Time filter

Source Type

News Article | October 27, 2016
Site: www.eurekalert.org

Acute myeloid leukemia (AML) is an aggressive cancer known for drug resistance and relapse. In an effort to uncover new treatment strategies, researchers at University of California San Diego School of Medicine and Moores Cancer Center discovered that a cell surface molecule known as CD98 promotes AML. The study, published October 27 by Cancer Cell, also shows that inhibiting CD98 with the therapeutic antibody IGN523 blocks AML growth in patient-derived cells and mouse models. "To improve therapeutic strategies for this disease, we need to look not just at the cancer cells themselves, but also at their interactions with surrounding cells, tissues, molecules and blood vessels in the body," said co-senior author Tannishtha Reya, PhD, professor of pharmacology at UC San Diego School of Medicine and Moores Cancer Center. "In this study, we identified CD98 as a critical molecule driving AML growth. We showed that blocking CD98 can effectively reduce leukemia burden and improve survival by preventing cancer cells from receiving support from the surrounding environment." Reya led the study together with Mark Ginsberg, MD, professor of medicine at UC San Diego School of Medicine and Moores Cancer Center. Co-author Edward van der Horst, PhD, senior director at Igenica Biotherapeutics Inc., provided the anti-CD98 antibody IGN523. AML is a type of cancer in which the bone marrow makes abnormal white blood cells, red blood cells or platelets. Reya's team and others have previously shown that leukemia cells interact with their surroundings in the body via molecules on their cell surfaces, and that these interactions can help the cancer cells divide, replicate and metastasize. CD98 is a molecule found on the surface of cells, where it controls how cells stick to one another. CD98 is known to play a role in the proliferation and activation of certain immune cells. CD98 levels are also known to be elevated in some solid tumors, and linked to poor prognosis. To determine CD98's role in AML, in this latest study Reya's team engineered mouse models that lack the molecule. They found that the loss of CD98 blocked AML growth and improved survival. CD98 loss largely spared normal blood cells, which the researchers said indicates a potential therapeutic window. Further experiments revealed that leukemia cells lacking CD98 had fewer stable interactions with the lining of blood vessels -- interactions that were needed to fuel AML growth. Next, the researchers wanted to see what would happen if they blocked CD98 in AML with a deliverable inhibitor. In 2015, Igenica Biotherapeutics Inc. tested IGN523, a humanized antibody that specifically binds and inhibits CD98, in a phase 1 clinical trial at Moores Cancer Center and elsewhere. The trial's goal was to determine a safe dose for IGN523 administration in AML patients. In this study, Reya and team tested IGN523 in their own AML models. The researchers found that IGN523 blocks CD98's AML-promoting activity in both mouse models of AML and human cells in the laboratory. They also transplanted human patient-derived AML cells into mice and treated the recipients soon after with either IGN523, the anti-CD98 antibody, or with a control antibody. Anti-CD98-treatment effectively eliminated AML cells. In contrast, AML in control mice expanded more than 100-fold. "This study suggests that human AML can't get established without CD98, and that blocking the molecule with anti-CD98 antibodies could be beneficial for the treatment of AML in both adults and children," Reya said. Moving forward, Reya and team are working to further define whether CD98 could be targeted to treat pediatric AML. "Many of the models we used in this work were based on mutations found in childhood AML," she said. "While many childhood cancers have become very treatable, childhood AML continues to have a high rate of relapse and death. We plan to work with pediatric oncologists to test if anti-CD98 agents can be effective against pediatric AML, and whether it can improve responses to current treatments. I think this is particularly important to pursue since the anti-CD98 antibody has already been through phase I trials, and could be more easily positioned to test in drug-resistant pediatric AML." The American Cancer Society estimates that there will be about 19,950 new cases of AML and about 10,430 deaths from the disease in the United States in 2016, mostly adults. Approximately 500 children are diagnosed with AML in the U.S. each year, and it's the most common second cancer among children treated for other cancers, according to St. Jude Children's Research Hospital.


News Article | October 29, 2016
Site: www.sciencedaily.com

Acute myeloid leukemia (AML) is an aggressive cancer known for drug resistance and relapse. In an effort to uncover new treatment strategies, researchers at University of California San Diego School of Medicine and Moores Cancer Center discovered that a cell surface molecule known as CD98 promotes AML. The study, published October 27 by Cancer Cell, also shows that inhibiting CD98 with the therapeutic antibody IGN523 blocks AML growth in patient-derived cells and mouse models. "To improve therapeutic strategies for this disease, we need to look not just at the cancer cells themselves, but also at their interactions with surrounding cells, tissues, molecules and blood vessels in the body," said co-senior author Tannishtha Reya, PhD, professor of pharmacology at UC San Diego School of Medicine and Moores Cancer Center. "In this study, we identified CD98 as a critical molecule driving AML growth. We showed that blocking CD98 can effectively reduce leukemia burden and improve survival by preventing cancer cells from receiving support from the surrounding environment." Reya led the study together with Mark Ginsberg, MD, professor of medicine at UC San Diego School of Medicine and Moores Cancer Center. Co-author Edward van der Horst, PhD, senior director at Igenica Biotherapeutics Inc., provided the anti-CD98 antibody IGN523. AML is a type of cancer in which the bone marrow makes abnormal white blood cells, red blood cells or platelets. Reya's team and others have previously shown that leukemia cells interact with their surroundings in the body via molecules on their cell surfaces, and that these interactions can help the cancer cells divide, replicate and metastasize. CD98 is a molecule found on the surface of cells, where it controls how cells stick to one another. CD98 is known to play a role in the proliferation and activation of certain immune cells. CD98 levels are also known to be elevated in some solid tumors, and linked to poor prognosis. To determine CD98's role in AML, in this latest study Reya's team engineered mouse models that lack the molecule. They found that the loss of CD98 blocked AML growth and improved survival. CD98 loss largely spared normal blood cells, which the researchers said indicates a potential therapeutic window. Further experiments revealed that leukemia cells lacking CD98 had fewer stable interactions with the lining of blood vessels -- interactions that were needed to fuel AML growth. Next, the researchers wanted to see what would happen if they blocked CD98 in AML with a deliverable inhibitor. In 2015, Igenica Biotherapeutics Inc. tested IGN523, a humanized antibody that specifically binds and inhibits CD98, in a phase 1 clinical trial at Moores Cancer Center and elsewhere. The trial's goal was to determine a safe dose for IGN523 administration in AML patients. In this study, Reya and team tested IGN523 in their own AML models. The researchers found that IGN523 blocks CD98's AML-promoting activity in both mouse models of AML and human cells in the laboratory. They also transplanted human patient-derived AML cells into mice and treated the recipients soon after with either IGN523, the anti-CD98 antibody, or with a control antibody. Anti-CD98-treatment effectively eliminated AML cells. In contrast, AML in control mice expanded more than 100-fold. "This study suggests that human AML can't get established without CD98, and that blocking the molecule with anti-CD98 antibodies could be beneficial for the treatment of AML in both adults and children," Reya said. Moving forward, Reya and team are working to further define whether CD98 could be targeted to treat pediatric AML. "Many of the models we used in this work were based on mutations found in childhood AML," she said. "While many childhood cancers have become very treatable, childhood AML continues to have a high rate of relapse and death. We plan to work with pediatric oncologists to test if anti-CD98 agents can be effective against pediatric AML, and whether it can improve responses to current treatments. I think this is particularly important to pursue since the anti-CD98 antibody has already been through phase I trials, and could be more easily positioned to test in drug-resistant pediatric AML." The American Cancer Society estimates that there will be about 19,950 new cases of AML and about 10,430 deaths from the disease in the United States in 2016, mostly adults. Approximately 500 children are diagnosed with AML in the U.S. each year, and it's the most common second cancer among children treated for other cancers, according to St. Jude Children's Research Hospital.


News Article | December 1, 2016
Site: www.eurekalert.org

Previous studies identified the Hippo pathway kinases LATS1/2 as a tumor suppressor, but new research led by University of California San Diego School of Medicine scientists reveals a surprising role for these enzymes in subduing cancer immunity. The findings, published in Cell on December 1, could have a clinical role in improving efficiency of immunotherapy drugs. "Before our study, no one knew that the Hippo pathway was regulating immunogenicity," said first author Toshiro Moroishi, MD, PhD, postdoctoral researcher at UC San Diego Moores Cancer Center. "LATS1/2 deletion in cancer cells improves tumor immunogenicity, leading to the destruction of cancerous cells by enhancing anti-tumor immune responses." Hippo pathway signaling regulates organ size by moderating cell growth, apoptosis and stem cell renewal, but dysregulation contributes to cancer development. In vitro studies of Hippo pathway kinases LATS1/2 showed that the loss of these enzymes promoted cell proliferation and tumor survival. In vivo research using immune-compromised mouse models also supports a tumor suppressor function of the Hippo pathway. However, when Moroishi and team deleted LATS1/2 from mouse cancer cells and examined tumor growth in models with healthy immune systems researchers found that immunogenicity -- the ability to stimulate an immune response -- improved, destroying cancer cells. Researchers caution that immune systems of mouse models are different from the human immune system so the response might be different and further studies are needed. If the outcome proves to be the same, using a LATS1/2 inhibitor alone or in combination with an immune checkpoint inhibitor may stimulate the immune system of patients that previously did not respond to immunotherapy treatments. Currently, most immunotherapy research focuses on targeting the immune system, but the new findings reveal that tumor cells may also be vulnerable to inhibitors. "Inhibiting LATS1/2 could be an attractive approach to treat cancer," said Kun-Liang Guan, PhD, Distinguished Professor of Pharmacology at Moores Cancer Center and senior author of the study. "LATS is an ideal target because there are many kinase inhibitors that have been successfully developed as cancer drugs." This study focused on breast cancer, melanoma and squamous cell carcinoma but the same could be applied to other cancers, said Moroishi. Study co-authors include: Tomoko Hayashi, Yu Fujita, Dennis A. Carson, UC San Diego; Wei-Wei Pan, UC San Diego and Jiaxing University; Matthew V. Holt, and Jun Qin, Baylor College of Medicine. Disclosure: Kun-Liang Guan is co-founder of Vivace Therapeutics and holds equity interest.


PubMed | University of California at San Diego and Moores Cancer Center and
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Pathological antibodies have been demonstrated to play a key role in type II immune hypersensitivity reactions, resulting in the destruction of healthy tissues and leading to considerable morbidity for the patient. Unfortunately, current treatments present significant iatrogenic risk while still falling short for many patients in achieving clinical remission. In the present work, we explored the capability of target cell membrane-coated nanoparticles to abrogate the effect of pathological antibodies in an effort to minimize disease burden, without the need for drug-based immune suppression. Inspired by antibody-driven pathology, we used intact RBC membranes stabilized by biodegradable polymeric nanoparticle cores to serve as an alternative target for pathological antibodies in an antibody-induced anemia disease model. Through both in vitro and in vivo studies, we demonstrated efficacy of RBC membrane-cloaked nanoparticles to bind and neutralize anti-RBC polyclonal IgG effectively, and thus preserve circulating RBCs.

Loading Moores Cancer Center and collaborators
Loading Moores Cancer Center and collaborators