TAG: "Drugs"

Scientists describe novel drug mechanism that fights brain cancer

UC Davis findings could lead to better therapies against many hard-to-treat cancers.

By Dorsey Griffith, UC Davis

Researchers at UC Davis have developed and characterized a molecule that interferes with the internal regulation of cancer cells, causing them to self-destruct. This novel mechanism was found to be effective against glioma cells – responsible for a usually fatal type of brain cancer – and could be applicable to other highly aggressive cancers.

The article, to be published in the April 2015 issue of Molecular Pharmacology, is available online at doi:10.1124/mol.114.096602.

“We have elucidated the mode of action of a drug that destroys glioma cells in a manner that has not previously been described,” said Nagarekha Pasupuleti, lead author of the study and project scientist in the Department of Neurology. “We anticipate that it will lead to new treatments to fight cancers that are resistant to standard therapies.”

The investigators performed a series of studies utilizing high-content analysis, which quantifies changes in living cells in response to a drug treatment. The lab focused on the effects of a patented small molecule previously developed at UC Davis, known as UCD38B, on four different human glioma cell lines.

Gliomas arise from glia cells in the brain, which provide structural support and protection to neurons. Treatment of glioma typically involves a combination of surgery, radiation therapy and chemotherapy. Although apparently eradicated from the body after treatment, the cancer has a high rate of recurrence.

According to Pasupuleti, the problem with conventional therapy is that a subpopulation of non-dividing cancer cells tends to remain unaffected by treatment. These cells, which have many properties in common with normal stem cells, remain quiescent for a time, later replicate and regenerate the tumor. This population of glioma-initiating cancer cells resides in tumor regions having negligible or no blood supply and minimal oxygen, making them very difficult to destroy.

The research team’s study showed that UCD38B is effective against such non-dividing glioma cells, as well as dividing cells destroyed by conventional therapy. They found that UCD38B acts by targeting a cellular regulatory system called the urokinase plasminogen activator system. This system is normally important when tissue needs to be re-organized, such as during wound healing, a process that requires new cells to be made and others destroyed. Components of the urokinase plasminogen activator system have been found to be highly active in many aggressive cancers, including gliomas, as well as metastatic breast, lung and pancreatic cancers. The system is believed to play an important role in the ability of cancer cells to grow uncontrollably and metastasize to other parts of the body.

UCD38B disrupts the intracellular components of the urokinase plasminogen activator system. After entering glioma cells, UCD38B causes “mis-trafficking” of urokinase plasminogen activator system components to the wrong region of the cancer cell, ultimately triggering the cells to signal their own destruction rather than proliferate. UCD38B does this by disrupting the cell’s endosomal transport system, which normally functions to direct cellular components to areas where they may be needed, or if not needed, destroyed. Within a few hours of administration, UCD38B causes plasminogen activator system components to be sent to mitochondria near the cell nucleus instead of the cell surface, causing factors to be released that destroy the cell.

Preliminary studies in rodents implanted with human glioma cells have found that a new small molecule based upon UCD38B is very effective in destroying this population of hypoxic glioma cells within the tumor without evidence of adverse effects. The research team will continue these studies and, in collaboration with the UC Davis School of Veterinary Medicine, hopes to try the drug in dogs with high-grade glial brain cancers, for which there are no other treatment options.

“Understanding the drug mechanism of action of UCD38B and its more potent derivatives is the culmination of many years of work of characterizing the processes causing cancer recurrence and developing molecules that target therapeutically resistant cancer cell types,” said Fredric Gorin, principal investigator, chair of the UC Davis Department of Neurology School of Medicine and professor of molecular biosciences in the UC Davis School of Veterinary Medicine. “We are hopeful that this new class of drug will one day become an important adjunct to conventional therapies in fighting these especially difficult-to-treat cancers.”

The article is titled “Mis-trafficking of endosomal urokinase proteins triggers drug-induced glioma non-apoptotic cell death.”

In addition to Gorin and Pasupuleti, Ana Cristina Grodzki of the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine, was a co-author and played an important role in quantifying the endosomal trafficking caused by UCD38B.

This research was funded by National Institutes of Health, Neurological Sciences grants (NS040489 NS060880) to the UC Davis School of Medicine, the UC Davis Research Investments in Science and Engineering (RISE) and the MIND Institute Intellectual and Developmental Disabilities Research Center (IDDRC) grant (U54 HD079125).

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Cystic fibrosis discovery may lead to new strategy to help patients breathe easier

UCSF-led team ID’s why disease thickens mucus in lungs, explores possible new treatments.

By Pete Farley, UC San Francisco

A team led by UC San Francisco professor of medicine John Fahy, M.D., has discovered why mucus in the lungs of people with cystic fibrosis (CF) is thick, sticky and difficult to cough up, leaving these patients more vulnerable to lung infection.

Fahy and his team found that in CF – contrary to previous belief – inflammation causes new molecular bonds to form within mucus, transforming it from a liquid to an elastic sludge.

The scientists also made headway in the lab in exploring a potential new therapeutic approach to dissolve those bonds and return the mucus to a liquid that is easier for the lungs to clear.

CF is a lifelong inherited disease that affects the lungs and digestive system. There is no cure. About 30,000 children and adults in the United States have CF.

Fahy said that the research, a collaborative effort between UCSF, University College Dublin (UCD) in Ireland and the Cleveland Clinic (CC) in Ohio, has implications for other lung conditions characterized by thickened mucus, such as chronic obstructive pulmonary disorder (COPD) and asthma.

The work was reported in today’s (Feb. 25) issue of Science Translational Medicine.

Polymers – naturally-occurring molecules in mucus that form long chains – are the key to the discovery.

Until now, scientists had thought that CF mucus is thicker than healthy mucus because it has a greater concentration of DNA polymers. To test that idea, Fahy and his group exposed mucus samples taken from CF patients to two current CF medications: Pulmozyme, a drug that breaks up DNA polymers, and N-acetylcysteine (NAC), which targets disulfide bonds between mucin polymers. Mucin is a protein that is the major constituent of mucus.

“We thought Pulmozyme would be more effective than NAC in liquefying the mucus, because CF sputum contains lots of DNA,” said Fahy. “But to our surprise, NAC worked much better.”

Using confocal microscopy, the scientists learned why: CF mucus consists of a dense core of mucin with a layer of DNA wrapped around it, like a thin blanket draped over a solid pillow. Thus, while Pulmozyme makes mucus less stiff by eliminating DNA, NAC succeeds in liquefying it by breaking up the mucin.

Fahy and his team then investigated why mucin in CF is so compacted. They found that mucin polymers become linked together crosswise by newly forged disulfide bonds. Fahy likened the polymers to logs floating down a river. “The logs can float down the river as long as they are floating independently,” he said. “But if you bolt them together side to side, they will clog the river.”

The researchers found that inflammation causes the extra disulfide bonds to form, when mucin polymers are exposed to highly reactive oxygen molecules released by inflammatory cells in a process called oxidative stress.

This observation was confirmed by a device invented by lead investigator Leo Shaopeng Yuan, of the UCSF Cardiovascular Research Institute. In separate chambers, mucus from healthy volunteers was exposed to pure oxygen and pure nitrogen. The mucus exposed to oxygen became thick and elastic within seconds. The mucus exposed to nitrogen remained liquid.

“This qualitative change, driven by oxidation, happens with other natural polymers,” said Fahy. “Think of latex, which starts out as liquid tree sap. When it’s vulcanized – a process of chemical cross-linking – it turns into the solid rubber we use in tires.”

Fahy noted that patients who are treated with pure oxygen in hospital intensive care units have long been known to develop sticky mucus. “This could be a function of the oxygen that’s used to treat them,” he said.

Finally, the research team turned its attention to the possibility of creating new treatments for CF that would target disulfide bonds in mucin polymers directly and efficiently.

NAC, which targets mucin polymer bonds, is already an approved medication used to break up mucus. “However,” said Fahy, “there are problems with it. It’s a relatively weak drug, and it smells like rotten eggs.”

Team member Stefan Oscarson, Ph.D., a medicinal chemist from UCD, designed TDG, an experimental compound that targets disulfide bonds. TDG liquefied mucus samples from CF patients much more efficiently than NAC.

Fahy cautioned that TDG cannot yet be given to human beings. He noted that while the team has applied for funding to develop their promising new therapeutic approach, “there are at least five years of testing ahead before we can say we have a new medication.”

Fahy predicted that the new finding will explain the reason for thick mucus in other lung diseases known to be associated with oxidative stress, including COPD and asthma. “We’re very confident that we’ve uncovered a ubiquitous mechanism here,” he said.

Co-authors of the study are Martin Hollinger, Ph.D., of UCD; Marrah E. Lachowicz-Scroggins, Ph.D., Sheena C. Kerr, Ph.D., Eleanor M. Duncan, M.D., and Brian M. Daniel, R.R.T., of UCSF; Sudakshina Ghosh Ph.D., Serpel C. Erzurum, M.D., Belinda Willard, Ph.D., and Stanley L. Hazen, M.D., Ph.D., of the Cleveland Clinic; Xiaozhu Huang, M.D., of UCSF; and Stephen D. Carrington, Ph.D., of UCD.

The study was supported by funds from the National Institutes of Health and Genentech.

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Technology optimizes cancer therapy with nanomedicine drug combinations

UCLA bioengineers develop platform that offers personalized approach to treatment.

By Brianna Aldrich, UCLA

In greater than 90 percent of cases in which treatment for metastatic cancer fails, the reason is that the cancer is resistant to the drugs being used. To treat drug-resistant tumors, doctors typically use multiple drugs simultaneously, a practice called combination therapy. And one of their greatest challenges is determining which ratio and combination — from the large number of medications available — is best for each individual patient.

Dr. Dean Ho, a professor of oral biology and medicine at the UCLA School of Dentistry, and Dr. Chih-Ming Ho, a professor of mechanical engineering at the UCLA Henry Samueli School of Engineering and Applied Science, have developed a revolutionary approach that brings together traditional drugs and nanotechnology-enhanced medications to create safer and more effective treatments. Their results are published in the peer-reviewed journal ACS Nano.

Chih-Ming Ho, the paper’s co-corresponding author, and his team have developed a powerful new tool to address drug resistance and dosing challenges in cancer patients. The tool, Feedback System Control.II, or FSC.II, considers drug efficacy tests and analyzes the physical traits of cells and other biological systems to create personalized “maps” that show the most effective and safest drug-dose combinations.

Currently, doctors use people’s genetic information to identify the best possible combination therapies, which can make treatment difficult or impossible when the genes in the cancer cells mutate. The new technique does not rely on genetic information, which makes it possible to quickly modify treatments when mutations arise: the drug that no longer functions can be replaced, and FSC.II can immediately recommend a new combination.

“Drug combinations are conventionally designed using dose escalation,” said Dean Ho, a co-corresponding author of the study and the co-director of the Jane and Jerry Weintraub Center for Reconstructive Biotechnology at the School of Dentistry. “Until now, there hasn’t been a systematic way to even know where the optimal drug combination could be found, and the possible drug-dose combinations are nearly infinite. FSC.II circumvents all of these issues and identifies the best treatment strategy.”

The researchers demonstrated that combinations identified by FSC.II could treat multiple lines of breast cancer that had varying levels of drug resistance. They evaluated the commonly used cancer drugs doxorubicin, mitoxantrone, bleomycin and paclitaxel, all of which can be rendered ineffective when cancer cells eject them before they have had a chance to function.

The researchers also studied the use of nanodiamonds to make combination treatments even more effective. Nanodiamonds — byproducts of conventional mining and refining operations — have versatile characteristics that allow drugs to be tightly bound to their surface, making it much harder for cancer cells to eliminate them and allowing toxic drugs to be administered over a longer period of time.

The use of nanodiamonds to treat cancer was pioneered by Dean Ho, a professor of bioengineering and member of the UCLA Jonsson Comprehensive Cancer Center and the California NanoSystems Institute.

“This study has the capacity to turn drug development, nano or non-nano, upside-down,” he said. “Even though FSC.II now enables us to rapidly identify optimized drug combinations, it’s not just about the speed of discovering new combinations. It’s the systematic way that we can control and optimize different therapeutic outcomes to design the most effective medicines possible.”

The study found that FSC.II-optimized drug combinations that used nanodiamonds were safer and more effective than optimized drug-only combinations. Optimized nanodrug combinations also outperformed randomly designed nanodrug combinations.

“This optimized nanodrug combination approach can be used for virtually every type of disease model and is certainly not limited to cancer,” said Chih-Ming Ho, who also holds UCLA’s Ben Rich Lockheed Martin Advanced Aerospace Tech Endowed Chair. “Additionally, this study shows that we can design optimized combinations for virtually every type of drug and any type of nanotherapy.”

Both Dean Ho and Chih-Ming Ho have collaborated with other researchers and have validated FSC.II’s efficacy in many other types of cancers, infectious diseases and other diseases.

Other co-authors were Hann Wang, Dong-Keun Lee, Kai-Yu Chen and Kangyi Zhang, all of UCLA’s department of bioengineering, School of Dentistry, California NanoSystems Institute and Jonsson Cancer Center; Jing-Yao Chen of UCLA’s department of chemical and biomolecular engineering; and Aleidy Silva of UCLA’s department of mechanical and aerospace engineering.

The work was supported in part by the National Cancer Institute, the National Science Foundation, the V Foundation for Cancer Research, the Wallace H. Coulter Foundation, the Society for Laboratory Automation and Screening, and Beckman Coulter Life Sciences.

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Doctorate program will study substance abuse, its consequences

Collaboration between UC San Diego, SDSU among first in nation.

By Scott LaFee, UC San Diego

A new Joint Doctoral Program (JDP) in Interdisciplinary Research on Substance Use has been launched by the Division of Global Public Health in the UC San Diego School of Medicine and San Diego State University’s School of Social Work. The program will emphasize research devoted to studying the use and misuse of alcohol and drugs – and related social and health consequences.

“This program is the first of its kind,” said JDP co-director Steffanie Strathdee, Ph.D., professor and head of the UC San Diego Global Health Initiative. “Given that substance use has a growing health and societal impact in the U.S. and globally, this program could not come at a better time.”

The JDP will focus on research designed to identify and assess substance use risk and create intervention programs for preventing or ameliorating high‐risk behaviors related to substance use. It will include training to craft and evaluate disease prevention and health promotion recommendations and help guide public health policies.

María Luisa Zúñiga, Ph.D., JDP co-director and associate professor in SDSU’s School of Social Work, said “SDSU and UC San Diego have a long history of jointly offering cutting edge, high-demand programs. This new doctoral program is designed to train the next generation of researchers to lead interdisciplinary research efforts that will meaningfully address substance use issues of national and global impact. Our graduates will be highly sought after in fields including medicine, social work and public health, as well as research firms and governmental health departments.”

The new JDP is the 14th such program offered by UC San Diego and SDSU. Others include highly acclaimed programs in public health and clinical psychology.

Funding from SDSU Division of Academic Affairs and College of Health and Human Services will cover tuition fees and a teaching associate stipend for four students per year for up to four years. Students will spend the first year of study at SDSU, the second at UC San Diego and subsequent years working with faculty from both campuses.

For more information on the joint doctoral program in Interdisciplinary Substance Use Studies, visit socialwork.sdsu.edu/degrees-programs/graduate-programs/phd-substance-use-studies/phd-overview.

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Scientists limit accelerated cellular aging caused by meth use

Grasp of underlying molecular mechanisms could improve addiction recovery efforts.

Daniele Piomelli, UC Irvine

The ravaged faces of methamphetamine addicts tell a terrible tale – abusing the drug dramatically accelerates aging. Now scientists from UC Irvine and the Italian Institute of Technology have discovered how this occurs at the cellular level and identified methods to limit the process.

With funding from the National Institute on Drug Abuse to probe the effects of methamphetamine on the “lipidome” (the complete lipid profile of representative organs and tissues) in rats that self-administer the drug, UCI’s Daniele Piomelli and his IIT colleagues found that its use caused abnormalities in cellular fat metabolism, triggering extreme inflammation marked by a considerable rise in the formation of ceramides, pro-inflammatory molecules that can foster cell aging and death.

Study results appear in the open-access online journal PLOS ONE.

Methamphetamine is a highly addictive psychostimulant that profoundly damages the brain and other body organs. Postmortem examinations of human tissues have linked use of the drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis, but the molecular mechanisms underlying these findings have remained unknown.

The Piomelli team learned that this cellular cascade involves the recruitment of nuclear factor kappa beta, a protein that under healthy conditions helps control DNA encoding of proteins. But as the cell is flooded with methamphetamine-induced signaling, nuclear factor kappa beta triggers excessive signaling in pathways that engender dramatic increases in ceramide activity.

“We found this signaling process to be key for advanced cellular aging, which is at the heart of the accelerated aging influenced by methamphetamine abuse,” said Piomelli, the Louise Turner Arnold Chair in the Neurosciences.

Having identified these mechanisms, the researchers tested existing inhibitors of nuclear factor kappa beta signaling, which succeeded in limiting ceramide formation. This prevented methamphetamine-induced cell aging and systemic inflammation in rats self-administering the drug, curtailing their health deterioration.

“These results suggest new therapeutic strategies to reduce the adverse consequences of methamphetamine abuse and improve the effectiveness of abstinence treatments,” Piomelli said.

He is currently working with colleagues at the Italian Institute of Technology, in Genoa, to create a pharmaceutical application of these inhibitor compounds.

Giuseppe Astarita and Agnesa Avanesian-Thomas of UCI; Benedetto Grimaldi, Natalia Realini and Abdul Basit of the Istituto Italiano di Tecnologia; and Zuzana Justinova, Leigh V. Panlilio and Steven R. Goldberg of the National Institute on Drug Abuse contributed to the study – supported by NIDA through grant RC2 DA028902 and its intramural research program.

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Building mini-brains to study disorders caused by HIV, meth use

UC San Diego scientist wins $2.5M award to create stem cell-derived models.

By Scott LaFee, UC San Diego

A UC San Diego School of Medicine project involving the creation of miniature models of the human brain – developed with stem cells – to study neurological disorders caused by HIV and methamphetamine use has been named one of five recipients of the 2015 Avant-Garde Award for HIV/AIDS Research from the National Institute on Drug Abuse (NIDA).

The project, headed by Tariq M. Rana, Ph.D., professor of pediatrics, will receive $500,000 per year for five years.

“The human cerebral cortex has evolved strikingly compared to those of other species, and no animal model accurately captures human-specific brain functions,” said Rana. “The creation of mini-brains, or organoids, will permit, for the first time, study of the toxic effects of addiction and HIV on the human brain in a dish. This offers us the exciting opportunity to design patient-specific model systems, which could potentially revolutionize drug discovery and precision medicine for central nervous system disorders.”

The Avant-Garde Awards are granted to scientists who propose high-impact research that could open new avenues for prevention and treatment of HIV/AIDS among drug abusers. The term “avant-garde” is used to describe highly innovative approaches that have the potential to be transformative.

“Despite the success of combined antiretroviral therapies, HIV remains a chronic disease with a host of debilitating side effects that are exacerbated in those suffering from substance use disorders,” said NIDA Director Nora D. Volkow, M.D.  “These scientists have proposed creative approaches that could transform the way we think about HIV/AIDS research, and could lead to the development of exciting new tools and strategies to prevent infections and improve the lives of substance abusers infected with HIV.”

The other 2015 recipients are:

  • Don C. Des Jarlais, Ph.D., Mount Sinai Beth Israel
  • Eli Gilboa, Ph.D., University of Miami School of Medicine
  • Nichole Klatt, Ph.D., University of Washington, Seattle
  • Alan D. Levine, Ph.D., Case Western Reserve University

For more information about the Avant-Garde Award Program and 2015 recipients, visit drugabuse.gov/about-nida.

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Researchers ID new compound that takes aim at neuropathic pain

UC Davis findings could lead to drugs that prevent debilitating chronic pain syndromes.

Fred Gorin, UC Davis

By Phyllis Brown, UC Davis

A new compound discovered by a team of UC Davis investigators has potent actions against production of a chemical that is implicated in the development of chronic pain following a peripheral nerve injury in the spinal cord.

The compound, a molecule named 6-chloro-8-(glycinyl)-amino-β-carbolin, or 8-Gly carb, provides an important new avenue of research for developing drugs to prevent the severe pain that sometimes remains long after an injury or infection has healed.

The findings are published in The Journal of Pharmacology and Experimental Therapeutics.

“We have discovered a new compound that is 43 times more potent in inhibiting nitrous oxide production than the current reference compound known to have this action,” said Fredric Gorin, professor and chair of the UC Davis Department of Neurology and co-principal investigator for the study. “That makes 8-Gly carb a potentially very fruitful focus for new drug development against neuropathic pain syndromes.”

Neuropathic pain is a disorder characterized by often severe pain that sometimes develops following nerve damage resulting from conditions such as shingles, injury, amputation, autoimmune inflammation and cancer. Months or even years after the initial trauma, the area can remain extremely painful, a condition believed to result from the brain misinterpreting nerve signals from the area. The pain can be completely spontaneous or triggered by something normally as innocuous as a light touch or temperature change. Traditional pain treatment with non-steroidal anti-inflammatory drugs and even opioids such as morphine is usually ineffective.

The condition is believed to develop from immune cells called microglia, a type of macrophage that resides in the spinal cord and provides an important defense against injury and infection. Following a trauma to a peripheral nerve, microglia release a host of chemicals, among them cytokines that are important for recovery, and nitrous oxide, which is believed to be a key factor in initiating and sustaining inflammation associated with the establishment of neuropathic pain. Inhibiting the production of nitrous oxide at the time of a nerve injury may be an important mechanism to prevent the later development of a chronic pain syndrome, Gorin said.

The class of drug to which 8-Gly carb belongs is known as β-carbolines, a large group of natural and synthetic organic compounds, some of which are known to reduce nitrous oxide production. Previously characterized β-carbolines block a precursor — tumor necrosis factor α — in the nitrous oxide production pathway, also resulting in the reduction of the expression of the cytokine interleukin -1β; however, experiments show that 8-Gly carb does not reduce levels of tumor necrosis factor α or the cytokine. The exact mechanism of nitrous oxide by the new compound is poorly understood and will be a focus of future research, according to Gorin.

“A compound like 8-Gly carb that selectively targets nitrous oxide production and does not block cytokine expression makes a promising candidate for drug development aimed at preventing a neuropathic pain syndrome without interfering with recovery,” Gorin said. “We look forward to extending this research by developing and testing this compound and related ones in the laboratory and eventually in clinical trials.”

Gorin noted that this research resulted from a fruitful collaboration between the UC Davis Schools of Medicine and Veterinary Medicine, as well as with the University of Louisville, Kentucky. Pamela Lein, professor in the Department of Molecular Biosciences of the UC Davis Veterinary School of Medicine, is co-principal investigator and another study author.

Other authors include Ana Cristina Grodzki, Nagarekha Pasupuleti of UC Davis and Bhaskar Poola and Michael Nantz of the University of Louisville, Kentucky.

The study was funded by the UC Davis MIND Institute and the National Institute of Environmental Health Sciences (R01-ES017592) and UC Davis Research Investments in the Sciences and Engineering (RISE) Program (R01-NS060880).

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Why some targeted cancer drugs lose effectiveness

UCSF-led work suggests combination therapies could overcome drug resistance.

By Pete Farley, UC San Francisco

A protein called YAP, which drives the growth of organs during development and regulates their size in adulthood, plays a key role in the emergence of resistance to targeted cancer therapies, according to a new study led by UC San Francisco researchers.

By precisely identifying the mechanism by which elevated levels of YAP promote the survival of cancer cells, the new work points the way to combination therapies that may overcome resistance to individual targeted drugs, the scientists said.

Though cancer drugs aimed at specific genetic mutations have had some success in recent years, most patients who have a good initial response eventually develop resistance to these therapies, most likely because cancer cells engage alternative survival mechanisms that lie outside the biological pathways targeted by the drugs.

Though oncologists have the option of switching to a different targeted drug after resistance takes hold, many cancer researchers believe that a better strategy would be to forestall cancer cells’ eventual escape routes by using customized combinations of targeted drugs at the outset of therapy.

“Instead of trying to figure out why patients have developed resistance after it has emerged, we need to decipher what survival tactic tumor cells will be most dependent on when they are challenged with targeted therapy,” said the senior author of the study, Trever Bivona, M.D., Ph.D., UCSF assistant professor of medicine and a member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “We want to learn how to wipe out that alternative survival pathway at the beginning of therapy — to pull the rug out from under those cells right away.”

In the new research, published in today’s (Feb. 9) online issue of Nature Genetics, an international team of scientists led by Bivona used a gene-silencing tool called short-hairpin RNAs (shRNAs) to tamp down the activity, one by one, of more than 5,000 proteins in lung cancer cells that carried cancer-causing mutations in a gene called BRAF. By simultaneously treating the cells with the cancer drug vemurafenib (Zelboraf), which specifically targets faulty BRAF proteins, the researchers were able to determine whether the drug was more effective when the action of other particular proteins was blocked.

These experiments quickly and decisively fingered YAP in vemurafenib resistance, as all six YAP-directed shRNAs employed by the scientists significantly enhanced the drug’s effectiveness at killing BRAF-mutant cancer cells. The researchers saw similar results with trametinib (Mekinist), which targets a BRAF-activated protein called MEK. Working with other types of cancer cells carrying BRAF mutations, including cells from human melanoma, colon, and thyroid cancers, the researchers again found that suppressing YAP enhanced the effectiveness of both vemurafenib and trametinib.

The collective lab-dish results held up in experiments with animal models in which cells from melanoma and colon cancer were injected under the skin of mice and formed tumors: vemurafenib and trametinib were far more effective in treating these tumors when YAP had been suppressed.

The researchers then turned to cells carrying mutations in another important cancer-driving gene, called RAS. Cancers with these mutations are particularly problematic, because the RAS protein is widely considered to be “undruggable”— no effective targeted therapies have been developed for tumors expressing mutant RAS. Like BRAF, the RAS protein also activates MEK, but MEK-targeted therapies have not been particularly effective in patients with RAS-mutant tumors.

After YAP suppression, however, the MEK inhibitor trametinib was highly effective when tested in RAS-mutant lung cancer, melanoma, and pancreatic cancer cells, and also against RAS-mutant lung tumors implanted in animals.

To ensure that these findings were clinically relevant, the authors examined human tumor samples and found that YAP was highly expressed in BRAF- and RAS-mutant lung cancer and melanoma before patients had received any treatment. Moreover, patients whose tumors had higher YAP levels were more likely to have had an incomplete response when treated with a BRAF and/or MEK inhibitor. Finally, YAP levels rose in tumors when patients developed resistance to those therapies.

The researchers found that YAP exerts its effects across a wide variety of cancer types via a single mechanism involving a protein called BCL-xL, which sends out signals that prevent cells from self-destructing. High YAP levels in cancer cells keep BCL-xL activated, overwhelming the ability of targeted drugs to successfully kill off the cells.

Therefore, when vemurafenib or trametinib treatment was combined with inhibitors of BCL-xL, the drugs were much more effective than when either was given alone, indicating that a combined therapy targeting both the MEK and YAP pathways may be effective in overcoming resistance to targeted therapies for many BRAF- and RAS-mutant tumors.

Bivona emphasized that YAP’s role in organ development was first discovered in the fruit fly Drosophila, and he sees the research as a testament to the importance of basic biological research to improving human health. “YAP was the No. 1 hit in our screening process, but it wasn’t much of a leap to think it might be promoting resistance to targeted therapy, because it had been shown to promote organ growth and cell proliferation in other organisms and systems,” he said. “So this work stood on the shoulders of very good, purely basic science.”

Because BCL-xL has widespread roles in the body, however, BCL-xL inhibitors may prove too toxic to be practical, Bivona said, adding that he and colleagues are exploring partnerships with pharmaceutical companies to develop compounds that target YAP directly.

“This is the first paper to establish that YAP is a bona fide mechanism of resistance to RAF and MEK inhibition,” Bivona said, “and it’s exciting to contemplate and plan what we may be able to do with this knowledge to help cancer patients by improving their precision treatment.”

Other UCSF faculty members taking part in the work include Eric A. Collisson, M.D., assistant professor of medicine and HDFCCC member; Martin McMahon, Ph.D., the Efim Guzik Distinguished Professor in Cancer Biology at HDFCCC; and Alain Algazi, M.D., clinical instructor in the Department of Medicine and HDFCCC member. They were joined by scientists from the Catalan Institute of Oncology, Barcelona, Spain; the Hospital Universitario de la Princesa, Madrid, Spain; the Center for Predictive Molecular Medicine, Chieti, Italy; the Memorial Sloan Kettering Cancer Center; the New York University Cancer Institute; the Vall dHebron Institute of Oncology, Barcelona, Spain; Massachusetts General Hospital; and MD Anderson Cancer Center.

The work was supported by funds from an NIH Director’s New Innovator Award to Trever Bivona, the Howard Hughes Medical Institute, the Doris Duke Charitable Foundation, the American Lung Association, the National Lung Cancer Partnership, the Sidney Kimmel Foundation for Cancer Research, and the Searle Scholars Program.

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Genomics initiative launch draws enthusiastic industry, academic partners

UC Berkeley-UCSF partnership will apply new gene-editing techniques to improve health.

By Robert Sanders, UC Berkeley

Several hundred guests crowded the lobby of the Li Ka Shing Center for Biomedical and Health Sciences Wednesday night (Feb. 4) as the campus celebrated the launch of the Innovative Genomics Initiative (IGI), a partnership between UC Berkeley and UC San Francisco researchers and the biopharmaceutical industry to perfect new gene-editing techniques and apply them to drug development and global health in general.

Among the attendees were a representative from the Li Ka Shing Foundation, which was an early lead supporter of IGI, as well as representatives from two pharmaceutical companies – AstraZeneca and Agilent – that have signed agreements to partner with IGI to use the CRISPR/Cas9 technology to better understand diseases and speed the development of new drugs to treat them.

“The science is cool, but the kind of collaborative structure we have is cool as well,” said Lorenz Mayr, vice president for reagents and assay development at AstraZeneca.

IGI, located in the Li Ka Shing Center for Genomic Engineering, was formed after Berkeley biochemist Jennifer Doudna and her colleagues discovered precision “DNA scissors,” a complex of RNA and protein called CRISPR/Cas9, that can snip DNA at very specific targets in a the genome, allowing scientists to cut out or edit defective genes, or add new genes. Doudna, a professor of molecular and cellular biology and a Howard Hughes Medical Institute investigator, hopes that IGI will make the Bay Area, with its wealth of scientific and clinical research and its business, technology and investment innovation, a global hub for development and application of the groundbreaking technology.

“The Bay Area offers a unique combination of world-leading academic research facilities and clinical institutions with a vibrant and innovative biotech sector,” said Doudna, who cofounded IGI with Jonathan Weissman, a UCSF professor of cellular and molecular pharmacology and HHMI investigator. “There is no better place in the world to spark innovation and discovery in the field of genomics.”

The technology is already being explored by IGI collaborator Jennifer Puck, medical director of the UCSF Clinical and Translational Science Institute’s Pediatric Clinical Research Center, as a possible way to treat severe combined immunodeficiency (SCID), often called the “Bubble Boy” disease. Puck’s work has focused on the genetic cause of SCID and the development of gene-targeted therapies for SCID.

Other scientists around the globe are applying CRISPR/Cas9 to understand and explore new treatments for diabetes, HIV/AIDS, blood cancers and rare genetic diseases like Huntington’s.

“Professor Jennifer Doudna’s groundbreaking scientific work and her launch of the Innovative Genomics Initiative are emblematic of all that we strive for in our research endeavors at Berkeley,” UC Berkeley Chancellor Nicholas Dirks said in a statement. “With its enormous potential to dramatically improve the health and well-being of people around the world, the IGI is another wonderful example of how this university’s research enterprise contributes to the greater good.”

AstraZeneca, IGI’s first partner, plans to use CRISPR/Cas9 to identify and validate gene targets relevant to cancer; cardiovascular, metabolic, respiratory, autoimmune and inflammatory diseases; and regenerative medicine to understand their precise roles in these conditions.

“We are excited to pair the IGI’s premier expertise in CRISPR/Cas9 gene editing and regulation with AstraZeneca’s deep experience in therapeutics,” said Jacob Corn, IGI’s scientific director. “I’m confident that, in working side-by-side with scientists at AstraZeneca, our collaboration will positively impact drug discovery and development to hasten treatments to patients.”

For more on IGI’s new partnerships, link to IGI’s website and AstraZeneca’s press release.

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Patient advocates, big pharma fund nation’s first angioedema treatment center

Center at UC San Diego will treat rare hereditary swelling disease.

By Judy Piercey and Jackie Carr, UC San Diego

It is rare for an “orphan” disease (typically a condition that affects fewer than 200,000 people nationwide) to have a specific center dedicated to providing treatment and research. And it is even more unusual for big pharmaceutical companies to invest in an endowment to fund this type of center. Fortunately, the U.S. Hereditary Angioedema Association (HAEA), a nonprofit patient advocacy organization, along with four pharmaceutical companies — Shire Human Genetics Therapies Inc., ViroPharma Inc. (which merged with Shire), Dyax Corp. and CSL Bering — pledged a total of $4.6 million to help make the U.S. HAEA Angioedema Center at UC San Diego Health System a reality. A number of individuals, including those with the disease, also provided private support.

The grand opening of the first-ever comprehensive angioedema center in the United States was celebrated Jan. 31. Diverse forms of swelling, known collectively as angioedema, may involve almost any area of the body. During attacks, patients are frequently unable to engage in normal life activities; the attacks could even be life threatening. What triggers the swelling is largely unknown.

“The U.S. HAEA Angioedema Center at UC San Diego will lead the charge in establishing ‘model’ approaches to HAE treatment that focus on allowing patients to lead as normal of a life as possible,” said U.S. HAEA President Anthony J. Castaldo. “As an advocacy organization founded and run by patients and caregivers, we have an inherently high level of empathy for what our patients go through in dealing with this chronic, debilitating and potentially fatal rare disease.”

Castaldo understands from personal experience the heavy financial and emotional toll this genetic disease has on families. “My oldest daughter began having frequent and debilitating HAE attacks at age five, and at the time, there were no acute therapies available,” he shared. “In fact, anabolic steroids to prevent attacks were the only therapies available in the United States. A treatment for HAE attacks was available in other countries, so we purchased the medicine (which was quite expensive) from overseas sources while simultaneously working with pharmaceutical companies who were conducting clinical trials to get desperately needed medicines approved in the U.S. Hundreds of HAE families have watched as loved ones suffer and, in the case of throat swellings, die from this dreadful disease.”

During his search for relief and care for the disease, Castaldo met Dr. Bruce Zuraw, UC San Diego professor of medicine, who offered hope. Today, Zuraw is the center’s director and inaugural recipient of the U.S. HAEA Endowed Chair at UC San Diego.

From research in genetics to the most advanced treatments, the center’s unique “bench-to-bedside” approach is at the forefront of personalized angioedema medical care. “With our research and clinical expertise and partnership with the U.S. Hereditary Angioedema Association, we can improve patients’ lives, save lives and ultimately find a cure,” said Zuraw.

Besides helping patients get properly diagnosed as early as possible, a driving factor for establishing the center is to consolidate the expertise now needed to navigate rapidly evolving treatment options for the disease.

Children of an affected parent have a 50 percent chance of inheriting the disease and hereditary angioedema is thought to impact one person in 50,000, suggesting that there are more than 6,000 affected individuals in the U.S. Because the disease is so rare, people with the condition often go undiagnosed or misdiagnosed for years.

“The disease may be misdiagnosed as a food or medication allergy, a bowel disorder or a gynecological condition, leading to unnecessary surgeries or even death if a patient has a swelling attack in the throat,” explained Dr. Marc Riedl, associate professor of medicine and the center’s clinical director.

Emmanuel Dulac, senior vice president of rare diseases at Shire Human Genetics Therapies Inc., added, “Our philosophy at Shire is to put patients and their caregivers at the heart of everything we do—it is what drives us on a daily basis and what we believe gives us a personal connection to the patient community.”

The new U.S. HAEA Angioedema Center is located at 8899 University Center Lane in University Towne Center. Additional private support is needed to ensure treatment and a possible cure for those suffering from angioedema. Donors are encouraged to make a gift online.

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Paramedics may be best first lineof defense in treating stroke patients

First-of-its-kind study, led by UCLA, offers hope for faster, more effective care.

By Kim Irwin, UCLA

A consortium led by UCLA physicians has found that paramedics can safely start providing people with medication in the first minutes after the onset of a stroke instead of waiting for them to receive treatment at a hospital.

Although the drug tested, magnesium sulfate, did not improve patient outcomes, the research points to a new method for treating stroke patients quickly.

For people who have suffered a stroke, immediate treatment is key — the more time that passes before the restoration of blood flow, the higher the likelihood that stroke victims will suffer irreversible brain damage.

The study findings indicate that paramedics can give intravenous medications to stroke patients within the “golden hour,” the window during which treatments are most likely to help patients survive and avoid debilitating, long-term neurological damage. That finding is a game-changer, said Dr. Jeffrey Saver, the study’s co-principal investigator and director of the UCLA Stroke Center.

“The trial succeeded in its goal of devising a means to deliver promising drugs to stroke patients in the first minutes, when there’s the greatest amount of brain to save. We have opened a new therapeutic window that is now being used to test other compounds and deliver clot-busting drugs to patients in the field,” said Saver, who also is a professor of neurology at the David Geffen School of Medicine at UCLA. “Stroke is a true emergency condition. Time lost is brain lost — for every minute that goes by without restoration of blood flow, 2 million nerve cells are lost.”

The study appears in today’s (Feb. 5) issue of the New England Journal of Medicine.

The phase 3 Field Administration of Stroke Therapy–Magnesium (FAST–MAG) clinical trial involved collaboration among 315 ambulances, 40 emergency medical service agencies, 60 receiving hospitals, 715 emergency physicians, 210 neurologists, 26 neurosurgeons and 2,988 paramedics in Los Angeles and Orange counties. In the study, half of the 1,700 patients had the study drug administered within 45 minutes, while 74 percent were treated within the golden hour.

“This study involved an unprecedented cooperative effort of paramedics in the field and emergency physicians serving as investigators,” said Dr. Sidney Starkman, co-principal investigator and co-director of the UCLA Stroke Center.

“Through this study we were able to instill permanently in everyone’s mind the idea that ‘time is brain.’ We believe this represents a paradigm shift in the treatment of stroke and potentially numerous other neurological conditions,” said Starkman, who also is professor of emergency medicine and neurology at the Geffen School. “We demonstrated that paramedics not only are eager to provide the best possible patient care, but also are capable of being invaluable partners in an intense, time-dependent clinical trial.”

Today, the only ways to treat strokes caused by blocked blood vessels are to reopen the arteries with tissue plasminogen activator, a clot-busting drug, or to use catheters to remove the clot. But, in general, neither can be done until the patient arrives at the hospital and undergoes a CT scan to rule out bleeding in the brain. Additional treatments can only be offered after that, by which time substantial brain injury may already have occurred.

The FAST–MAG trial used magnesium because in animal studies it dilated blood vessels and increased blood flow in the brain. Magnesium also countered the damaging calcium buildup that occurs when cells are deprived of oxygen. It had been already approved for use in humans, it had a good safety profile and paramedics were familiar with it.

“Now we are tasked with finding a different agent or combination of agents that can improve stroke outcomes within that golden hour,” Saver said. “The ambulance treatment platform can be used around the world to test promising agents.”

Dr. Bill Koenig, medical director of the Los Angeles County Emergency Medical Service Agency, worked closely with Saver and Starkman on the FAST-MAG study.

“To assist paramedic recognition of stroke victims, the nationally recognized Los Angeles Pre-hospital Stroke Screen was developed,” Koenig said. “FAST-MAG also served as an impetus to create the Los Angeles County System of Stroke Hospitals, which every year treats over 10,000 stroke victims. When the day comes that a medication can successfully treat stroke in its early stages, this novel system in Los Angeles will be well positioned to immediately apply the treatment to our patients. I am confident that with the dedicated investigators, along with a finely tuned EMS system, that discovery will be sooner rather than later.”

Dr. Walter Koroshetz, acting director of the National Institute of Neurological Disorders and Stroke, said this study shows that it is possible to get treatments to stroke patients even before they arrive at a hospital.

“Because a blocked blood vessel causes brain damage over minutes to hours, this pre-hospital approach to treatment is sure to be adopted and refined in clinical research studies,” Koroshetz said. “Ultra-early brain salvage in stroke patients will someday surely reduce the tremendous burden of disability and death due to stroke.”

Saver said clinical trials currently being conducted in the U.S., Canada and England are testing new compounds using the early treatment infrastructure created by the FAST–MAG study.

Stroke is the fifth leading cause of death in the U.S. and is a major cause of adult disability. About 800,000 people in the U.S. have strokes each year, and one person dies from a stroke every four minutes, on average.

The study was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.

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FDA approves new drug to treat estrogen-receptor-positive breast cancer

UCLA research played key role in development of Ibrance.

UCLA Drs. Dennis Slamon (left) and Richard Finn

By Reggie Kumar, UCLA

The U.S. Food and Drug Administration today (Feb. 3) approved a new drug to treat patients with advanced breast cancer, signaling a new strategy for arresting tumor growth and extending the time before cancer worsens in women with metastatic disease.

The drug, Ibrance (palbociclib), was studied in 165 post-menopausal women with advanced estrogen–receptor positive (ER+) and HER2–negative (HER2-) breast cancer who had received no prior systemic therapy for their metastatic disease. In 2013, after patients in a clinical study led by UCLA researchers showed a dramatic improvement, the FDA granted the drug “breakthrough therapy” status, allowing it to be fast-tracked for approval.

ER+/HER2- is the most common type of breast cancer; it is traditionally treated with therapies like tamoxifen or letrozole that target the hormone receptor pathway.

“Ibrance is the first drug in its class to be approved by the FDA,” said Dr. Richard Finn, the study’s principal investigator and a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “All of us at UCLA are very proud of the important role we played in bringing this new agent to patients.”

Developed by Pfizer, Ibrance targets proteins in cancer cells — cyclin D kinase 4 (CDK 4) and cyclin D kinase 6 (CDK 6) — preventing the cells from dividing. A multiyear phase two study found a significantly higher progression-free survival rate for patients with advanced ER+/HER2- breast cancer who were given palbociclib in addition to letrozole, a standard anti-estrogen treatment, compared with women who received letrozole alone.

“With the FDA approval, this study represents a potential practice-changing result,” said Dr. Dennis Slamon, director of the Revlon/UCLA Women’s Cancer Research Program and director of clinical and translational research at the Jonsson Cancer Center. “I believe palbociclib will now become a standard treatment approach for postmenopausal women with ER+/HER2- metastatic breast cancer.”

Developing Ibrance

The research originated in 2007, when Finn and Slamon met with Pfizer to discuss palbociclib and other experimental drugs in the company’s pipeline.

In preclinical trials, the drug showed encouraging results against human breast cancer cells in culture dishes — and specifically against ER+ cancer cells. This led to a clinical study collaboration with Pfizer led by Finn and Slamon built on work at the Jonsson Cancer Center’s Translational Oncology Research Laboratory.

A phase 2 study evaluated the drug in 165 post-menopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic therapy for their metastatic disease. It showed progression-free survival was 20.2 months for patients who received palbociclib plus letrozole, compared with 10.2 months for those who received the letrozole alone. The results also indicated a 51 percent reduction in the risk of disease progression when palbociclib was used with letrozole.

“What is really remarkable is that we doubled the median progression-free survival,” Finn said. “That type of result is not often seen in cancer medicine.”

Over 80 percent of the women in the study with metastatic ER+ breast cancer received some benefit from the treatment. The drug’s safety profile is distinct from traditional chemotherapy, but it does result in a lowered white blood cell count, which is manageable.

A phase three international clinical trial of the drug conducted by Finn and Slamon with Pfizer in approximately 660 people with advanced ER+/HER2- breast cancer has been completely enrolled.

Survivor stories

Janet Klein was first diagnosed with stage 1 ER+ breast cancer in 2004, and she decided to undergo a double mastectomy. A few years later, doctors discovered that the breast cancer had returned as metastatic disease in her bones.

Dr. Sara Hurvitz, a UCLA oncologist and member of the Jonsson Cancer Center, told Klein about the clinical trial at UCLA. Klein enrolled and was prescribed Ibrance in combination with an anti-estrogen treatment. Nine months later, her scans showed no evidence of the cancer.

“I had a large party with a lot of champagne,” she said. “It was life-changing but in a good way.” said Klein.

Klein, now 59, said the FDA approval was cause for more celebration. “Sixty percent of all women diagnosed with this disease have my variety, and this drug having this sort of an impact, so fast and so effectively, is earth shattering.”

Gloria Zollar, 78, joined the phase two clinical trial in 2010 after her UCLA oncologist discovered that her advanced breast cancer had spread to her bones. She has been on treatment since that then.

But after only a year of treatment, doctors noticed that Zollar’s tumors had stopped progressing — allowing her to remain active and continue playing golf.

“I am now in remission, and every day I’m thankful to God that I’m alive and able to see my great-grandchildren and spend time with them,” Zollar said.

She also is excited that the drug is now available to other women. “I am very pleased that other women could have a second chance at life like many of us who participated in the trial,” Zollar said.

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