Research and Clinical Trials News

Research and Clinical Trials News

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New therapy strategy could help treat cancer that has spread from breast to brain

  • Tuesday, 13 August 2013 21:40

UCLA researchers successfully combine cellular and gene therapies

Researchers at UCLA's Jonsson Comprehensive Cancer Center have successfully combined cellular therapy and gene therapy in a mouse-model system to develop a viable treatment strategy for breast cancer that has spread to a patient's brain.

The research, led by Carol Kruse, a professor of neurosurgery and member of the Jonsson Cancer Center and the UCLA Brain Research Institute, was published Aug. 1 in the journal Clinical Cancer Research.

Breast cancer is the most common form of cancer in women, and metastasis is a major cause of health deterioration and death from the disease. Managing metastasis is difficult for several reasons: The circulatory network known as the blood–brain barrier prevents many anti-cancer drugs from reaching areas of the brain to which cancer has spread, and Metastases have a tendency to spring up in multiple brain locations simultaneously, making current treatments such as radiation challenging.

Cellular therapy is a type of immunotherapy that uses T cells, the foot soldiers of the Immune System, that have been sensitized in the laboratory to kill breast cancer cells. These sensitized T cells are injected into the parts of the brain to which cancer has spread. The research shows that the T cells can move through tissue and recognize and directly kill the Tumor cells.

With the gene therapy, genetically modified cancer cells are killed by a drug called 5-flurocytosine (5-FC). To get the gene into the cancer cells, the researchers first insert it into a virus that can infect the tumor cells. After the virus has infected the cells, non-toxic 5-FC is given to the patient. Tumor cells infected by the virus convert the non-toxic drug to a toxic form that kills the cancer cells. Dr. Noriyuki Kasahara, a professor in the department of medicine at UCLA, developed the gene therapy method in his laboratory.

While the two methods alone each show efficacy in mouse models, the greatest reduction in metastatic brain tumor size occurred when the cellular and gene therapies were combined, the researchers said.

"There is a significant lack of federally funded research addressing translational studies on brain metastases of systemic cancers, even though metastatic brain tumors occur 10 times more frequently than primary brain tumors in humans," Kruse said. "These patients have a dismal Prognosis because the brain represents a 'sanctuary site' where appropriate access by many chemotherapeutics is ineffective. Our research addresses this unmet need."

Both experimental therapies are being tested individually in ongoing clinical trials for primary Malignant brain tumors; this presents a unique opportunity for the rapid translation of these technologies from the laboratory to the clinic for breast and other types of cancer that metastasize to the brain, the researchers said.

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This study was supported by the U.S. Army Research Materiel Command; the California Breast Cancer Research Program; the National Center for Advancing Translational Sciences of the National Institutes of Health: the UCLA Clinical Translational Science Institute; the Joan S. Holmes Memorial Research Fund; the Joan S. Holmes Memorial Postdoctoral Fellowship; and Tocagen Inc.

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years.

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Immune system molecule promotes tumor resistance to anti-angiogenic therapy

  • Tuesday, 13 August 2013 21:36

A team of scientists, led by Napoleone Ferrara, MD, has shown for the first time that a signaling protein involved in inflammation also promotes Tumor resistance to anti-angiogenic therapy.

The findings by Ferrara – professor of pathology at the University of California, San Diego School of Medicine and senior deputy director for basic science at the UC San Diego Moores Cancer Center – and colleagues at Genentech, a biotechnology firm based in South San Francisco, are published in the August 4 Advance Online Publication of the journal Nature Medicine.

Angiogenesis is a physiological process in which new blood vessels form from existing vessels. It is fundamental to early development and wound healing, but some cancer tumors exploit angiogenesis to promote blood vessel growth and fuel a tumor's transition from a benign to a Malignant state.

In the late 1980s, Ferrara led efforts to identify a key gene (VEGF) involved in angiogenesis and subsequent development of the first drugs to block VEGF-mediated growth in a variety of cancers, among them lung, kidney, brain and colorectal. Researchers discovered, however, that similar to other therapies, VEGF-targeting drugs may lose effectiveness as tumors develop resistance, allowing cancers to recur.

The latest research highlights the role of interleukin-17 or IL-17, one of a family of signaling molecules called cytokines that are involved in the body's immune response. Ferrara and colleagues discovered that IL-17 signaling in tumor- infiltrating T cells, part of the body's adaptive immune response, encourages resistance to the VEGF-blockade in mouse models.

"Our work has the potential to have major translational and therapeutic relevance," said Ferrara. "By inhibiting the effects of IL-17 with monoclonal antibodies or other blockers, we can potentially improve the clinical efficacy of VEGF-targeting drugs."

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Co-authors include Alicia S. Chung, Xiumin Wu, Guanglei Zhuang, Hai Ngu, Ian Kasman, Jianhuan Zhang, Jean-Michel Vernes, Zhaoshi Jiang, Y. Gloria Meng, Franklin V. Peale and Wenjun Ouyang, all at Genentech, Inc.

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Protein involved in nerve-cell migration implicated in spread of brain cancer

  • Tuesday, 13 August 2013 21:27

Understanding how neurons move sheds light on how Cancer cells invade health tissues

The invasion of brain- Tumor cells into surrounding tissue requires the same protein molecule that neurons need to migrate into position as they differentiate and mature, according to new research from the University of Illinois at Chicago College of Medicine and published August 7 in the online journal PLOS ONE.

The researchers investigated similarities between the transition of neural stem cells into neurons and the process whereby cancer cells invade surrounding tissues.

"Both processes involve the mobilization of cells," says Anjen Chenn, director of clinical pathology and molecular diagnostics at UIC. "During embryonic development, stem cells that go on to become neurons must migrate long distances to other parts of the brain before they mature into adult neurons. We thought that this type of cell migration might have similarities with cancer cells that spread from tumors."

Chenn and colleagues analyzed the proteins expressed by embryonic mouse neural stem cells as they began their migration.

They found that one protein, cadherin11, was found in especially high concentrations in these transitioning cells.

Chenn said the protein "regulates how the cells stick to each other and is also important in helping cells pull themselves along certain pathways as they travel to their final destinations."

When the researchers caused the protein to be overexpressed in embryonic mice, the neural stem cells began their migration prematurely.

"This confirmed that cadherin11 was involved in the initiation of migration," said Chen.

To determine whether the protein was involved in the invasion of cancer cells into healthy tissues, the researchers looked at its function in glioblastoma, the most common and aggressive type of adult brain cancer. They examined survival data from patients with glioblastoma and noticed that patients whose tumors expressed elevated levels of the cadherin11 gene had the worst survival rates.

"We also saw that in our tissue samples, the tumor cells with high expression of cadherin11 tended to be located near blood vessels, suggesting that the protein could be involved in encouraging blood vessels to enervate tumors," Chenn said.

When Chenn and his colleagues mixed cells from blood vessel walls with human glioblastoma cells, the glioblastoma cells increased their expression of cadherin11.

"We have long known that tumors recruit their own blood supply, but this finding was particularly interesting because it suggests that blood vessels might actually be stimulating tumor cells to come to them," Chenn said. "Our results together indicate that cadherin11 is critical in inducing cell migration in cancer, and could be an important therapeutic target for preventing its spread."

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Jessica Schulte, Jianing Zhang, Lihui Yin, Maya Srikanth, Sunit Das and John Kessler of Northwestern University; Justin Lathia and Jeremy Rich of the Cleveland Clinic, and Eric Olson of the State University of New York, Syracuse, also contributed to this research.

This work was supported by March of Dimes Research Scholars Grant #1-FY10-504, the Wendy Will Case Fund (Chicago, IL), and a Brain Research Fund Seed Grant (Chicago, IL) to A. C., the Northwestern University Flow Cytometry Facility and the Northwestern University Cell Imaging Facility both supported by a Cancer Center Support Grant (NCI CA060553).

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Cell maturity pathway is deleted or weak in glioblastoma multiforme

  • Tuesday, 13 August 2013 21:22

Brain Tumor cells in arrested development contribute to cell variety that protects Cancer

HOUSTON -- A program that pushes immature cells to grow up and fulfill their destiny as useful, dedicated cells is short-circuited in the most common and deadly form of brain tumor, scientists at The University of Texas MD Anderson Cancer Center report this week in the Early Edition of the Proceedings of the National Academy of Sciences (PNAS).

Stuck in what amounts to cellular adolescence, these precursor cells accumulate, contributing to the variability among Glioblastoma Multiforme (GBM) cells that make it so difficult to treat, said first author Jian Hu, Ph.D., instructor of Genomic Medicine.

"This arrested development is driven by the GBM cells' plasticity -- their stem-cell-like ability to produce many types of cells -- and the breakdown of the cellular maturation process known as terminal differentiation," said senior author and MD Anderson President Ronald DePinho, M.D.

By searching for genes missing from GBM cells, rather than mutated, Hu and colleagues discovered a key differentiation pathway whose absence fuels tumor growth. "If glioblastoma cells were to undergo differentiation, the tumor would stop growing," Hu said. "But we've shown that if the terminal differentiation circuitry is gone, they get stuck in the middle and produce many different cell types."

Such cellular diversity, or heterogeneity, is a hallmark of cancer that helps it survive and progress. The "multiforme" in glioblastoma multiforme reflects the heterogeneity among and inside tumors.

The publication in PNAS is DePinho's Inaugural Paper, the first published in the journal by new members of the National Academy of Sciences. DePinho was elected to the prestigious academy in 2012. PNAS also published a question-and-answer interview with DePinho this week.

Cancer stem cells: heterogeneity machines

"When a normal neural stem cell divides, it makes one copy of itself and one copy of a precursor cell destined to differentiate into a neuron, an astrocyte or an oligodendrocyte," Hu said.

GBM cells appear locked in a stem-like state, which can lead to runaway division of undifferentiated cells.

A microarray analysis of 71 human glioblastoma samples revealed high levels of stem cell and precursor cell markers for neurons and supportive cells. Fewer cells expressed markers of terminal differentiation. Overall, there were high levels of cellular heterogeneity dominated by immature cells. Higher-grade gliomas had greater heterogeneity.

Sifting genes involved in nervous system development

The team then surveyed The Cancer Genome Atlas GBM database looking for genes that have a known role in nervous system development and are frequently deleted. Of 71 genes identified, A2BP1 caused a notable reduction in colony formation in a GBM cell line. A2BP1 is a gene-splicing factor active in neural development that has been implicated in developmental and psychiatric disorders when mutated.

By profiling 430 TCGA GBM samples, the researchers found A2BP1 deleted in 10 percent of tumors. However, additional analysis showed that its protein is absent or steeply reduced in 90 percent of samples. The gene also is deleted in other nervous system tumors, and in 48 percent of colon cancer samples and 18 percent of sarcomas, suggesting a major tumor-suppressing role across cancers.

Silencing A2BP1 in GBM- Prone premalignant neural stem cells led to tumor formation in mouse brains after 15 weeks, while control mice were tumor-free through 25 weeks. Forcing expression of the gene in mouse and human Glioma stem cell lines impaired tumor formation by causing immature cells to try to differentiate into neurons, which subsequently died from apoptosis.

Gene that turns on A2BP1 identified

To explain the difference between A2BP1's deletion in only 10 percent of tumors but the absence or reduction of its protein in 90 percent of tumors, the team searched for transcription factors that turn on A2BP1 that might also be deleted or suppressed.

They found Myt1L deleted in 5 percent of samples and its protein absent or greatly reduced in 80 percent of tumors. Expression or suppression of Myt1L had similar effects in stem cell lines and mice to those caused by the same actions in A2BP1.

Myt1L also is one of three genes known to trans-differentiate fibroblast cells into neurons, this research makes the first connection between Myt1L and A2BP1, Hu said.

A multistep analysis of RNAs that interact with A2BP1 pointed to the known tumor-suppressor TPM1 as a key gene in mediating A2BP1's differentiation and cancer-blocking activity.

TPM1 proteins come in two forms, one found to have much higher cancer-blocking activity than the other. Splicing of TPM1 by A2BP1 increased levels of the version greater tumor-suppressing activity. Subsequent experiments showed that this version of TPM1 protein significantly reduced glioblastoma formation, invasion and migration in cell cultures and stymied tumor formation in mice.

A GBM-suppressing chain of events

In addition to discovering the deletion and suppression of A2BP1 in GBM, the team established that Myt1L switches on A2BP1, which splices TPM1 into a cell-differentiating, tumor-suppressing mode. "This is probably not the only way that A2BP1 suppresses tumors, but it's a key mechanism," Hu said.

Some therapies, mainly in blood malignancies, work by forcing immature cells to differentiate. There's been some hope that differentiation therapy might work on glioblastoma, but Hu notes that it's likely to be less effective if the cell's differentiation machinery is missing.

Their research could lead to biomarkers that indicate whether differentiation therapy will work against a given tumor. A combination of drugs that block stemness pathways and activate Myt1L-A2PB1 differentiation might provide an effective treatment for GBM, the authors noted.

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Other co-authors are Allen Ho, Liang Yuan, Baoli Hu, Ph.D., Sujun Hua, Ph.D., Soyoon Sarah Hwang and Yaoqui Alan Wang, Ph.D., of both Cancer Biology and Genomic Medicine; Jianhua Zhang, Ph.D., of Genomic Medicine and the Institute of Applied Cancer Science; Lynda Chin, M.D., Genomic Medicine; Boyi Gan, Ph.D., of Experimental Radiation Oncology; Tianyi Hu of Trinity College of Arts and Sciences at Duke University; Hongwu Zheng, Ph.D., of Cold Spring Harbor Laboratory in New York, and Gongxiong Wu, M.D., of Joslin Diabetes Center, Harvard Medical School.

This research was funded by grants from the National Cancer Institute of the National Institutes of Health (5K99CA172700, PO1 5PO1CA095616 and UO1 5UO1CA084313); the Leukemia and Lymphoma Society; the U.S. Department of Defense; Helen Hay Whitney Foundation, Juvenile Diabetes Research Foundation and an Exploration-Hypothesis Development Grant.

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There's life after radiation for brain cells

  • Tuesday, 13 August 2013 21:15

Johns Hopkins researchers suggest neural stem cells may regenerate after anti- Cancer treatment

Scientists have long believed that healthy brain cells, once damaged by radiation designed to kill brain tumors, cannot regenerate. But new Johns Hopkins research in mice suggests that neural stem cells, the body's source of new brain cells, are resistant to radiation, and can be roused from a hibernation-like state to reproduce and generate new cells able to migrate, replace injured cells and potentially restore lost function.

"Despite being hit hard by radiation, it turns out that neural stem cells are like the special forces, on standby waiting to be activated," says Alfredo Quiñones-Hinojosa, M.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and leader of a study described online today in the journal Stem Cells. "Now we might figure out how to unleash the potential of these stem cells to repair human brain damage."

The findings, Quiñones-Hinojosa adds, may have implications not only for brain cancer patients, but also for people with progressive neurological diseases such as multiple sclerosis (MS) and Parkinson's disease (PD), in which Cognitive functions worsen as the brain suffers permanent damage over time.

In Quiñones-Hinojosa's laboratory, the researchers examined the impact of radiation on mouse neural stem cells by testing the rodents' responses to a subsequent brain injury. To do the experiment, the researchers used a device invented and used only at Johns Hopkins that accurately simulates localized radiation used in human cancer therapy. Other techniques, the researchers say, use too much radiation to precisely mimic the clinical experience of brain cancer patients.

In the weeks after radiation, the researchers injected the mice with lysolecithin, a substance that caused brain damage by inducing a demyelinating brain Lesion, much like that present in MS. They found that neural stem cells within the irradiated subventricular zone of the brain generated new cells, which rushed to the damaged site to rescue newly injured cells. A month later, the new cells had incorporated into the demyelinated area where new myelin, the protein insulation that protects nerves, was being produced.

"These mice have brain damage, but that doesn't mean it's irreparable," Quiñones-Hinojosa says. "This research is like detective work. We're putting a lot of different clues together. This is another tiny piece of the puzzle. The brain has some innate capabilities to regenerate and we hope there is a way to take advantage of them. If we can let loose this potential in humans, we may be able to help them recover from radiation therapy, strokes, brain trauma, you name it."

His findings may not be all good news, however. Neural stem cells have been linked to brain Tumor development, Quiñones-Hinojosa cautions. The radiation resistance his experiments uncovered, he says, could explain why glioblastoma, the deadliest and most aggressive form of brain cancer, is so hard to treat with radiation.

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The research was supported by grants from the National Institutes of Health's National Institute of Neurological Disorders and Stroke (RO1 NS070024), the Maryland Stem Cell Research Fund, the Robert Wood Johnson Foundation, the Howard Hughes Medical Institute, the PROMETEO grant, the Red de Terapia Celular (TerCel) from Instituto de Salud Carlos III, and the Consejo Nacional de Ciencia y Tecnología.

Other Johns Hopkins researchers involved in the study include Vivian Capilla-Gonzalez, Ph.D.; Hugo Guerrero-Cazares, M.D., Ph.D.; Janice Bonsu; Oscar Gonzalez-Perez, M.D.; Pragathi Achanta, Ph.D.; John Wong, Ph.D.; and Jose Manuel Garcia-Verdugo, Ph.D.

For more information: http://tinyurl.com/ofqkea3

JOHNS HOPKINS MEDICINE

Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM's mission is to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, more than 38 primary health care outpatient sites and other businesses that care for national and international patients and activities. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years by U.S. News & World Report.

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