BreakThrough Digest Medical News |
- Researchers discover ‘Achilles’ heel’ for lymphoid leukemia
- First-in-man study demonstrates the therapeutic effect of RNAi gene silencing in cancer treatment
- Newly identified natural protein blocks HIV, other deadly viruses
| Researchers discover ‘Achilles’ heel’ for lymphoid leukemia Posted: 10 Feb 2013 09:00 PM PST An international research team coordinated at the IRCM in Montréal found a possible alternative treatment for lymphoid leukemia. Led by Dr. Tarik Möröy, the IRCM’s President and Scientific Director, the team discovered a molecule that represents the disease’s “Achilles’ heel” and could be targeted to develop a new approach that would reduce the adverse effects of current treatments such as chemotherapy and radiation therapy. The study’s results are being published today in the prestigious scientific journal Cancer Cell.
The researchers’ results have direct implications for the treatment of acute lymphoblastic leukemia (ALL), one of the four most common types of leukemia. ALL is a cancer of the bone marrow and blood that progresses rapidly without treatment. Current treatments consist of chemotherapy and radiation therapy, which are both highly toxic and non-specific, meaning that they damage healthy cells as well as tumour tissues. “Even when effective, patients can suffer dramatic side effects from these treatments,” says Dr. Möröy, who is also Director of the Hematopoiesis and Cancer research unit at the IRCM and corresponding author of the study. “Therefore, they would directly benefit from an improved therapy that could reduce the necessary dose of radiation or chemotherapy, and thus their side effects, while maintaining the treatments’ efficacy. Therapies that target specific molecules have shown great promise. This is why, for the past 20 years, I have been studying a molecule called Gfi1, which plays an important role in the development of blood cells and cancer.” When normal cells are transformed into tumour cells, the body responds by activating a tumour suppressor protein that induces cell death. Tumour cells must therefore counteract cell death in order to survive. “With this study, we found that leukemic cells depend on the Gfi1 molecule for their survival,” explains Dr. Cyrus Khandanpour, co-first author of the study and University Hospital physician at University Duisburg-Essen in Germany. “In fact, this molecule helps the malignant cells avoid death by hindering the activity of the tumour suppressor protein. Our results show that when Gfi1 is removed in mice that suffer from T-cell leukemia, the tumour disappears and the animals survive.” “Following this discovery, we wanted to test whether it could be used as a viable approach to treat leukemia in humans,” adds Dr. Möröy. “We transplanted cells from a patient with T-cell leukemia into a mouse. We then inhibited the Gfi1 molecule using a commercially-available agent, and noticed that it stopped the expansion of human leukemia in the bone marrow, peripheral blood and spleen, without leading to adverse effects.” “These results are a significant indication that therapies targeting the molecule Gfi1 would work in human patients,” says Dr. H. Leighton Grimes, co-corresponding author of the study from the Cincinnati Children’s Hospital Medical Center. “In fact, if our results translate to patients, they could improve the prognosis of people suffering from lymphoid malignancies,” adds Dr. James Phelan, the study’s co-first author and recent PhD graduate in Dr. Grimes’ laboratory. “Our study suggests that a molecular-based therapy targeting Gfi1 would not only significantly improve response rates, but may also lower effective doses of chemotherapy agents or radiation, thereby reducing harmful side effects,” concludes Dr. Khandanpour, who is also a visiting scientist at the IRCM. “Gfi1 represents an Achilles’ heel for lymphoid leukemia and we are continuing to work so that our approach may soon move to clinical trials.” ### About acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is one of the four most common types of leukemia and affects blood cells and the immune system. The disease develops when immature white blood cells are overproduced in the bone marrow, crowd out normal cells, and eventually spread to other organs. Acute refers to the relatively short time course of the disease, as it can be fatal in as little as a few weeks if untreated. According to the Leukemia & Lymphoma Society of Canada, ALL is the most common type of cancer in children from one to seven years old, and the most common type of leukemia in children from infancy up to age 19. Four out of five children with ALL are cured of their disease after treatment. The number of adults and their remission lengths have grown significantly over the past 30 years. An estimated 4,800 people in Canada were expected to develop leukemia in 2010. About the study The article published in Cancer Cell was a collaborative project between Tarik Möröy’s team in Montréal, Cyrus Khandanpour in Germany, H. Leighton Grimes and James Phelan from Cincinnati in the United States, and Bertie Göttgens from Cambridge in the United Kingdom. Collaborators from Dr. Möröy’s IRCM laboratory include Lothar Vassen, Riyan Chen, Marie-Claude Gaudreau and Joseph Krongold. Research at the IRCM was funded by grants from the Canadian Institutes of Health Research (CIHR), the Canada Research Chair program, the IRCM and the Cole Foundation. For more information on this discovery, please refer to the article summary published online by Cancer Cell: http://www.cell.com/cancer-cell/abstract/S1535-6108(13)00036-6. About Tarik Möröy Tarik Möröy obtained a PhD in biochemistry from the Ludwig-Maximilians University in Munich, Germany. He is the IRCM’s President and Scientific Director, Full IRCM Research Professor and Director of the Hematopoiesis and Cancer research unit. Dr. Möröy is also Full professor-researcher in the Department of Microbiology and Immunology (accreditation in biochemistry) at the Université de Montréal, and Adjunct Professor in the Department of Medicine (Division of Experimental Medicine) and the Department of Biochemistry at McGill University. Dr. Möröy holds the Canada Research Chair in Hematopoiesis and Immune Cell Differentiation. For more information, visit www.ircm.qc.ca/moroy. About the IRCM Founded in 1967, the Institut de recherches cliniques de Montréal (www.ircm.qc.ca) is currently comprised of 36 research units in various fields, namely immunity and viral infections, cardiovascular and metabolic diseases, cancer, neurobiology and development, systems biology and medicinal chemistry. It also houses three specialized research clinics, eight core facilities and three research platforms with state-of-the-art equipment. The IRCM employs 425 people and is an independent institution affiliated with the Université de Montréal. The IRCM Clinic is associated to the Centre hospitalier de l’Université de Montréal (CHUM). The IRCM also maintains a long-standing association with McGill University. About the Canadian Institutes of Health Research (CIHR) CIHR is the Government of Canada’s health research investment agency. CIHR’s mission is to create new scientific knowledge and enable its translation into better health, more effective health services and products, and a stronger Canadian health care system. Composed of 13 Institutes, CIHR provides leadership and support to more than 14,100 health researchers and trainees across Canada. Contact: Julie Langelier |
| First-in-man study demonstrates the therapeutic effect of RNAi gene silencing in cancer treatment Posted: 10 Feb 2013 09:00 PM PST The new study published in Cancer Discovery, the flagship journal of the American Association of Cancer Research (AACR), involving three Spanish and six American research centres, presents significant results in treating cancer patients with nanoparticles containing ribonucleic acid interference (RNAi) molecules. This marks the first time that the therapeutic effect of RNAi has been demonstrated in humans.
Barcelona, 11 February 2013. A study led by Dr Josep Tabernero, the Director of Clinical Research at the Vall d’Hebron Institute of Oncology (VHIO) and Head of the Medical Oncology Department at the Vall d’Hebron University Hospital, shows for the first time that ribonucleic acid interference (RNAi) is effective in the treatment of cancer patients. Harnessing these molecules to silence genes involved in the development and growth of cancer cells is an important step forward in developing a new and more targeted type of cancer therapy. Dr Josep Tabernero, lead author of this study, said: “This is the first evidence to show that RNAi can be administered to cancer patients effectively, leading to significant tumour response.” RNAi is a gene-silencing mechanism that uses a subtype of RNA molecules to interfere with and silence genes. RNAi plays a vital role in normal cell development and differentiation, in cancer and viral defence, as it is powerful mechanism in the regulation of gene expression. Besides being a key natural cellular phenomenon, gene silencing shows great potential as a therapeutic device to shut down genes that have become hyperactive through cancer. However, researchers have encountered difficulties in administering RNAi, as the molecules must penetrate cells in therapeutically effective concentrations, which in turn requires structural modifications. In the new study, led by the Vall d’Hebron Institute of Oncology (VHIO), along with several other cancer research centres and the U.S. biotech company Alnylam, scientists have developed a lipid nanoparticle approach that can deliver two of these molecules targeted against the genes encoding two key proteins involved in the development of cancer cells (VEGF and KSP). This system takes the form of a novel drug (ALN-VSP) made up of RNAi molecules and lipid nanoparticles (LNPs). The new paper, published in the journal Cancer Discovery, presents the results of a Phase I clinical trial, involving 41 patients with advanced cancer that had metastasised to the liver. These patients were treated with the new drug twice a week with intravenous doses of between 0.01-1.5 mg/kg. The trial found that not only was the drug safely administered, but also presented good evidence for clinical utility. In 11 of the 37 patients, the disease either did not progress or stabilized after six months of treatment. In some cases of patients with metastasis to the liver or abdominal lymph glands, there was a complete regression of metastasis. (It should be noted that the liver typically responds better to treatment due to its excellent capacity to absorb these molecules.) The research team performed a pharmacodynamics analysis to determine the impact of the drug on the tumours by taking biopsy samples from the patients before and after the drug was administered. This revealed the presence of the RNAi constructs in the samples, thus showing that the structurally modified molecules reached the tumour and were effective. Having previously tested the drug on animals, this first-in-man clinical test has demonstrated that an efficient formula has been developed to transport and deliver RNAi with clinically promising results. The results will have to be confirmed and extended in additional clinical studies. The importance of clinical research
This study, which also involved other international research centres including the Dana-Farber Cancer Institute (Boston) and the Memorial Sloan-Kettering Cancer Center (New York), plus two other Spanish centres — the Hospital Virgen del Rocío in Seville and the INCLIVA Health Research Institute in Valencia — is potentially transformative for new drug discovery that will allow targeted, population-based studies. Knowledge of the molecular biology of cancer has expanded greatly over the past decade, leading to the identification of potential therapeutic agents for developing tumour-selective drugs. The Research Unit for Molecular Therapy of Cancer – “la Caixa”, conducts Phase I clinical trials for new anticancer drugs. The choice of the most appropriate anticancer drug for each patient depends on a detailed analysis of the specific molecular changes in each tumour. This exciting approach entails a paradigm shift in the individualized treatment of patients. Clinical trials play a vital role in developing new cancer treatments as they form the basis of scientifically recognised clinical research. Drugs must be proven to be both safe and efficacious in clinical trial volunteers before they can be formally approved by the appropriate government agency. ### For further information, please contact: Contact: Amanda Wren |
| Newly identified natural protein blocks HIV, other deadly viruses Posted: 10 Feb 2013 09:00 PM PST A team of UCLA-led researchers has identified a protein with broad virus-fighting properties that potentially could be used as a weapon against deadly human pathogenic viruses such as HIV, Ebola, Rift Valley Fever, Nipah and others designated “priority pathogens” for national biosecurity purposes by the National Institute of Allergy and Infectious Disease.
In a study published in the January issue of the journal Immunity, the researchers describe the novel antiviral property of the protein, cholesterol-25-hydroxylase (CH25H), an enzyme that converts cholesterol to an oxysterol called 25-hydroxycholesterol (25HC), which can permeate a cell’s wall and block a virus from getting in. Interestingly, the CH25H enzyme is activated by interferon, an essential antiviral cell-signaling protein produced in the body, said lead author Su-Yang Liu, a student in the department of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA. “Antiviral genes have been hard to apply for therapeutic purposes because it is difficult to express genes in cells,” said Liu, who performed the study with principal investigator Genhong Cheng, a professor of microbiology, immunology and molecular genetics. “CH25H, however, produces a natural, soluble oxysterol that can be synthesized and administered. “Also, our initial studies showing that 25HC can inhibit HIV growth in vivo should prompt further study into membrane-modifying cholesterols that inhibit viruses,” he added. The discovery is particularly relevant to efforts to develop broad-spectrum antivirals against an increasing number of merging viral pathogens, Liu said. Working with Jerome Zack, a professor of microbiology, immunology and molecular genetics and an associate director of the UCLA AIDS Institute, the researchers initially found that 25HC dramatically inhibited HIV in cell cultures. Next, they administered 25HC in mice implanted with human tissues and found that it significantly reduced their HIV load within seven days. The 25HC also reversed the T-cell depletion caused by HIV. By contrast, mice that had the CH25H gene knocked out were more susceptible to a mouse gammaherpes virus, the researchers found. In collaboration with Dr. Benhur Lee, a professor of pathology and laboratory medicine and a member of the UCLA AIDS Institute, they discovered that 25HC inhibited HIV entry into the cell. Furthermore, in cell cultures, it was found to inhibit the growth of other deadly viruses, such as Ebola, Nipah and the Rift Valley Fever virus. Intriguingly, CH25H expression in cells requires interferon. While interferon has been known for more than 60 years to be a critical part of the body’s natural defense mechanism against viruses, the protein itself does not have any antiviral properties. Rather, it triggers the expression of many antiviral genes. While other studies have identified some antiviral genes that are activated by interferon, this research gives the first description of an interferon-induced antiviral oxysterol through the activation of the enzyme CH25H. It provides a link to how interferon can cause inhibition of viral membrane fusion, Liu said. He noted some weaknesses in the research. For instance, 25HC is difficult to deliver in large doses, and its antiviral effect against Ebola, Nipah and other highly pathogenic viruses have yet to be tested in vivo. Also, the researchers still need to compare 25HC’s antiviral effect against other HIV antivirals. ### Additional study co-authors were Roghiyh Aliyari, Kelechi Chikere, Matthew D. Marsden and Olivier Pernet, of UCLA; Jennifer K. Smith, Rebecca Nusbaum and Alexander N. Frieberg, of the University of Texas?Galveston; and Guangming Li, Haitao Guo and Lishan Su, of the University of North Carolina?Chapel Hill. The National Institutes of Health (grants R01 AI078389, AI069120, AI080432, AI095097, AI077454, AI070010 and AI028697), the Warsaw Fellowship, the UCLA Center for AIDS Research (CFAR), the UCLA AIDS Institute, the UCLA Clinical and Translational Science Institute (CTSI), and the Pacific Southwest Regional Center of Excellence (PSWRCE) for Biodefense and Emerging Infectious Diseases funded this study. The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer. For more news, visit the UCLA Newsroom and follow us on Twitter. Contact: Enrique Rivero |
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