BreakThrough Digest Medical News |
- Molecule treats leukemia by preventing cancer cell repair, Jackson Laboratory scientists report
- New drug combination therapy developed to treat leukemia
- IDRI and Medicago report positive results for Phase I clinical trial for an H5N1 vaccine
- Scientists reverse memory loss in animal brain cells
- Cell-permeable peptide shows promise for controlling cardiovascular disease
| Molecule treats leukemia by preventing cancer cell repair, Jackson Laboratory scientists report Posted: 16 Apr 2013 09:00 PM PDT Researchers at The Jackson Laboratory have identified a molecule that prevents repair of some cancer cells, providing a potential new “genetic chemotherapy” approach to cancer treatment that could significantly reduce side effects and the development of treatment resistance compared with traditional chemotherapy.
In healthy people, white blood cells called B cells (or B lymphocytes) are a kind of sophisticated tool kit, making antibodies against pathogens or other invaders. In the process of antibody production, B cells turn on the gene known as activation-induced cytidine deaminase (AID), which acts as a sort of molecular scissors that cut the chromosomes within the B cell. This is needed to rearrange pieces of the B-cell chromosomes and produce different “flavors” of antibodies that do different jobs. But in some cancers this process goes wrong, with AID acting out of control and creating mutations and chromosome rearrangements that make the tumor more aggressive. Those AID-induced cancers proliferate with help from the cell-repair mechanism known as homologous recombination (HR). Researchers in the laboratory of Associate Professor Kevin Mills, Ph.D., identified a molecule called DIDS (for 4,4′-diisothiocyanatostilbene-2-2′-disulfonic acid) that blocks the DNA repair action in chronic lymphocytic leukemia (CLL), causing the cancer cells to die. “This treatment affects every cell in the body,” Mills says. “But by its mode of action it kills only tumor cells that are expressing AID, yet it is almost entirely harmless to normal, healthy cells.” The research, published in The Journal of Experimental Medicine, is the latest proof of principle for what Mills calls “genetic chemotherapy”: using the mechanisms involved in genetic instability in cancer, to cause tumor cell self-destruction. For the new paper, authors Kristin Lamont, Ph.D., a postdoctoral associate, and Muneer Hasham, Ph.D. an associate research scientist, both in the Mills laboratory, tested DIDS in normal mouse cells, mouse cancer cells, human cancer cell lines and human primary cancers. “We collected 74 different primary patient CLL samples,” Lamont says, “and measured AID expression in those samples. We found that about 40 percent of them express AID, and if we treated those with DIDS in vitro, the AID-expressing ones had significantly higher levels of DNA damage and died.” Mills adds, “Demonstrating that this works on primary cancer cells moves us one step closer to eventually testing this in patients.” The DIDS treatment approach, Mills adds, also addresses the issues of side effects, a major problem with standard chemotherapy. “By its selectivity for cancer cells, DIDS reduces the issue of the really nasty side effects associated with chemotherapy treatments,” Mills explains. Moreover, the list of cancers associated with aberrant AID expression is growing, so the treatment approach could apply not only to leukemia but also a range of other cancer types. Mills’ collaborators at Memorial Sloan-Kettering Cancer Center in New York shared their expertise in DNA repair to understand the action of the DIDS molecule. “We hypothesized that the molecule would work as it did,” Mills says, “but they helped us to determine exactly why and how it works.” Since the researchers submitted the paper for publication, they have developed a new and better potential treatment molecule. “One of our goals is to design an even better molecule,” Mills says. “And we’ve done that. We now have a new molecule in that same class, that delivers significantly more potency, with just as much selectivity as the original molecule.” Cyteir Therapeutics, Inc. a startup biotechnology company founded by Mills in 2012, continues to pursue development of the new molecule for cancer therapy, while Dr. Mills and his team at Jackson will keep studying the cellular mechanisms, in the hope of finding yet more potential new cancer drugs. Cyteir Therapeutics is now ramping up the R&D efforts necessary to take the genetic chemotherapy treatment to clinical trials, possibly in 2014. ### This work, which took place in The Jackson Laboratory’s NCI-designated Cancer Center, was a collaboration with oncologists at Cancer Care of Maine, part of Eastern Maine Medical Care in Bangor, Maine, and the Maine Center for Cancer Medicine and Maine Medical Center Research Institute, both in Scarborough, Maine. The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif., and a new genomic medicine institute in Farmington, Conn. It employs a total staff of more than 1,450. Its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. Contact: Joyce Peterson |
| New drug combination therapy developed to treat leukemia Posted: 16 Apr 2013 09:00 PM PDT A new, pre-clinical study by researchers at Virginia Commonwealth University Massey Cancer Center suggests that a novel drug combination could lead to profound leukemia cell death by disrupting the function of two major pro-survival proteins. The effectiveness of the therapy lies in its ability to target a pro-survival cell signaling pathway known as PI3K/AKT/mTOR, upon which the leukemia cells have become dependent.
In the study, published in the journal Cancer Research, researchers combined the drug ABT-737 with another agent BEZ235. ABT-737 targets proteins known as B-cell lymphoma 2 (Bcl-2) and Bcl-xL, which prevent apoptosis, a form of cell suicide, in cancer cells. BEZ235 directly inhibits the PI3K/AKT/mTOR pathway, and as a result, reduces the expression of another anti-apoptotic protein known as Mcl-1, which is not targeted by ABT-737. Among their many functions, signaling pathways regulate biological processes required for cellular survival. The PI3K/AKT/mTOR pathway helps keep apoptosis in check, in part, by controlling the production of Mcl-1. However, the pathway can become dysregulated in cancer, and in so doing, contribute to uncontrolled tumor growth and resistance to conventional cancer therapies. It is activated in 50 to 80 percent of patients with acute myelogenous leukemia (AML), and in some, but not all cases, is associated with genetic mutations. Significantly, disabling both anti-apoptotic proteins, Bcl-2 and Bcl-xL, in conjunction with Mcl-1, caused profound cell death of leukemia cells in the test tube as well as in animal models of AML. “This study builds on many years of work in our laboratory investigating the mechanisms that regulate apoptosis in human leukemia cells. To the best of our knowledge, it is the first to raise the possibility that activation of the P13K/AKT/mTOR pathway, rather than genetic mutations within the pathway, may represent the best predictor of leukemia cell responses to these targeted agents,” says one of the study’s key researchers Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, program co-leader of Developmental Therapeutics and Cancer Cell Signaling research member at VCU Massey Cancer Center. “These findings could lead to a new therapeutic strategy for patients with AML and potentially other diseases by targeting patients whose leukemia cells display activation of a specific survival pathway.” Grant’s team made another discovery that helped explain the new therapy’s effectiveness. They found that the therapy releases and/or activates the pro-apoptotic proteins Bim, Bak and Bax, which help trigger apoptosis. Thus, in addition to disabling major pro-survival proteins, the combination therapy also helps to unleash several additional proteins that promote apoptosis. Moving forward, Grant and his team hope to work with pharmaceutical companies and the National Cancer Institute to develop strategies combining inhibitors of the PI3K/AKT/mTOR pathway with Bcl-2 family antagonists for the treatment of patients with AML. ### Grant collaborated on this research with lead author Mohamed Rahmani, Ph.D., associate professor of internal medicine at the VCU School of Medicine, who spearheaded this research. Other collaborators included David C. Williams M.D., Ph.D., co-director of the Tissue and Data Acquisition and Analysis Core at VCU Massey Cancer Center, researcher in the Developmental Therapeutics program at Massey and assistant professor in the VCU Department of Pathology; and Andrea Ferreira-Gonzalez, Ph.D., professor in the VCU Department of Pathology. This research was supported by National Institutes of Health grants CA93738, CA100866-01, CA130805, CA142509, and CA148431; awards from the Leukemia and Lymphoma Society of America and the Multiple Myeloma Research Foundation; and, in part, by funding from VCU Massey Cancer Center’s NIH-NCI Cancer Center Support Grant P30 CA016059. The full manuscript of this study can be found online at: http://cancerres.aacrjournals.org/content/73/4/1340.long. News directors: Broadcast access to VCU Massey Cancer Center experts is available through VideoLink ReadyCam. ReadyCam transmits video and audio via fiber optics through a system that is routed to your newsroom. To schedule a live or taped interview, contact Alaina Farrish, (804) 628-4578. About VCU Massey Cancer Center VCU Massey Cancer Center is one of only 67 National Cancer Institute-designated institutions in the country that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It has one of the largest offerings of clinical trials in Virginia and serves patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at http://www.massey.vcu.edu or call 877-4-MASSEY for more information. About VCU and the VCU Medical Center Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see http://www.vcu.edu. Contact: Alaina Farrish |
| IDRI and Medicago report positive results for Phase I clinical trial for an H5N1 vaccine Posted: 16 Apr 2013 09:00 PM PDT IDRI (Infectious Disease Research Institute), a Seattle-based non-profit research organization that is a leading developer of adjuvants used in vaccines combating infectious disease, and Medicago Inc. (TSX: MDG; OTCQX: MDCGF), a biopharmaceutical company focused on developing highly effective and competitive vaccines based on proprietary manufacturing technologies and Virus-Like Particles (VLPs), today reported positive interim results from a Phase I clinical trial for an H5N1 Avian Influenza VLP vaccine candidate (“H5N1 vaccine”). The results were announced at the World Vaccine Congress in Washington, DC. The H5N1 vaccine was found to be safe and well-tolerated and induced a solid immune response exceeding the three CHMP (Committee for Medicinal Products for Human Use) immunogenicity criteria for licensure of influenza vaccines. The vaccine was tested in three different configurations: using IDRI’s Glucopyranosyl Lipid A (“GLA”) formulated adjuvant, given both intramuscularly and intradermally, and using alum intramuscularly. All three configurations exceeded the CHMP criteria.
“These positive U.S. clinical trial results confirm that our H5N1 vaccine candidate is the best in class in our opinion, positioning Medicago as a significant player in the global pandemic market. The robustness of our H5N1 vaccine coupled with our rapid speed of production, offers a vastly improved solution in preparing for and managing potential pandemics. We also believe that our H5N1 vaccine with alum is the only alum-adjuvanted pandemic vaccine to achieve the three CHMP immunogenicity criteria,” said Andy Sheldon, President and CEO of Medicago. “Moreover, the combination of our vaccine candidate with IDRI’s adjuvant generated a robust immune response. In the case of a pandemic, governments will require the rapid development of an effective vaccine within their borders to conquer the spread of the virus, with our cost-effective and capital inexpensive system we are perfectly poised to obtain this objective. In summary, all three configurations tested of the H5N1 vaccine meet the CHMP criteria for licensure, placing us in a strong position with multiple product options. We will further investigate the use of alum and formulated GLA in a Phase II trial to be initiated in May 2013 with results expected in Q3 2013.” The trial results also underscore IDRI’s leadership position in the field of adjuvants, with a focus on developing products that will reduce the burden of global infectious disease. “This study design and results demonstrate the potential for significant ‘dose-sparing’ — increasing the number of available doses by reducing the amount of vaccine needed per individual, in a simple to administer format,” said Dr. Steven Reed, IDRI Founder, President and Chief Scientific Officer, who presented the trial results at the World Vaccine Congress, along with Dr. Brian Ward, Professor of Medicine & Microbiology, McGill University, member of Medicago’s scientific advisory committee and Medical Officer. “This H5N1 vaccine candidate represents the next generation of flu vaccines, combining our adjuvant technology with Medicago’s rapid VLP technology and the intradermal delivery device from NanoPass.” Study Design
The Phase I clinical trial, which commenced in September 2012, enrolled 100 healthy adult volunteers, aged 18-49 years, at three locations in the U.S., testing for safety and immune response. The vaccine was also tested in comparison to Medicago’s H5N1 vaccine with alum. The trial is funded by a multi-million dollar grant IDRI received from the Defense Advanced Research Projects Agency (DARPA), a division of the United States Department of Defense, to investigate the safety and immunogenicity of a novel adjuvant with a Nicotiana benthamiana produced vaccine candidate. Each study participant in the trial received two doses of a given formulation in order to collect and compare data. The trial focused on evaluating the safety and immunogenicity of the H5N1 vaccine, combined with IDRI’s GLA adjuvant, which has been exclusively licensed to Immune Design Corp for certain fields, including influenza. The vaccine was administered intramuscularly or intradermally. The intradermal route of administration was also tested in comparison with intramuscular delivery, using an FDA licensed device (MicronJet600®, NanoPass Technologies) as the micro-needle device was previously shown in seasonal and pandemic flu tests to allow significant dose sparing. This study is among the first to test intradermal adjuvants and is the first time GLA has been tested intradermally. Safety and Immunogenicity Results
The H5N1 vaccine candidate has been tested in over 300 healthy volunteers to date, none of which have experienced any serious adverse reactions. The H5N1 vaccine candidate was found to be safe and well tolerated. As planned in the clinical design, monitoring of adverse events will continue for one year. All three configurations of adjuvant and route of administration for 20ug of the H5N1 vaccine candidate induced a solid immune response against the H5N1 viral strain that exceeded the CHMP immunogenicity criteria for licensure of influenza vaccines which are 40% seroconversion, 70% seroprotection and 2.5x geometric mean increase (GMI). For a 20ug dose of the H5N1 vaccine plus; 2.5ug GLA-AF administered intradermally (ID), 2.5ug GLA-AF delivered Intramuscularly (IM) and 0.5ug alum formulation administered IM, a four-fold increase in HI titers (seroconversion) was observed in 65.0%, 80.0% and 83.3% of subjects, respectively. The seroprotection rate was 70.0%, 85.0% and 89.9%, respectively. The GMI was 10.3x, 8.7x, and 11.4x, respectively. About H5N1
According to the Centers for Disease Control and Prevention, the highly pathogenic avian influenza A (H5N1) virus is a deadly virus that occurs mainly in birds including domestic poultry. Though relatively rare, sporadic human infections with this virus have occurred and caused serious illness and death. Because of the unpredictability of pandemic flu, efforts are being made to create and stockpile a vaccine to combat H5N1 that reduces the amount of vaccine needed per person and can be easily administered. About Medicago’s pandemic flu vaccine candidate
Medicago’s H5N1 vaccine candidate was formulated to protect against the Indonesian influenza virus. It is manufactured in Nicotiana benthamiana, a relative of the tobacco plant, using the Company’s proprietary VLP technology. VLPs may have several advantages over traditional flu vaccines. They are made to look like a virus, allowing them to be recognized readily by the body’s immune system, however, they lack the core genetic material making them non-infectious and unable to replicate. Medicago’s technology only requires the genetic sequence of a viral strain and not the live influenza virus. This key difference allows vaccines to be manufactured within four weeks of obtaining the genetic sequence of a pandemic strain. This is in contrast with current manufacturing technologies which rely on strain adaptation and can only deliver a vaccine six months after a pandemic is declared. ### About IDRI
IDRI is a Seattle-based non-profit organization committed to applying innovative science to the research and development of products to prevent, detect, and treat infectious diseases of poverty. By integrating capabilities, IDRI strives to create an efficient pathway bringing scientific innovation from the lab to the people who need it most. For more information, go to http://www.idri.org. About Medicago
Medicago is a clinical-stage biopharmaceutical company developing novel vaccines and therapeutic proteins to address a broad range of infectious diseases worldwide. The Company is committed to providing highly effective and competitive vaccines and therapeutic proteins based on its proprietary VLP and manufacturing technologies. Medicago is a worldwide leader in the development of VLP vaccines using a transient expression system which produces recombinant vaccine antigens in plants. This technology has potential to offer more potent vaccines with speed and cost advantages over competitive technologies, enabling the development of a vaccine for testing in approximately one month after the identification and reception of genetic sequences from a pandemic strain. This production time frame has the potential to allow vaccination of the population before the first wave of a pandemic, and supply large volumes of vaccine antigens to the world market. Medicago also intends to expand development into other areas such as biosimilars and biodefense products where the benefits of our technologies can make a significant difference. Additional information about Medicago is available at http://www.medicago.com. About NanoPass Technologies Ltd.
NanoPass is the developer of MicronJet600?, an FDA-registered intradermal microneedles device. NanoPass has concluded the world’s first intradermal pandemic (H1N1) flu vaccine clinical study and additional seasonal flu studies, demonstrating equivalent or superior immunogenicity to standard intramuscular delivery using only 20% of the dose. Forward Looking Statements
This news release includes certain forward-looking statements or forward-looking information for the purposes of applicable securities laws and such statements and information are based upon current expectations, which involve risks and uncertainties associated with Medicago’s business and the environment in which the business operates. Any statements contained herein that are not statements of historical facts may be deemed to be forward-looking, including those identified by the expressions “anticipate”, “believe”, “plan”, “estimate”, “expect”, “intend”, and similar expressions to the extent they relate to Medicago or its management. The forward-looking statements are not historical facts, but reflect Medicago’s current expectations regarding future results or events. Such statements include but are not limited to statements about the collaboration with IDRI and the Phase I clinical trial. These forward-looking statements are subject to a number of risks and uncertainties that could cause actual results or events to differ materially from current expectations, including the matters discussed under “Risk Factors and Uncertainties” in Medicago’s Annual Information Form filed on March 28, 2013, with the regulatory authorities. Medicago assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those reflected in the forward-looking statements. Contact: Medicago Christina Cameron NanoPass Contact: Lee Schoentrup |
| Scientists reverse memory loss in animal brain cells Posted: 16 Apr 2013 09:00 PM PDT Neuroscientists at The University of Texas Health Science Center at Houston (UTHealth) have taken a major step in their efforts to help people with memory loss tied to brain disorders such as Alzheimer’s disease.
Using sea snail nerve cells, the scientists reversed memory loss by determining when the cells were primed for learning. The scientists were able to help the cells compensate for memory loss by retraining them through the use of optimized training schedules. Findings of this proof-of-principle study appear in the April 17 issue of the Journal of Neuroscience. “Although much works remains to be done, we have demonstrated the feasibility of our new strategy to help overcome memory deficits,” said John “Jack” Byrne, Ph.D., the study’s senior author, as well as director of the W.M. Keck Center for the Neurobiology of Learning and Memory and chairman of the Department of Neurobiology and Anatomy at the UTHealth Medical School. This latest study builds on Byrne’s 2012 investigation that pioneered this memory enhancement strategy. The 2012 study showed a significant increase in long-term memory in healthy sea snails called Aplysia californica, an animal that has a simple nervous system, but with cells having properties similar to other more advanced species including humans. Yili Zhang, Ph.D., the study’s co-lead author and a research scientist at the UTHealth Medical School, has developed a sophisticated mathematical model that can predict when the biochemical processes in the snail’s brain are primed for learning. Her model is based on five training sessions scheduled at different time intervals ranging from 5 to 50 minutes. It can generate 10,000 different schedules and identify the schedule most attuned to optimum learning. “The logical follow-up question was whether you could use the same strategy to overcome a deficit in memory,” Byrne said. “Memory is due to a change in the strength of the connections among neurons. In many diseases associated with memory deficits, the change is blocked.” To test whether their strategy would help with memory loss, Rong-Yu Liu, Ph.D., co-lead author and senior research scientist at the UTHealth Medical School, simulated a brain disorder in a cell culture by taking sensory cells from the sea snails and blocking the activity of a gene that produces a memory protein. This resulted in a significant impairment in the strength of the neurons’ connections, which is responsible for long-term memory. To mimic training sessions, cells were administered a chemical at intervals prescribed by the mathematical model. After five training sessions, which like the earlier study were at irregular intervals, the strength of the connections returned to near normal in the impaired cells. “This methodology may apply to humans if we can identify the same biochemical processes in humans. Our results suggest a new strategy for treatments of cognitive impairment. Mathematical models might help design therapies that optimize the combination of training protocols with traditional drug treatments,” Byrne said. He added, “Combining these two could enhance the effectiveness of the latter while compensating at least in part for any limitations or undesirable side effects of drugs. These two approaches are likely to be more effective together than separately and may have broad generalities in treating individuals with learning and memory deficits.” ### Other co-authors from the UTHealth Medical School included: Douglas A. Baxter, Ph.D., professor; Paul Smolen, Ph.D., assistant professor; and Len Cleary, Ph.D., professor. The paper, which is titled “Deficit in Long-Term Synaptic Plasticity is Rescued by a Computationally Predicted Stimulus Protocol,” received support from National Institutes of Health grants (NS019895 and NS073974). Contact: Robert Cahill |
| Cell-permeable peptide shows promise for controlling cardiovascular disease Posted: 15 Apr 2013 09:00 PM PDT Atherosclerosis ? sometimes called “hardening of the arteries” ? is a leading cause of death and morbidity in Western countries. A cell-permeable peptide containing the NF-?B nuclear localization sequence (NLS) shows promise as a potential agent in controlling the development of atherosclerotic disease. This study is published in the May 2013 issue of The American Journal of Pathology.
Atherosclerosis is a chronic inflammatory disease of the arterial and vascular wall. The objective of many therapeutic compounds is to modulate atherogenesis ? the process that leads to the formation of fatty tissue-containing plaques that stick to the cell wall. Numerous cellular and molecular inflammatory components are involved in the disease process, and uncontrolled activation of pro-inflammatory transcription factors, such as nuclear factor-B (NF-?B), plays a significant role. Several NF-?B inhibitors are in phase II-III clinical trials against various inflammatory diseases, but most cardiovascular research is still in the preliminary laboratory experimental phase. Investigators in Spain, the United States, the United Kingdom, and Germany studied the anti-inflammatory and atheroprotective effects of a cell-permeable peptide containing the NF-?B NLS. In vitro tests clearly established that NLS peptide blocks the nuclear import of activated NF-?B and inhibits NF-?B activation in vascular cells. These findings were corroborated in vivo in ApoE knockout mice, an experimental model relevant to human atherosclerosis. In these experiments, the mice were fed a high-fat diet and treated with either NLS peptide or vehicle (control group). The results showed that systemic administration of NLS peptide reduced the nuclear NF-?B activity in vascular smooth muscle cells (VSMCs) and macrophages of aortic plaques of mice. More importantly, NLS peptide inhibited lesion development in mice either at the onset of atherosclerosis (early treatment) or after the development of advanced plaques (delayed treatment), without affecting serum cholesterol levels. The results also demonstrated that NLS peptide alters plaque composition and inflammation in atherosclerotic lesions. “The NF-?B system is a crucial factor regulating the expression of genes in different steps of the atherosclerotic process, from early phases characterized by lipid modification, chemotaxis, adhesion of leukocytes, monocyte differentiation, foam cell formation, and inflammatory cytokine expression to more advanced lesions involving cell death, migration and proliferation of VSMCs, and fibrous cap formation,” explained lead investigator Carmen Gomez-Guerrero, PhD, of the Renal and Vascular Inflammation Laboratory, IIS-Fundación Jiménez Díaz, Autonoma University, Madrid, Spain. “Our study demonstrates that targeting NF-?B nuclear translocation hampers inflammation and atherosclerosis development and identifies cell-permeable NLS peptide as a potential anti-atherosclerotic agent,” she said. “These properties make cell-permeable NLS peptide a promising prevention/intervention strategy to inhibit inflammation in cardiovascular diseases.” Contact: David Sampson |
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