{"id":332,"date":"2015-01-27T11:08:45","date_gmt":"2015-01-27T19:08:45","guid":{"rendered":"https:\/\/keck.usc.edu\/news\/protein-based-therapy-shows-promise-against-resistant-leukemia\/"},"modified":"2023-11-19T12:05:25","modified_gmt":"2023-11-19T20:05:25","slug":"protein-based-therapy-shows-promise-against-resistant-leukemia","status":"publish","type":"post","link":"https:\/\/keck.usc.edu\/news\/protein-based-therapy-shows-promise-against-resistant-leukemia\/","title":{"rendered":"Protein-based therapy shows promise against resistant leukemia"},"content":{"rendered":"\n \n \n\n\n\n\n\n\n\n
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\n\n \n Press Release<\/span>\n\n\n\n<\/div>\n \n \n
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Protein-based therapy shows promise against resistant leukemia<\/h1>\n\n\n<\/div>\n \n \n
\n Debra Kain<\/span>\n \n January 27, 2015<\/span>\n <\/div>\n \n \n
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Fatih Uckun (Photo courtesy of Children\u2019s Hospital Los Angeles)<\/figcaption>\n <\/figure>\n \n \n \n\n<\/div>\n \n\n <\/div><\/div>\n\r\n\r\n\n\n \n \n\n\n\n\n\n\n\n
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Resistance of leukemia cells to contemporary chemotherapy is one of the most formidable obstacles to treating acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Now Keck School of Medicine faculty and researchers at Children\u2019s Hospital Los Angeles (CHLA) have designed and developed a new protein-based therapy they believe will prove highly effective against drug-resistant leukemia cells. It may also amplify the potency of standard treatment options such as chemotherapy and radiation therapy.
\nTheir work, published online January 26 by the Journal of Clinical Investigation<\/em>, demonstrated the efficacy and safety of the new fusion protein in mouse models of aggressive human leukemia using leukemia cells taken directly from patients with ALL.
\nOccurring at an annual rate of 35 to 40 cases per million people in the U.S., ALL represents approximately 25 percent of cancer diagnoses among children under the age of 15. Historically, ALL had a high mortality rate; nearly 80 percent of children who developed the disease did not survive long term. Today, those numbers have been reversed, with almost 80 percent of children affected by ALL achieving long-term survival.
\n\u201cThat\u2019s great news, unless your child is one of the 20 percent,\u201d said the study\u2019s principal investigator, Fatih M. Uckun, professor of research pediatrics at the Keck School of Medicine. Uckun is also part of the Children\u2019s Center for Cancer and Blood Disease at CHLA and the USC Norris Comprehensive Cancer Center, and a principal investigator with USC Stem Cell. \u201cDespite advances in available therapies, unmet and urgent needs remain in the fight against leukemia. We still have children with disease that our drugs can\u2019t help enough. And for patients who relapse, their chances of long-term survival are less than 20 percent. We\u2019ve got to do better.\u201d
\nTNF-related apoptosis-inducing ligand (TRAIL) is a protein functioning as a ligand that induces apoptosis, or cell death. Produced by the immune system cells, it has the potential to cause apoptosis in tumor cells by binding to two so-called \u201cdeath receptors,\u201d also known as TRAIL-receptor 1 and TRAIL-receptor 2.
\n\u201cTRAIL is a naturally occurring part of the body\u2019s immune system that kills cancer cells without toxicity to normal cells. However, earlier clinical trials using TRAIL as a potential anti-cancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to \u2018decoy\u2019 receptors,\u201d explained Uckun, who is also a professor of pediatrics at Keck School of Medicine of USC.
\nUckun and collaborators discovered a previously unknown protein \u2014 CD19-Ligand \u2014 a natural ligand of human CD19, which is expressed by almost all ALL cells. They hypothesized that fusing it by genetic bioengineering to the portion of TRAIL (known as sTRAIL) that can kill cancer cells, would produce a powerful weapon against leukemia cells. Unlike chemotherapy drugs, this precision medicine candidate would seek out, bind and destroy only leukemia cells carrying CD19 as the target docking site.
\nThey successfully accomplished this unique assembly of the two proteins in a single \u201cfusion protein\u201d and named this protein therapeutic candidate \u201cCD19L-sTRAIL.\u201d In their study, Uckun and collaborators have demonstrated that their engineering converted sTRAIL into a much more potent \u201cmembrane-anchored\u201d form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant form of human leukemia cells.
\n\u201cDue to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL, and consistently killed more than 99 percent of aggressive leukemia cells taken directly from children with ALL \u2014 not only in the test tube, but also in mice,\u201d said Uckun.
\nAdministering only two or three doses of CD19L-sTRAIL significantly improved the survival outcome of mice challenged with an otherwise invariably fatal dose of human leukemia cells, without side effects. Its therapeutic potency in mice was superior to that of standard chemotherapy combinations as well as radiation therapy.
\n\u201cThe biggest challenge is to cure patients who experience a recurrence of their cancer, despite intensive chemotherapy,\u201d Uckun concluded. \u201cWe are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia.\u201d
\nAdditional contributors include Dorothea E. Myers, Zahide Ozer, Osmond J. D\u2019Cruz and Hong Ma of the Children\u2019s Center for Cancer and Blood Diseases and Children\u2019s Hospital Los Angeles; Sanjive Qazi of CHLA and Gustavus Adolphus College, St. Paul, MN; and Rebecca Rose of Rose Pathology Services, St. Paul. The project was supported by a 2011 V-Foundation Translational Research Award and in part by DHHS grants R21-CA-164098, U01-CA-151837 and R01-CA-154471 from the National Cancer Institute, part of the National Institutes of Health.<\/p>\n\n\n\n<\/div>\n <\/div>\n\n\n <\/div><\/div>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":31,"featured_media":333,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"advgb_blocks_editor_width":"","advgb_blocks_columns_visual_guide":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[6],"tags":[65,20,436],"class_list":["post-332","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-press-release","tag-department-of-pediatrics","tag-research","tag-usc-stem-cell"],"acf":[],"yoast_head":"\nProtein-based therapy shows promise against resistant leukemia<\/title>\n<meta name=\"robots\" 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