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Wakelee H.A.,Stanford University | Lee J.-W.,Dana-Farber Cancer Institute | Hanna N.H.,Indiana University | Traynor A.M.,University of Wisconsin - Madison | And 2 more authors.
Journal of Thoracic Oncology | Year: 2012

Introduction: Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase-II study in heavily pretreated non-small-cell lung cancer (NSCLC) patients (≥ 2 prior therapies) used a randomized discontinuation design. Methods: Patients received 400 mg of sorafenib orally twice daily for two cycles (2 months) (step 1). Responding patients on step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease 2 months after randomization. Results: There were 299 patients evaluated for step 1; of these, 81 eligible patients were randomized on step 2 and received sorafenib (n = 50) or placebo (n = 31). The 2-month disease control rates after randomization were 54% and 23% for patients initially receiving sorafenib and placebo, respectively, p = 0.005. The hazard ratio for progression on step 2 was 0.51 (95% [confidence interval] CI 0.30, 0.87, p = 0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), hazard ratio 0.67 (95% CI 0.40-1.11), p = 0.117. A dispensing error occurred, which resulted in the unblinding of some patients, but not before completion of the 8-week initial step 2 therapy. Toxicities were manageable and as expected. Conclusions: The results of this randomized discontinuation trial suggest that sorafenib has single-agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC. Copyright © 2012 by the International Association for the Study of Lung Cancer.


Li Z.,University of North Carolina at Chapel Hill | Pei X.-H.,University of North Carolina at Chapel Hill | Pei X.-H.,University of Miami | Yan J.,University of North Carolina at Chapel Hill | And 6 more authors.
Molecular Cell | Year: 2014

The Cullin 9 (CUL9) gene encodes a putative E3 ligase that localizes in the cytoplasm. Cul9 null mice develop spontaneous tumors in multiple organs; however, both the cellular and the molecular mechanisms of CUL9 in tumor suppression are currently unknown. We show here that deletion of Cul9 leads to abnormal nuclear morphology, increased DNA damage, and aneuploidy. CUL9 knockdown rescues the microtubule and mitosis defects in cells depleted for CUL7 or OBSL1, two genes that are mutated in a mutually exclusive manner in 3M growth retardation syndrome and function in microtubule dynamics. CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7. Depletion of CUL7 decreases survivin level, and overexpression of survivin rescues the defects caused by CUL7 depletion. We propose a 3M-CUL9-survivin pathway in maintaining microtubule and genome integrity, normal development, and tumor suppression. © 2014 Elsevier Inc.


UT Southwestern Medical Center chemists have successfully used synthetic nanoparticles to deliver tumor-suppressing therapies to diseased livers with cancer, an important hurdle scientists have been struggling to conquer. Late-stage liver cancer is a major challenge for therapeutic intervention. Drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers explain. UT Southwestern scientists crafted synthetic “dendrimer” nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the journal Proceedings of the National Academy of Sciences. “We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease,” says Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center. “We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development.” Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17 percent, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. Critical to understanding this problem, and developing the new therapy, was a close collaboration between Siegwart and Dr. Hao Zhu, Assistant Professor at the Children’s Medical Center Research Institute at UT Southwestern, and a practicing oncologist. “Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers,” says Zhu, also Assistant Professor of Internal Medicine and Pediatrics at UT Southwestern. The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma — the most common form of liver cancer — prompted the authors to develop non-toxic carriers and explore “miRNA” therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect. To address this problem, UTSW scientists chemically synthesized more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Siegwart says. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity. The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival. The multidisciplinary UTSW research team included Dr. Kejin Zhou, Liem Nguyen, Jason Miller, Dr. Yunfeng Yan, Dr. Petra Kos, Dr. Hu Xiong, Lin Li, Dr. Jing Hao, and Jonathan Minnig. The Siegwart Research Group uses a materials chemistry approach to tackle challenges in cancer therapy and diagnosis. The lab is currently focused on the development of improved materials for effective delivery of siRNA, miRNA, mRNA, and CRISPR strategies to manipulate gene expression in tumors and develop the next generation of cancer therapies. The research was supported by the Cancer Prevention and Research Institute of Texas (CPRIT), the Welch Foundation, the American Cancer Society, and the Mary Kay Foundation. Additional support for individual researchers included the Howard Hughes Medical Institute (HHMI), the Pollack Foundation, the National Institutes of Health, and the Burroughs Wellcome Fund.


Home > Press > Scientists synthesize nanoparticles that can deliver tumor suppressors to damaged livers Abstract: UT Southwestern Medical Center chemists have successfully used synthetic nanoparticles to deliver tumor-suppressing therapies to diseased livers with cancer, an important hurdle scientists have been struggling to conquer. Late-stage liver cancer is a major challenge for therapeutic intervention. Drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers explained. UT Southwestern scientists crafted synthetic "dendrimer" nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the journal, Proceedings of the National Academy of Sciences. "We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease," said Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center. "We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development." Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17 percent, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. Critical to understanding this problem, and developing the new therapy, was a close collaboration between Dr. Siegwart and Dr. Hao Zhu, Assistant Professor at the Children's Medical Center Research Institute at UT Southwestern, and a practicing oncologist. "Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers," said Dr. Zhu, also Assistant Professor of Internal Medicine and Pediatrics at UT Southwestern. The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma - the most common form of liver cancer - prompted the authors to develop non-toxic carriers and explore "miRNA" therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect. To address this problem, UTSW scientists chemically synthesized more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Dr. Siegwart said. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity. The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival. The multidisciplinary UTSW research team included Dr. Kejin Zhou, Liem Nguyen, Jason Miller, Dr. Yunfeng Yan, Dr. Petra Kos, Dr. Hu Xiong, Lin Li, Dr. Jing Hao, and Jonathan Minnig. The Siegwart Research Group uses a materials chemistry approach to tackle challenges in cancer therapy and diagnosis. The lab is currently focused on the development of improved materials for effective delivery of siRNA, miRNA, mRNA, and CRISPR strategies to manipulate gene expression in tumors and develop the next generation of cancer therapies. ### The research was supported by the Cancer Prevention and Research Institute of Texas (CPRIT), the Welch Foundation, the American Cancer Society, and the Mary Kay Foundation. Additional support for individual researchers included the Howard Hughes Medical Institute (HHMI), the Pollack Foundation, the National Institutes of Health, and the Burroughs Wellcome Fund. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 45 NCI-designated Comprehensive Cancer Centers in the nation. The Simmons Cancer Center includes 13 major cancer care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevention of cancer worldwide. The Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Participating Site by the NCI, and the only cancer center in North Texas to be so designated. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


Late-stage liver cancer is a major challenge for therapeutic intervention. Drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers explained. UT Southwestern scientists crafted synthetic "dendrimer" nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the journal, Proceedings of the National Academy of Sciences. "We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease," said Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center. "We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development." Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17 percent, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. Critical to understanding this problem, and developing the new therapy, was a close collaboration between Dr. Siegwart and Dr. Hao Zhu, Assistant Professor at the Children's Medical Center Research Institute at UT Southwestern, and a practicing oncologist. "Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers," said Dr. Zhu, also Assistant Professor of Internal Medicine and Pediatrics at UT Southwestern. The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma - the most common form of liver cancer - prompted the authors to develop non-toxic carriers and explore "miRNA" therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect. To address this problem, UTSW scientists chemically synthesized more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Dr. Siegwart said. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity. The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival. The multidisciplinary UTSW research team included Dr. Kejin Zhou, Liem Nguyen, Jason Miller, Dr. Yunfeng Yan, Dr. Petra Kos, Dr. Hu Xiong, Lin Li, Dr. Jing Hao, and Jonathan Minnig. The Siegwart Research Group uses a materials chemistry approach to tackle challenges in cancer therapy and diagnosis. The lab is currently focused on the development of improved materials for effective delivery of siRNA, miRNA, mRNA, and CRISPR strategies to manipulate gene expression in tumors and develop the next generation of cancer therapies. Journal reference: Proceedings of the National Academy of Sciences

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