BreakThrough Digest Medical News |
- Experimental drug combination selectively destroys lymphoma cells
- Tiny capsule effectively kills cancer cells
- Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s
| Experimental drug combination selectively destroys lymphoma cells Posted: 05 Feb 2013 09:00 PM PST Laboratory experiments conducted by scientists at Virginia Commonwealth University Massey Cancer Center suggest that a novel combination of the drugs ibrutinib and bortezomib could potentially be an effective new therapy for several forms of blood cancer, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).
The study, published in the British Journal of Hematology, showed that the experimental drug combination killed cancer cells through a form of cell suicide known as apoptosis, but was relatively non-toxic to normal, healthy cells. Ibrutinib is a new agent that inhibits the B-cell receptor (BCR) signaling complex, which plays an important role in the survival of malignant B-cells. It has shown very promising initial results in the treatment of patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL), DLBCL and MCL. The synergistic interaction of the two drugs proved lethal even to lymphoma cells that had become resistant to bortezomib, when used alone. “Bortezomib is currently used to treat MCL and multiple myeloma, but, unfortunately, many patients develop resistance to the drug,” says the study’s principle investigator 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. “We are hopeful that this combination therapy may circumvent such resistance and eventually help fill an urgent need for more effective therapies for patients with these uncommon blood disorders.” With cultured DLBCL and MCL cells in laboratory experiments spearheaded by Girija Dasmahapatra, Ph.D., lead author of the study’s manuscript and instructor in the Department of Internal Medicine at VCU School of Medicine, the scientists found that ibrutinib blocked several molecular pathways that the cancer cells use for growth and survival. When ibrutinib was combined with bortezomib, the scientists observed a high level of synergism between the two drugs that resulted in profound cell death due to DNA damage, culminating in apoptosis. The research findings suggest that the effectiveness of the combination therapy against bortezomib-resistant lymphoma cells may stem from ibrutinib’s ability to block signaling pathways used by the cancer cells to survive bortezomib exposure. Specifically, exposure of DLBCL and MCL cells to ibrutinib blocked the cancer-promoting NF-?B, AKT and ERK1/2 signaling pathways. These signaling pathways provide cells with the ability to adapt to otherwise harmful environmental stimuli by transmitting messages from receptors located at the cell’s surface to proteins within the cell that trigger a variety of biological processes. In particular, NF-?B, AKT and ERK1/2 have been shown to carry out many functions that allow cancer cells to survive and proliferate. Significantly, each of these pathways has been implicated in the development of resistance to proteasome inhibitors such as bortezomib. “We have provided a framework for understanding how an agent like ibrutinib might be employed to enhance the activity of an established anti-cancer agent like bortezomib,” says Grant. “We are currently working with representatives from the pharmaceutical industry and the National Cancer Institute to develop a new treatment strategy in which ibrutinib will be combined with proteasome inhibitors like bortezomib for the treatment of patients with lymphomas and potentially other blood cancers.” ### Grant and Dasmahapatra collaborated on this study with Hiral Patel and Tri Nguyen, Ph.D., from the Department of Internal Medicine at VCU School of Medicine; Paul Dent, Ph.D., Universal Corporation Distinguished Professor for Cancer Cell Signaling, vice chair of the department of neurosurgery and member of the Developmental Therapeutics research program at VCU Massey; and Richard I. Fisher, M.D., and Jonathan Friedberg, M.D., from the James T. Wilmot Cancer Center at the University of Rochester. This research was supported by National Institutes of Health grants CA63753, CA93738 and CA100866; Lymphoma SPORE award 1P50 CA130805; award R6059-06 from the Leukemia and Lymphoma Society of America; the Multiple Myeloma Research Foundation; Myeloma Spore grant P50CA142509; the V 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 is available online at: http://onlinelibrary.wiley.com/doi/10.1111/bjh.12206/abstract;jsessionid=D5165E95BC0631E5D3EAA2F6888ABC45.d01t02 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 John Wallace, (804) 628-1550. 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 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 www.vcu.edu. Contact: John Wallace |
| Tiny capsule effectively kills cancer cells Posted: 05 Feb 2013 09:00 PM PST A tiny capsule invented at a UCLA lab could go a long way toward improving cancer treatment. Devising a method for more precise and less invasive treatment of cancer tumors, a team led by researchers from the UCLA Henry Samueli School of Engineering and Applied Science has developed a degradable nanoscale shell to carry proteins to cancer cells and stunt the growth of tumors without damaging healthy cells.
In a new study, published online Feb. 1 in the peer-reviewed journal Nano Today, a group led by Yi Tang, a professor of chemical and biomolecular engineering and a member of the California NanoSystems Institute at UCLA, reports developing tiny shells composed of a water-soluble polymer that safely deliver a protein complex to the nucleus of cancer cells to induce their death. The shells, which at about 100 nanometers are roughly half the size of the smallest bacterium, degrade harmlessly in non-cancerous cells. The process does not present the risk of genetic mutation posed by gene therapies for cancer, or the risk to healthy cells caused by chemotherapy, which does not effectively discriminate between healthy and cancerous cells, Tang said. “This approach is potentially a new way to treat cancer,” said Tang. “It is a difficult problem to deliver the protein if we don’t use this vehicle. This is a unique way to treat cancer cells and leave healthy cells untouched.” The cell-destroying material, apoptin, is a protein complex derived from an anemia virus in birds. This protein cargo accumulates in the nucleus of cancer cells and signals to the cell to undergo programmed self-destruction. The polymer shells are developed under mild physiological conditions so as not to alter the chemical structure of the proteins or cause them to clump, preserving their effectiveness on the cancer cells. Tests done on human breast cancer cell lines in laboratory mice showed significant reduction in tumor growth. “Delivering a large protein complex such as apoptin to the innermost compartment of tumor cells was a challenge, but the reversible polymer encapsulation strategy was very effective in protecting and escorting the cargo in its functional form,” said Muxun Zhao, lead author of the research and a graduate student in chemical and biomolecular engineering at UCLA. Tang’s group continues to research ways of more precisely targeting tumors, prolonging the circulation time of the capsules and delivering other highly sought-after proteins to cancer cells. The research team also included former UCLA Engineering student Zhen Gu, now an assistant professor in the joint biomedical engineering department at the University of North Carolina at Chapel Hill and North Carolina State University, and University of Southern California researchers including graduate student Biliang Hu, postdoctoral scholar Kye-Il Joo and associate professor Pin Wang. The Nano Today paper also will be published in a future print edition of the journal. ### The research was funded by the David and Lucille Packard Foundation and a breast cancer research grant from the Congressionally Directed Medical Research Program. The UCLA Henry Samueli School of Engineering and Applied Science, established in 1945, offers 28 academic and professional degree programs and has an enrollment of more than 5,000 students. The school’s distinguished faculty are leading research to address many of the critical challenges of the 21st century, including renewable energy, clean water, health care, wireless sensing and networking, and cybersecurity. Ranked among the top 10 engineering schools at public universities nationwide, the school is home to nine multimillion-dollar interdisciplinary research centers in wireless sensor systems, wireless health, nanoelectronics, nanomedicine, renewable energy, customized computing, the smart grid, and the Internet, all funded by federal and private agencies and individual donors. Contact: Bill Kisliuk |
| Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s Posted: 04 Feb 2013 09:00 PM PST A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system’s ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer’s disease.
In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer’s Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance. Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque. The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA. “Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer’s,” said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA. For the study, scientists drew blood samples from both Alzheimer’s patients and healthy controls, then isolated critical immune cells called macrophages from the blood. Macrophages are responsible for gobbling up amyloid-beta and other waste products in the brain and body. The team incubated the immune cells overnight with amyloid-beta. They added either an active form of vitamin D3 called 1alpha,25?dihydroxyvitamin D3 or an active form of the omega-3 fatty acid DHA called resolvin D1 to some of the cells to gauge the effect they had on inflammation and amyloid-beta absorption. Both 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 improved the ability of the Alzheimer’s disease patients’ macrophages to gobble-up amyloid-beta, and they inhibited the cell death that is induced by amyloid-beta. Researchers observed that each nutrition molecule utilized different receptors and common signaling pathways to do this. Previous work by the team, based on the function of Alzheimer’s patients’ macrophages, showed that there are two groups of patients and macrophages. In the current study, researchers found that the macrophages of the Alzheimer’s patients differentially expressed inflammatory genes, compared with the healthy controls, and that two distinct transcription patterns were found that further define the two groups: Group 1 had an increased transcription of inflammatory genes, while Group 2 had decreased transcription. Transcription is the first step leading to gene expression. “Further study may help us identify if these two distinct transcription patterns of inflammatory genes could possibly distinguish either two stages or two types of Alzheimer’s disease,” said study author Mathew Mizwicki, an assistant researcher at the David Geffen School of Medicine at UCLA. While researchers found that 1alpha,25-dihydroxyvitamin D3 and resolvin D1 greatly improved the clearance of amyloid-beta by macrophages in patients in both groups, they discovered subtleties in the effects the two substances had on the expression of inflammatory genes in the two groups. In Group 1, the increased-inflammation group, macrophages showed a decrease of inflammatory activation; in Group 2, macrophages showed an increase of the inflammatory genes IL1 and TLRs when either 1alpha,25-Dihydroxyvitamin D3 or resolvin D1 were added. More study is needed, Fiala said, but these differences could be associated with the severity of patients’ nutritional and/or metabolic deficiencies of vitamin D3 and DHA, as well as the omega-3 fatty acid EPA (eicosapentaenoic acid). “We may find that we need to carefully balance the supplementation with vitamin D3 and omega-3 fatty acids, depending on each patient in order to help promote efficient clearing of amyloid-beta,” Fiala said. “This is a first step in understanding what form and in which patients these nutrition substances might work best.” According to Fiala, an active (not oxidized) form of omega-3 DHA, which is the precursor of the resolvin D1 used in this study, may work better than more commercially available forms of DHA, which generally are not protected against the oxidation that can render a molecule inactive. The next step is a larger study to help confirm the findings, as well as a clinical trial with omega-3 DHA, the researchers said. ### The Alzheimer’s Association contributed to the initial phase of the study. Fiala is a consultant for the Smartfish Company that is producing a drink with an active form of omega-3 DHA. Additional study authors include Guanghao Liu, Larry Magpantay, James Sayre, Avi Siani, Michelle Mahanian, Rachel Weitzman, Eric Hayden, Mark J. Rosenthal, Ilka Nemere, John Ringman and David B. Teplow. For more news, visit the UCLA Newsroom and follow us on Twitter. Contact: Rachel Champeau |
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