver," Dr. Iavarone said.

The analysis identified 15 driver genes that had been previously identified in other studies—confirming the accuracy of the technique—and 18 new driver genes that had never been implicated in glioblastoma.

Significantly, some of the most important candidates among the 18 new genes, such as LZTR1 and delta catenin, were confirmed to be driver genes in laboratory studies involving cancer stem cells taken from human tumors and examined in culture, as well as after they had been implanted into mice.

A New Model for Personalized Cancer Treatment

Because patients' tumors are powered by different driver genes, the researchers say that a complicated analysis will be needed for personalized glioblastoma treatment to become a reality. First, all the genes in a patient's tumor must be sequenced and analyzed to identify its driver gene.

"In some tumors it's obvious what the driver is; but in others, it's harder to figure out," said Dr.Iavarone.

Once the candidate driver is identified, it must be confirmed in laboratory tests with cancer stem cells isolated from the patient's tumor.

"Cancer stem cells are the tumor's most aggressive cells and the critical cellular targets for cancer therapies," said Dr. Lasorella. "Drugs that prove successful in hitting driver genes in cancer stem cells and slowing cancer growth in cell culture and animal models would then be tried in the patient."

IMAGE: About 15 percent of glioblastoma driver genes can be targeted with currently available drugs, suggesting that personalized treatment for some patients may be possible in the near future. Personalized therapy...

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Personalized Treatment Already Possible for Some Patients

For 85 percent of the known glioblastoma drivers, no drugs that target them have yet been approved.

But the Columbia team has found that about 15 percent of patients whose tumors are driven by certain gene fusions, FDA-approved drugs that target those drivers are available.

The study found that half of these patients have tumors driven by a fusion between the gene EGFR and one of several other genes. The fusion makes EGFR—a growth factor already implicated in cancer—hyperactive; hyperactive EGFR drives tumor growth in these glioblastomas.

"When this gene fusion is present, tumors become addicted to it—they can't live without it," Dr. Iavarone said. "We think patients with this fusion might benefit from EGFR inhibitors that are already on the market. In our study, when we gave the inhibitors to mice with these human glioblastomas, tumor growth was strongly inhibited."

Other patients have tumors that harbor a fusion of the genes FGFR (fibroblast growth factor receptor) and TACC (transforming acidic coiled-coil), first reported by the Columbia team last year. These patients may benefit from FGFR kinase inhibitors. Preliminary trials of these drugs (for treatment of other forms of cancer) have shown that they have a good safety profile, which should accelerate testing in patients with glioblastoma.

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The paper is titled, "The integrated landscape of driver genomic alterations in glioblastoma." The other contributors are: Veronique Frattini (CUMC), Vladimir Trifonov (CUMC), Joseph Minhow Chan (CUMC), Angelica Castano (CUMC), Marie Lia (CUMC), Francesco Abate (CUMC and Politecnico di Torino), Stephen T. Keir (Duke University Medical Center), Alan X. Ji (University of Toronto), Pietro Zoppoli (CUMC), Francesco Niola (CUMC and Italian Institute of Technology), Carla Danussi (CUMC), Igor Dolgalev (Memorial Sloan Kettering), Paola Porrati (Fondazione IRCCS Istituto Neurologico C. Besta), Serena Pellegatta (Fondazione IRCCS Istituto Neurologico C. Besta), Adriana Heguy (Memorial Sloan Kettering), Gaurav Gupta (CUMC), David J. Pisapia (CUMC), Peter Canoll (CUMC), Jeffrey N. Bruce (CUMC), Roger E. McLendon (Duke University Medical Center), Hai Yan (Duke University Medical Center), Ken Aldape (MD Anderson Cancer Center), Gaetano Finocchiaro (Fondazione IRCCS Istituto Neurologico C. Besta), Tom Mikkelsen (Henry Ford Health System), Gilbert G. Privé (University of Toronto), and Darell D. Bigner (Duke University Medical Center).

This work was supported by National Institutes of Health grants R01CA101644, R01CA131126, R01CA085628, R01CA127643, P50MH094267, U54CA121852, R01CA164152, and R01NS061776; Leukemia & Lymphoma Society, Canadian Cancer Society, Cancer Research Society, Stewart Foundation, Partnering for Cures, Lymphoma Research Foundation, Chemotherapy Foundation, Associazione Italiana per la Ricerca sul Cancro, Italian Ministry of Health, Italian Ministry of Welfare/Provincia di Benevento, and F.I.A.G.O.P. Additional support was provided by Giuseppe Bruno, Marianne Mebane, and Denise and David Chase.

Drs. Iavarone, Lasorella, and Rabadan and CUMC have filed a patent application related to the diagnostic and therapeutic use of gene fusions. Otherwise, the authors declare no financial or other conflicts of interest.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital encompasses pre-clinical and clinical research, treatment, prevention and education efforts in cancer. The Cancer Center was initially funded by the NCI in 1972 and became a National Cancer Institute (NCI)–designated comprehensive cancer center in 1979. The designation recognizes the Center's collaborative environment and expertise in harnessing translational research to bridge scientific discovery to clinical delivery, with the ultimate goal of successfully introducing novel diagnostic, therapeutic and preventive approaches to cancer. For more information, visit http://www.hiccc.columbia.edu.

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Children's Tumor Foundation award for Plymouth researcher

  • Friday, 02 August 2013 21:40

IMAGE: Dr. Lu Zhou from Plymouth University Peninsula Schools of Medicine and Dentistry. Dr. Zhou has been awarded the Young Investigator's Award by the Children's Tumor Foundation

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Dr. Lu Zhou, a member of a team of researchers at Plymouth University Peninsula Schools of Medicine and Dentistry whose area of expertise is brain tumours, has been awarded a fellowship by the Children's Tumor Foundation.

The Children's Tumor Foundation is a US-based charity which aims to improve the health and wellbeing of children with multiple tumours of the brain, neurofibromatosis (NF). By supporting research in this area it is hoped that therapies and cures may be developed for a condition for which the only treatments are invasive surgery and/or Chemotherapy.

Dr Zhou has been awarded the charity's Young Investigator Award, part of a programme that provides support for pre- and post-doctoral researchers pursuing careers in NF research. The award provides two years of salary ($108,000) and a $5,000 allowance over the life of the award to support attendance at the Foundation's annual NF Conference as well as other conferences and events relevant to NF.

The research that has attracted this award has seen Dr. Zhou investigate the role of certain proteins in the mechanisms that cause the growth and proliferation of NF tumours. By understanding how the mechanisms work, Dr. Zhou and his colleagues can develop therapies based on existing drugs which could halt the spread of NF tumours – contributing greatly to the Quality of life and survival rates of NF sufferers.

Dr. Zhou has worked in NF research since 2008, when he joined Professor Oliver Hanemann's world-recognised research group. Under Professor Hanemann's supervision, Dr. Zhou has developed his expertise and he has had research published in prestigious journals such as Cell, Neoplasia and Oncogene. His work has also received funding from Cancer Research UK.

He said: "I am delighted to receive the Children's Tumor Foundation; Young Investigator Award. It will help me to establish myself as an independent NF researcher and also network with other scientists in the field of NF research. This is not just good news for me – it is also good news for our research team which is taking a lead in innovative research designed to target NF."

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New therapy improves life span in melanoma patients with brain metastases, SLU researchers find

  • Thursday, 01 August 2013 22:13

IMAGE: John Richart, M.D., associate professor of internal medicine at SLU and principal investigator of the study, discusses a patient case with Melinda Chu, M.D., first-year dermatology resident.

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ST. LOUIS -- In a retrospective study, Saint Louis University researchers have found that patients with melanoma brain Metastases can be treated with large doses of interleukin-2 (HD IL-2), a therapy that triggers the body's own Immune System to destroy the Cancer cells.

The study that was recently published in Chemotherapy Research and Practice, reviews cases of eight patients who underwent this therapy at Saint Louis University.

John Richart, M.D., associate professor of internal medicine at SLU and principal investigator of the study, first treated a patient with the disease using the HD IL-2 treatment in 1999.

"Traditionally, melanoma patients with brain metastases have not been considered for HD IL-2 because treatment was thought to be futile," Richart said. "Our study shows that having this condition does not exclude a patient from getting this treatment and can in fact improve the length of their life."

Melanoma is the most dangerous form of skin cancer that begins in the melanin-producing cells called melanocytes. In some melanoma patients, the cancer spreads to the brain, causing multiple tumors that are difficult to treat. According to the CDC, melanoma is the third most common cancer causing brain metastases in the U.S. Richart said the median overall survival of patients with melanoma brain metastases is approximately four months whereas in the study, the median overall survival for patients was 8.7 months.

During the treatment, patients are given an IV medication -- a chemical the body naturally makes that stimulates the immune system to recognize and destroy melanoma cells -- for a period of six days while they are admitted to the hospital and are closely monitored by doctors and nurses. A patient requires four such six-day admission cycles in order to complete the course of the treatment.

To be eligible for HD IL-2 treatment, melanoma patients with brain metastases have to be in healthy shape with good brain function -- that is they cannot have brain lesions that are growing rapidly or show any symptoms of brain lesions. In the past, melanoma patients with brain metastases have been considered ineligible for this treatment because doctors thought that the treatment would cause life-threatening cerebral Edema, a complication that causes excess accumulation of fluids in the brain, and neurotoxicity, or irreversible damage to the brain or the nervous system.

"In this review, we found that there were no episodes of treatment-related mortality. Our findings demonstrate that HD IL-2 can be considered as an option for patients with melanoma brain metastases," said Melinda Chu, M.D., a first year dermatology resident at SLU and first author of the study. SLU is the only medical center in the region that provides this treatment.

"We need a highly skilled nursing staff for the HD-IL-2 program to be successful," Richart said. "Our nursing team at SLU is with each patient every step of the way, 24 hours a day. They help patients get through and continue the treatment."

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Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: infectious disease, liver disease, cancer, heart/lung disease, and aging and brain disorders.

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Technique filters cancer where chemo can't reach

  • Tuesday, 30 July 2013 16:36

A Cancer therapy that removes Malignant cells from a patient's Cerebrospinal fluid may soon be available to prevent Metastases and decrease complications of cancers involving the brain, according to Penn State medical researchers.

Many cancer types metastasize to the brain -- including breast cancer, pancreatic cancer, prostate cancer and leukemia -- but by filtering these malignant cells out of the cerebrospinal fluid (CSF), the researchers hope to decrease the chance of cancer spreading toward and away from the brain.

The brain and spinal cord are surrounded by cerebrospinal fluid, separated from the blood circulating throughout the rest of the body by a cellular lining known as the blood-brain barrier.

"Most chemotherapies have a difficult time crossing the blood-brain barrier, but cancer cells can if they have the right instructions," said Joshua E. Allen, postdoctoral fellow at the Penn State Hershey Cancer Institute.

The researchers have devised a way to move CSF through a filter outside the body that catches the cancer cells and then allows the CSF to flow back into the patient, Tumor cell-free.

"Currently nothing exists that can filter cerebrospinal fluid -- which, in some patients, contains malignant active cancer cells," said Akshal S. Patel, neurosurgery resident at the Penn State Milton S. Hershey Medical Center. "This therapy filters all cerebrospinal fluid."

Many treatments, including Chemotherapy, increase therapeutic resistance of cancer cells, Allen noted. However, filtering cells out does not offer the malignant cells an opportunity to develop therapeutic resistance.

Treatment providers can count the cells captured in the filter and use that to measure the severity of metastasis, another benefit to using this method.

Approximately 15 to 20 percent of metastatic breast cancer patients eventually develop brain metastases, according to the researchers.

"There is a high likelihood of breast cancer patients getting cancer cells in their cerebrospinal fluid," said Patel.

The researchers monitored the number of tumor cells in nine breast cancer patients with confirmed metastatic spread to their Central Nervous System. They counted both the number of tumor cells in the bloodstream and in the CSF.

Approximately half of these patients had tumor cells that moved through the blood-brain barrier. Allen and Patel found that this movement of tumor cells is not necessarily restricted to later phases of breast cancer, as previously thought.

With this new knowledge in mind, the researchers' proposed method can help treat breast cancer -- and other metastasizing cancers -- earlier and with potentially fewer drugs. This filtering of body fluid is similar to that used as standard care for leukemia, and offers potentially increased cure rates.

"The minimum this therapy would provide is straining the tumor cells out," said Allen. "But we could also include other therapies when returning the CSF to the body."

A provisional patent application for this method described by the inventors has been filed.

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Also working on this research were Wafik S. El-Deiry, American Cancer Society Research Professor, Rose Dunlap Professor, chief of the hematology/oncology division and associate director for Translational Research, Cancer Institute; and Michael J. Glantz, professor of neurosurgery, medicine and neurology.

The National Institutes of Health, the American Cancer Society and start-up funds from the Penn State Hershey Cancer Institute laboratory supported this work.

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Cell phones could increase cancer risk

  • Monday, 29 July 2013 20:00

Saliva from heavy cell phone users shows increased risk factors for Cancer, says a Tel Aviv University researcher

Scientists have long been worried about the possible harmful effects of regular cellular phone use, but so far no study has managed to produce clear results. Currently, cell phones are classified as carcinogenic category 2b – potentially carcinogenic to humans – by the International Agency for Research on Cancer (IARC). A new Tel Aviv University study, though, may bring bad news.

To further explore the relationship between cancer rates and cell phone use, Dr. Yaniv Hamzany of Tel Aviv University's Sackler Faculty of Medicine at Tel Aviv University and the Otolaryngology Head and Neck Surgery Department at the Rabin Medical Center looked for clues in the saliva of cell phone users. Since the cell phone is placed close to the salivary gland when in use, he and his fellow researchers, including departmental colleagues Profs. Raphael Feinmesser, Thomas Shpitzer and Dr. Gideon Bahar and Prof. Rafi Nagler and Dr. Moshe Gavish of the Technion in Haifa, hypothesized that salivary content could reveal whether there was a connection to developing cancer.

Comparing heavy mobile phone users to non-users, they found that the saliva of heavy users showed indications of higher oxidative stress – a process that damages all aspects of a human cell, including DNA — through the development of toxic peroxide and free radicals. More importantly, it is considered a major risk factor for cancer.

The findings have been reported in the journal Antioxidants and Redox Signaling.

Putting stress on tissues and glands

For the study, the researchers examined the saliva content of 20 heavy-user patients, defined as speaking on their phones for a minimum of 8 hours a month. Most participants speak much more, Dr. Hamzany says, as much as 30 to 40 hours a month. Their salivary content was compared to that of a control group, which consisted of deaf patients who either do not use a cell phone, or use the device exclusively for sending text messages and other non-verbal functions.

Compared to the control group, the heavy cell phone users had a significant increase in all salivary oxidative stress measurements studied.

"This suggests that there is considerable oxidative stress on the tissue and glands which are close to the cell phone when in use," he says. The damage caused by oxidative stress is linked to cellular and genetic mutations which cause the development of tumors.

Making the connection

This field of research reflects longstanding concerns about the impact of cell phone use, specifically the effects of radiofrequency non-ionizing electromagnetic radiation on human tissue located close to the ear, say the researchers. And although these results don't uncover a conclusive "cause and effect" relationship between cellular phone use and cancer, they add to the building evidence that cell phone use may be harmful in the long term, and point to a new direction for further research.

One potential avenue of future research would be to analyze a person's saliva prior to exposure to a cell phone, and then again after several intense minutes of exposure. This will allow researchers to see if there is an immediate response, such as a rise in molecules that indicate oxidative stress, Dr. Hamzany says.

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American Friends of Tel Aviv University supports Israel's leading, most comprehensive and most sought-after center of higher learning. Independently ranked 94th among the world's top universities for the impact of its research, TAU's innovations and discoveries are cited more often by the global scientific community than all but 10 other universities.

Internationally recognized for the scope and groundbreaking nature of its research and scholarship, Tel Aviv University consistently produces work with profound implications for the future.

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