TAG: "Cancer"

UCLA, Apple team on app to track breast cancer survivors’ experiences

Share the Journey: Mind, Body and Wellness after Breast Cancer available now on iTunes.

Patricia Ganz, UCLA

By Reggie Kumar, UCLA

UCLA cancer research pioneer Dr. Patricia Ganz and collaborators Apple and Sage Bionetworks today (March 9) announced the launch of Share the Journey: Mind, Body and Wellness after Breast Cancer, a patient-centered mobile app that empowers women to be partners in the research process by tracking their symptoms and successes.

Available for download today at the iTunes App Store, Share the Journey was developed by UCLA’s Jonsson Comprehensive Cancer Center, Penn Medicine, Dana-Farber Cancer Institute and Sage Bionetworks. The app is an interactive research study that aims to understand why some breast cancer survivors recover faster than others, why their symptoms vary over time and what can be done to improve symptoms.

Ganz, who is director of cancer prevention and control research at the Jonsson Cancer Center, was a key collaborator with Apple and Sage in developing Share the Journey, which marries science and technology by using surveys and sensor data on the iPhone to collect and track fatigue, mood and cognitive changes, sleep disturbances and reductions in exercise.

Share the Journey is one of five new apps being launched in conjunction with Apple’s ResearchKit, an open-source tool that serves as a streamlined hub for iOS apps that can help speed scientific progress toward cures by amplifying the patient voice in shaping research directions and outcomes.

Share the Journey shifts the center of care, healing and intervention into the hands of women who have survived breast cancer. Its creators say that collecting women’s experiences after breast cancer treatment will create a trove of data based on well-validated surveys and measurements that will be continuously improved upon based on the participants’ feedback.

Women who have undergone surgery, radiation or drug therapy to treat breast cancer often experience symptoms that affect their quality of life and impede recovery.

“We’re excited to use these new ResearchKit tools to expand participant recruitment and quickly gather even more data through the simple use of an app. The data it will provide takes us one step closer to developing more personalized care,” said Ganz, who also is a professor at the UCLA Fielding School of Public Health. “Access to more diverse patient-reported health data will help us learn more about long-term aftereffects of cancer treatments and provide us with a better understanding of breast cancer patients’ experience.”

Share the Journey is open to women between the ages of 18 and 80 who live in the United States, whether or not they have had breast cancer. Those who have not had breast cancer will contribute important data to the app that will help researchers understand which symptoms may be related to cancer treatment and which may be part of the normal aging process. The developers also are creating a Spanish-language version of the app and planning to expand the study to other countries.

“One reason to build these apps and run these studies is to see whether we can turn anecdotes into signals, and by generating signals find windows for intervention,” said Dr. Stephen Friend, president of Sage Bionetworks and a principal investigator for Share the Journey. “We’re most interested in disease variations and the hourly, daily or weekly ebb and flow of symptoms that are not being tracked and completely missed by biannual visits to the doctor.”

The platform is based on the concept that if individuals’ experiences were at the center of the research process, researchers working in virtual teams might be able to get efficient, inexpensive and ubiquitous ways of gathering information using websites, tablets or an app. This technology will allow Sage and other teams to include patients and other study participants as owners of their own data and equal partners.

“We need to better understand some of the long-term negative treatment effects, such as fatigue, that can be associated with the disease control benefits of cancer therapies. What are the biological mechanisms that underpin those effects and why some survivors are more vulnerable to those effects than others,” Ganz said.

“With Share the Journey, women can tell us when something’s wrong, and the app has the potential to capture valuable information on the patient experience. Our current cancer care system lacks the ability to predict or treat these chronic and enduring symptoms, but Share the Journey can set us on a path toward understanding why some people recover and some do not.”

In addition to Ganz, Apple and Sage were advised in development of Share the Journey by Drs. Ann Partridge and Judy Garber at Dana-Farber Cancer Institute, Dr. Kathryn Schmitz at the University of Pennsylvania Perelman School of Medicine and Dr. Susan Love at UCLA and the Dr. Susan Love Research Foundation.

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Childhood leukemia study reveals disease subtypes, new treatment option

1 of 8 patients might benefit from highly successful lymphoma drugs.

By Pete Farley, UC San Francisco

A new study of acute lymphoblastic leukemia (ALL), a blood cancer that primarily affects young children, has revealed that the disease has two distinct subtypes, and provides preliminary evidence that about 13 percent of ALL cases may be successfully treated with targeted drugs that have proved highly effective in the treatment of lymphomas in adults.

Usually emerging in children between 2 and 5 years of age, ALL occurs when the proliferation of white blood cells known as lymphocytes spirals out of control. The current standard of care for ALL employs high doses of chemotherapy that usually cure the disease, but may also have serious long-term effects on brain development, bone growth and fertility, so there is an unmet need for better therapies.

In addition to discovering the two ALL subtypes, the researchers, led by scientists from UC San Francisco and Oregon Health & Science University (OHSU), developed a simple lab test that determines whether patients fall into the less-common subtype that may respond to targeted therapy. One author of the new study, affiliated with MD Anderson Cancer Center in Texas, is already using this new test to recruit patients for a phase one clinical trial evaluating the use of targeted drugs for ALL.

The research and resulting clinical trial exemplify one of the main goals of precision medicine — improving health by identifying subtypes of disease that can be specifically targeted with drugs or other therapies.

“We hope patients in this newly identified subset can be treated with these targeted drugs, which have worked very well in patients with lymphoma and which are powerfully effective in the mouse experiments we have conducted on ALL,” said co-senior author Markus Müschen, M.D., Ph.D., professor of laboratory medicine at UCSF and a member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “These drugs have essentially no side-effects and relatively few effects on quality of life.”

Müschen said the new work, reported online in Cancer Cell today (March 9), grew out of a line of research on new treatments for lymphoma, which usually affects adults. That work, which culminated in papers published in The New England Journal of Medicine in 2013, showed that various forms of lymphoma respond well to treatment with ibrutinib (trade name Imbruvica) or idelalisib (trade name Zydelig), two drugs that precisely target the B-cell antigen receptor, a protein found in white blood cells.

“Because B-cells are also involved in ALL, we essentially recapitulated these studies, starting out with the basic science by studying genetic components of the B-cell antigen receptor in mice,” said Müschen. “We were surprised to find that, depending on the initial cancer-causing mutation, B-cell antigen receptor signaling is sometimes present in ALL, which suggested that ALL might also respond to the drugs that had been used in lymphoma.”

Led by first authors Huimin Geng, Ph.D., assistant professor of laboratory medicine at UCSF, postdoctoral fellow Christian Hurtz, Ph.D., also of UCSF, and Kyle Lenz, research assistant at OHSU, the group found that cells that exhibit B-cell antigen receptor signaling also express very high levels of a protein known as BCL-6. Then, using BCL-6 as a biomarker, the team used several methods to inhibit B-cell antigen receptor signaling, including treating cells with targeted compounds used in human lymphoma. All of these approaches successfully and selectively killed ALL cells, and similar results were seen in a mouse model of ALL.

The research group next studied 830 patients enrolled in four ongoing ALL clinical trials, in part to assess whether testing for BCL-6 expression would be a practical biomarker in the clinic to identify candidates for targeted therapy.

Virtually all of the bone marrow slices from 112 patients (13.5 percent) with active B-cell antigen receptor signaling showed “beautiful staining” of BCL-6 expression, Müschen said (in two patients only weak staining was seen). On the other hand, no BCL-6 staining was observed in patients lacking B-cell antigen receptor signaling. These results suggest that the BCL-6 test may have sufficient sensitivity and specificity to select patients for targeted therapy.

“Children are given high doses of chemotherapy for ALL because they are considered more resilient than adults, but there are long-term consequences that may not be obvious in childhood,” Müschen said. “Our idea is that by adding these new drugs we can reduce the amount of conventional chemotherapy or even replace it. In our experiments with mice, both combination therapy with low-dose chemotherapy and single-agent targeted therapy each worked very well. The new clinical trial using the BCL-6 biomarker should begin to bring us the answers.”

OHSU’s Bill Chang, M.D., Ph.D., was co-senior author of the study. The work was funded by the National Institutes of Health, the National Cancer Institute, the Hyundai Hope on Wheels program, the St. Baldrick’s Foundation, the Leukemia and Lymphoma Society, Tucker’s Toy Box Foundation, the William Lawrence and Blanche Hughes Foundation, the California Institute for Regenerative Medicine, and the U.K.’s Medical Research Council and National Institute for Health Research.

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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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UCLA celebrates naming of Agi Hirshberg Center for Pancreatic Diseases

Gift will advance breakthroughs in pancreatic cancer research.

By Mary Goodstein, UCLA

UCLA celebrated the naming of the UCLA Agi Hirshberg Center for Pancreatic Diseases on Feb. 28 at a gathering of Hirshberg’s family and friends. The naming was made possible by $10 million in gifts from Hirshberg to UCLA.

“Agi Hirshberg’s 18-year commitment to finding a cure has placed UCLA at the forefront of cutting-edge research on pancreatic cancer,” said UCLA Chancellor Gene Block. “In recognition of her visionary support and a generous new $5 million gift, we are pleased to name the UCLA Agi Hirshberg Center for Pancreatic Diseases.”

The campus event also was attended by UCLA faculty and staff as well as members of Women and Philanthropy — of which Hirshberg is president — and the board of visitors of the David Geffen School of Medicine at UCLA.

Hirshberg established the Hirshberg Foundation for Pancreatic Cancer Research in 1997 in memory of her late husband, Ronald S. Hirshberg, who died of pancreatic cancer at age 54. The innovative research supported by the foundation has changed the face of pancreatic cancer treatment. As the first beneficiary of the foundation’s giving, UCLA established the Ronald S. Hirshberg Translational Pancreatic Cancer Research Laboratory in 1998 and the Ronald S. Hirshberg Chair in Translational Pancreatic Cancer Research in 2000.

Funding from the Hirshberg Foundation has elevated the UCLA center to one of the nation’s premier comprehensive programs for pancreatic cancer and diseases, and it has laid the groundwork for a model in which the needs of people with pancreatic cancer are met in one location with the most advanced treatment options available.

“I strongly believe that the cure for pancreatic cancer is right around the corner. I feel it,” Hirshberg said. “This new commitment ensures continuous research results and allows us to continue on our path toward a cancer-free life.”

Hirshberg’s most recent gift will fund seed grants as well as the center’s highest-priority needs. The Hirshberg Foundation’s Seed Grant Program has helped propel pancreatic cancer research, serving as a springboard for multiple investigations at UCLA and other prestigious institutions and leading to additional investments from the National Institutes of Health and other organizations. Since the program’s inception in 2000, it has generated more than $65 million in additional support for research involving the molecular mechanisms of pancreatic cancer, early diagnosis, surgical and chemotherapeutic treatments, psychosocial approaches to disease management and prevention strategies.

“Agi Hirshberg raised the visibility of this devastating disease and has been instrumental in advancing pancreatic cancer research, not only at UCLA but across the nation,” said Dr. Vay Liang Go, director of the UCLA Center for Excellence in Pancreatic Diseases. “Her ongoing support of the multiple areas focused on pancreatic cancer at UCLA has led to pioneering investigations that have given many patients a chance to survive one of the most deadly forms of cancer.”

According to Dr. Howard Reber, distinguished professor of surgery emeritus, chief of gastrointestinal and pancreatic surgery, and director emeritus of the newly renamed center, “Agi Hirshberg has had a major role in the growth and development of one of the country’s busiest and most successful clinical programs for the multidisciplinary treatment of pancreatic cancer.”

Kathryn Carrico, UCLA’s assistant vice chancellor for health sciences development, said, “We applaud not only Agi’s vision, dedication and leadership, but also the power of her philanthropy.”

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Protein may be key to cancer’s deadly resurgences

HIGD1A may be a novel target for cancer therapy.

By Pete Farley, UC San Francisco

Tumor recurrence following a period of remission is the main cause of death in cancer. The ability of cancer cells to remain dormant during and following therapy, only to be reactivated at a later time, frequently with greater aggressiveness, is one of the least-understood aspects of the disease.

UCSF researchers working in the laboratory of Emin Maltepe, M.D., Ph.D., associate professor of pediatrics, led by associate research specialist Kurosh Ameri, Ph.D., have now identified a protein that plays a critical role in this process.

Tackling resistant cancer cells

Solid tumors have a core composed of necrotic, or dying, cells. Ameri and colleagues concentrated on the part of tumors that immediately surrounds these necrotic cores, which is known as the perinecrotic region.

Cancer cells in the perinecrotic region have traditionally been more difficult to eradicate than those nearer to the tumor surface, because they are deprived of both oxygen and nutrients – factors that promote resistance to therapy.

A classic regulator of cellular responses to low-oxygen conditions is the transcription factor known as hypoxia-inducible factor 1, or HIF-1. Perinecrotic regions paradoxically lack HIF-1 activity, but they retain expression of a small subset of HIF target genes.

The authors of the new study found that the protein product of one of these genes, a mitochondrial protein called HIGD1A, enables cells to survive in the extreme environment deep in the tumor by repressing their metabolism and the production of toxic reactive oxygen species (ROS).

Key protein represses tumor growth

When the scientists engineered tumors to overexpress HIGD1A, the tumors dramatically repressed their growth, as the team reported in the Feb. 17 issue of Cell Reports. But the overall survival of the tumor cells was significantly enhanced, and these effects were even seen in mice that lacked the HIF-1 protein.

To discern the mechanisms behind these effects, the authors looked for interactions between HIGD1A and other mitochondrial proteins. They found that it interacted with components of the electron transport chain responsible for oxygen consumption as well as ROS production. Expression of the HIGD1A protein reduced oxygen consumption but triggered increased mitochondrial ROS formation, which resulted in the activation of cellular antioxidant mechanisms driven by another critical metabolic regulatory protein, AMP-dependent kinase, or AMPK.

Surprisingly, the researchers found that the HIGD1A gene is not activated by hypoxia, or oxygen deprivation, in human cancers, even though the gene recruits HIF-1 to its promoter region. A lack of HIGD1A expression in response to hypoxia alone was due to increased methylation of the HIGD1A gene’s regulatory regions, which could be overcome in experiments either by applying pharmacological DNA-demethylating agents, or by combined oxygen/glucose deprivation, conditions that simulate the perinecrotic environment.

These data suggest that HIGD1A plays an important role in tumor dormancy mechanisms and may be a novel target for cancer therapy. Severe oxygen and nutrient deprivation decreases the levels of the enzyme DNA methyltransferase in multiple human cancers, allowing HIGD1A expression, and may represent a widespread mechanism enabling tumor cell survival in these HIF-deficient extreme environments.

By dissecting these mechanisms further, the researchers hope to find novel tools to target dormant cancer cells and decrease tumor recurrence rates.

Ameri and Maltepe conducted the study in collaboration with the laboratories of Manish Aghi, M.D., Ph.D., associate professor of neurological surgery; Joseph F. Costello, Ph.D., the Karen Osney Brownstein Endowed Chair in Molecular Neuro-Oncology; and Stefanie S. Jeffrey, M.D., John and Marva Warnock Professor of Surgery at Stanford School of Medicine.

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How stem cells are grown affects their genetic stability

Methods to multiply pluripotent cells for potential therapies raise worries about cancer.

By Scott LaFee, UC San Diego

The therapeutic promise of human stem cells is indisputably huge, but the process of translating their potential into effective, real-world treatments involves deciphering and resolving a host of daunting complexities.

Writing in today’s (Feb. 25) online issue of the journal PLOS ONE, researchers at the UC San Diego School of Medicine, with collaborators from The Scripps Research Institute (TSRI), have definitively shown for the first time that the culture conditions in which stem cells are grown and mass-produced can affect their genetic stability.

“Since genetic and epigenetic instability are associated with cancers, we worry that similar alterations in stem cells may affect their safety in therapeutic transplants. Certain mutations might make transplanted stem cells more likely to form tumors, introducing the risk of cancer where it didn’t exist before,” said co-corresponding author Louise Laurent, M.D., Ph.D., assistant professor and director of perinatal research in the Department of Reproductive Medicine at UC San Diego School of Medicine.

“This study shows the importance of quality control,” added Jeanne F. Loring, Ph.D., professor and director of the Center for Regenerative Medicine at TSRI, and adjunct professor in the UC San Diego Department of Reproductive Medicine and the study’s other co-corresponding author. “It’s almost certain these cells are safe, but we want to make sure they are free from any abnormalities.”

To exploit the transformative powers of human pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, requires producing them in large numbers for transplantation into patients.

“During this culturing process, mutations can occur, and mutations that increase cell survival or proliferation may be favored, such that the cells carrying such mutations could take over the culture,” said Laurent.

Human pluripotent stem cells are cultured in several different ways. Key variables are the surfaces upon which the cells are cultured, called the substrate, and the methods used to transfer cells from one culture dish into another as they grow, called the passage method.

Originally, scientists determined that stem cells grew best when cultured atop of a “feeder” layer that included other types of cells, such as irradiated mouse embryonic fibroblasts. For reasons not fully understood, these cells provide stem cells with factors that support their growth. However, concerns about the feeder cells also introducing undesirable materials into stem cells has prompted development of feeder-free cultures.

Moving cells from one culture dish to another has traditionally been done manually, with technicians physically separating the cultured cells into small clumps with an instrument. “It’s very labor-intensive,” said Laurent, “so new methods that use enzymes to separate individual cells were created.”

In the PLOS ONE paper, Laurent and colleagues compared stem cells grown on two substrates (with and without feeder cells) and passaged using manual and enzymatic methods. They report that the use of enzymes to passage the stem cells was strongly associated with increased genetic instability. Some of the mutations observed in the stem cells were previously known, but Laurent said others were seen for the first time, including deletion of a region of the genome that includes the gene P53, which is frequently deleted in cancer cells.

“I think these results call into question the use of enzymatic passaging, at least with enzymes that separate the cultures into single cells, for clinical use. However, we don’t want to imply that any culture method is absolutely ‘safe.’ Any new culture method should be evaluated for its impact on genetic stability, and every batch of cells destined for the clinic should be tested using sensitive high-resolution methods for detecting genetic alterations.

“The processes used to maintain and expand stem cell cultures for cell replacement therapies need to be improved, and the resulting cells must be carefully tested before use.”

Co-authors include Ibon Gariaonandia, Gerald K. Wambua, Heather L Schultheisz, Shannon Waltz, Yu-Chieh Wang, Ha Tran, Kristopher Nazor, Ileana Slavin, Candace Lynch and Ron Coleman, TSRI; Karen Sabatini, Francesca S. Boscolo, Trevor R. Leonardo and Gulsah Altun, TSRI and UCSD; Irene Gallego Romero, University of Chicago; David Reynolds and Steve Dalton, University of Georgia, Athens; and Hadar Amir, Robert Morey, Mana Parast and Yingchun Li, UCSD.

Funding for this research came, in part, from the California Institute for Regenerative Medicine (grants CL1-00502, RT1-01108, TR1-01250, RM1-01717, TB1-01193, TG2-01165), the National Institutes of Health (grants R33MH087925, P01GM085354, P01HL089471), the UC San Diego Department of Reproductive Medicine, the Hartwell Foundation, the Millipore Foundation, the Esther O’Keefe Foundation, the Marie Mayer Foundation, Autism Speaks, the Pew Charitable Trust and the Wellcome Trust.

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Inflammation, tissue regeneration, wound repair response linked

Finding has implications for potential treatments of cancers, inflammatory bowel disease.

By Scott LaFee, UC San Diego

Almost all injuries, even minor skin scratches, trigger an inflammatory response, which provides protection against invading microbes but also turns on regenerative signals needed for healing and injury repair – a process that is generally understood but remains mysterious in its particulars.

Writing in today’s (Feb. 25) online issue of Nature, an international team of scientists, headed by researchers at the University of California, San Diego School of Medicine, report finding new links between inflammation and regeneration: signaling pathways that are activated by a receptor protein called gp130. “We found that gp130 is capable of activating several signaling pathways that turn on a number of transcription factors known to have a key role in stem cell biology,” said the study’s lead author, Koji Taniguchi, M.D., Ph.D., assistant project scientist in the Department of Pharmacology at UC San Diego.

These transcription factors – specifically STAT3, YAP and Notch – stimulate the proliferation and survival of normal tissue stem cells, which lead to healing and repair, said senior author Michael Karin, Ph.D., Distinguished Professor Pharmacology and Pathology and head of UC San Diego’s Laboratory of Gene Regulation and Signal Transduction.

“While the work was mainly conducted on a mouse model of intestinal injury, similar to the one that underlies human inflammatory bowel disease (IBD), we provide evidence that the same mechanism may control liver regeneration, which suggests a general role in tissue repair,” said Karin.

In addition to explaining a key biomedical phenomenon, the researchers said the findings have important clinical implications for the treatment of IBD and colorectal cancer. The major signal sensed by gp130 is the inflammatory hormone (cytokine) IL-6 and closely related proteins. Expression of IL-6 has been found to be elevated in IBD, both in Crohn’s disease and ulcerative colitis, giving rise to the possibility that inhibition of IL-6 binding to its receptor – a complex between gp130 and a specific IL-6 binding protein – may ameliorate the pathology of IBD.

But just the opposite has been observed. Drugs that block the binding of IL-6 to its receptor complex actually increase the risk of intestinal perforation and bleeding, making them unsuitable for the treatment of IBD. The new work suggests that IL-6 and the signaling pathways it stimulates are not the cause of IBD, but are part of the natural protective reaction to the initial injury and inflammatory response associated with the onset of IBD.

The Taniguchi and Karin team say it is important that future treatments not interfere with the healing response triggered by IL-6 and gp130. Nonetheless, the same pathways involved in healing and regeneration can go awry and become chronically stimulated in colorectal cancer.

The new work defines several molecular targets suitable for development of new targeted therapies for this very common malignancy – the third leading cause of cancer-related death, though Karin cautioned that “such treatments should not be combined with conventional and highly toxic anti-cancer drugs whose major side effect is damage and inflammation of the intestinal mucosa, a disease known as mucositis that will only be exacerbated by blocking the regenerative response triggered by IL-6.”

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Study could point toward better decisions for treating men with prostate cancer

UCLA team analyzes data for more than 37,000 patients.

By Reggie Kumar, UCLA

UCLA researchers have found that radiation therapy is the most common treatment for men with prostate cancer regardless of the aggressiveness of the tumor, the risk to the patient or the patient’s overall prognosis. This finding lays the groundwork for doctors to make more informed decisions about treatment options and provide better information for people with the disease.

A team led by Dr. Karim Chamie, an assistant professor of urology at UCLA, analyzed data from 2004 through 2007 for more than 37,000 patients. They found that radiation therapy was the most common treatment for prostate cancer, and that the most significant factor in determining whether a man received radiation therapy was that he had been referred to a radiation oncologist. Urologists and surgeons, on the other hand, took into account the patient’s age and health as well as the aggressiveness of the cancer before recommending surgery.

“Doctors and patients view radiation as safe,” Chamie said. But he added that by two years after treatment, men often start to suffer side effects including urinary incontinence, bowel dysfunction, erectile dysfunction and radiation cystitis.

According to the report, those side effects and risks might be outweighed by the benefits of radiation for patients with aggressive cancer and otherwise long life expectancy. But for a patient with a slow-growing tumor and shorter life expectancy, radiation might not be worthwhile.

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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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UCSF receives $100M gift to advance health sciences mission

Landmark gift cements Chuck Feeney’s role as UC system’s top philanthropist.

Chuck Feeney

By Jennifer O’Brien, UC San Francisco

UC San Francisco has received a $100 million gift from visionary philanthropist Charles F. “Chuck” Feeney to support its new Mission Bay hospitals, world-class faculty and students, and research programs focused on the neurosciences and aging.

This donation brings the longtime supporter’s total UCSF giving to more than $394 million, making Feeney the single largest contributor to the University of California system.

“I get my gratification from knowing that my investments in medical research, education, and the delivery of health care at UCSF will provide lifelong benefits to millions of people not only in the Bay Area but also around the world,” said Feeney, who, despite his global presence as a successful entrepreneur and discerning philanthropist, prefers remaining out of the limelight. “I can’t imagine a more effective way to distribute my undeserved wealth.”

Reflecting on Feeney’s contributions, UCSF Chancellor Sam Hawgood, M.B.B.S., said, “As we celebrate UCSF’s 150th anniversary this year, it is only fitting that we acknowledge the unique role Chuck has played in our history. While his impact has been felt most profoundly during this past decade, his generosity will carry on forever at our university, in the San Francisco community, throughout the Bay Area and globally, as our faculty and students advance knowledge and provide the finest clinical care. We are honored that he has decided to invest again in UCSF.”

Feeney’s gifts to UCSF are most visible at the university’s Mission Bay campus, where he has provided indispensable support to create advanced facilities and foster the environment for the biomedical research and patient care that goes on within them.

Before the latest funding, Feeney’s most recent gift to the campus was to UCSF Global Health Sciences, enabling the October 2014 opening of Mission Hall, which houses global health researchers, scientists and students under the same roof for the first time. Feeney, who coined the term “giving while living,” also generously supported the building of the Smith Cardiovascular Research Building and the Helen Diller Family Cancer Research Building.

“Chuck Feeney has been our partner at Mission Bay for more than 10 years,” added Hawgood. “He immediately embraced the Mission Bay concept, and he has enthusiastically helped us shape a larger vision for the campus and finance its development because he knew that our research and clinical programs could not flourish without state-of-the-art buildings.”

Gift to support four primary areas

The Campaign for the UCSF Medical Center at Mission Bay
Funds will support the $600 million philanthropy goal of the $1.5 billion hospitals project. The latest donation builds upon the transformative $125 million matching gift Feeney made to support the hospitals complex and its programs in 2009, the largest gift received toward the campaign.

The opening of the 289-bed hospital complex – which includes UCSF Benioff Children’s Hospital San Francisco, UCSF Betty Irene Moore Women’s Hospital, UCSF Bakar Cancer Hospital, and the UCSF Ron Conway Family Gateway Medical Building – was the culmination of more than 10 years of planning and construction. Strategically located adjacent to UCSF’s renowned Mission Bay biomedical research campus, the new medical center places UCSF physicians in close proximity to UCSF researchers and nearby bioscience companies who are working to understand and treat a range of diseases, from cancer to neurological disorders.

“It’s been thrilling to see the reactions of our patients and their families as they encounter the amazing care offered at our new UCSF Mission Bay hospitals,” said Mark Laret, CEO of UCSF Medical Center and UCSF Benioff Children’s Hospitals. “This world-class experience would never have been possible without the support of Chuck Feeney who, as the largest contributor to the project, helped us create the hospitals of our dreams. Every patient cured, every breakthrough discovered at Mission Bay, will be thanks in part to Chuck. His legacy is unparalleled.”

Neuroscience and aging
The gift also supports UCSF’s pre-eminent neuroscience enterprise, including its Sandler Neurosciences Center and neurology programs at Mission Bay.

The center, a five-story, 237,000-square-foot building that opened in 2012, brings under one roof several of the world’s leading clinical and basic research programs in a collaborative environment. UCSF’s neurology and aging efforts are focused on finding new diagnostics, treatments, and cures for a number of intractable disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, migraine, epilepsy and autism. The programs also seek to integrate neuroscience and clinical disciplines with public health initiatives in order to disseminate and implement novel findings from research centers of excellence, as well as conduct community outreach to raise awareness about the diseases of aging.

“Chuck Feeney has taken a keen interest in the challenges of aging,” said Hawgood. “In turn, he has recognized UCSF’s extraordinary talent in the neurosciences, among both basic researchers and those who translate research into clinical care and public policy. This gift will build on UCSF’s strengths while encouraging strong partnerships at other research institutions around the world where Chuck also has made important investments.”

Student scholarships and housing
Even with its extraordinary academic firepower, UCSF has extremely limited funds to support scholarships for professional students in its schools of dentistry, medicine, nursing and pharmacy. Part of the gift will provide scholarship support, bolstering UCSF’s ability to recruit the best and brightest students, regardless of their financial circumstances.

Recent decreases in state funding led to tuition increases and higher demand for scholarships. This, in turn, increased student debt. Combined with Bay Area housing prices that are among the highest in the nation – from 2011 to 2013, the median rent increased by 24 percent – the prospect of overwhelming debt can deter economically vulnerable students as well as those from middle-class backgrounds from attending UCSF. By minimizing debt upon graduation, the scholarships will help ensure that a UCSF education remains in reach for students from underserved populations, as well as for those students who choose to become health care leaders in underserved communities.

“Scholarships give our students the gift of freedom: to make career choices based on purpose and passion, rather than the price of education; to use time to study, explore science, and volunteer to help others, rather than working to make ends meet; and to succeed because someone who never met them saw enough potential to invest in their dreams,” said Catherine Lucey, M.D., vice dean for education at UCSF’s School of Medicine. “These scholarships catalyze our schools’ ability to find, recruit, educate and nurture the workforce our country needs: talented professionals whose life experiences enable them to provide compassionate care to today’s diverse communities and advance science to improve the health of future communities.”

Faculty recruitment
The donation also will help UCSF recruit the next generation of promising faculty in an increasingly competitive marketplace.

New funding will attract junior faculty – who frequently find it more challenging to secure research funding – and provide initial startup funds as they launch their research careers and clinical practices. With decreasing federal support for young investigators, this gift will underwrite a new generation of brilliant upcoming faculty.

“While Chuck’s unprecedented generosity has been focused primarily on Mission Bay, he understands the power of the entire UCSF enterprise, from our cutting-edge stem cell research at Parnassus to our innovative cancer programs at Mount Zion,” Hawgood said. “We’re thrilled that Chuck has inspired other philanthropists to join him in creating one of the most vibrant life science communities in the world, where progress will ripple far beyond Mission Bay and the campus for generations to come.”

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Human neural stem cells restore cognitive functions impaired by chemotherapy

UC Irvine study reveals how they alleviate ‘chemobrain’ after cancer treatments.

Charles Limoli, UC Irvine

By Tom Vasich, UC Irvine

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to UC Irvine researchers.

In preclinical studies using rodents, they found that stem cells transplanted one week after the completion of a series of chemotherapy sessions restored a range of cognitive functions, as measured one month later using a comprehensive platform of behavioral testing. In contrast, rats not treated with stem cells showed significant learning and memory impairment.

The frequent use of chemotherapy to combat multiple cancers can produce severe cognitive dysfunction, often referred to as “chemobrain,” which can persist and manifest in many ways long after the end of treatments in as many as 75 percent of survivors – a problem of particular concern with pediatric patients.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said Charles Limoli, a UCI professor of radiation oncology.

Study results appear in the Feb. 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

Many chemotherapeutic agents used to treat disparate cancer types trigger inflammation in the hippocampus, a cerebral region responsible for many cognitive abilities, such as learning and memory. This inflammation can destroy neurons and other cell types in the brain.

Additionally, these toxic compounds damage the connective structure of neurons, called dendrites and axons, and alter the integrity of synapses – the vital links that permit neurons to pass electrical and chemical signals throughout the brain. Limoli compares the process to a tree being pruned of its branches and leaves.

Consequently, the affected neurons are less able to transmit important neural messages that underpin learning and memory.

“In many instances, people experience severe cognitive impairment that’s progressive and debilitating,” Limoli said. “For pediatric cancer patients, the results can be particularly devastating, leading to reduced IQ, asocial behavior and diminished quality of life.”

For the UCI study, adult neural stem cells were transplanted into the brains of rats after chemotherapy. They migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

Importantly, Limoli and his colleagues found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Munjal Acharya, Lori-Ann Christie, Vahan Martirosian, Nicole N. Chmielewski, Nevine Hanna, Katherine Tran, Alicia Liao and Vipan Parihar of UCI contributed to the study, which was funded by the National Institutes of Health (grant R01 NS074388581) and supported by UCI’s Institute for Clinical & Translational Science.

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UC Davis designated a lung cancer screening center

The only of its kind currently in the greater Sacramento area.

By Dorsey Griffith, UC Davis

UC Davis Health System has been endorsed by the American College of Radiology as a designated lung cancer screening center, the only of its kind currently in the greater Sacramento area.

The designation means that UC Davis has complied with stringent quality and safety requirements for its computed tomography (CT) scanning practices, and it confirms that UC Davis meets the required radiation-dose standards.

“This designation offers patients the security of an external review process to ensure that such exams are performed at the highest level of quality and safety,” said Friedrich D. Knollmann, professor of clinical radiology in the UC Davis Department of Radiology.

The designation follows a decision by the federal Centers for Medicare and Medicaid Services to recommend CT screening for individuals deemed at high risk for developing lung cancer. Those include men and women who have smoked more than a pack a day for 30 years or two packs a day for 15 years. The screening is limited to individuals over age 55 and up to 77 or 80 depending on the individual’s insurance.

Since Jan. 1, as set forth in the Affordable Care Act, private insurers must cover the screening for people who meet the criteria. The health care reform law stipulates that insurers must provide services recommended by the U.S. Preventive Services Task Force, an independent panel that analyzes data and makes recommendations about health screening.

The task force in December 2013 recommended low-dose CT screening for eligible individuals based on results of the groundbreaking National Lung Screening Trial, which determined that low-dose CT screening reduced the risk of dying from lung cancer in heavy smokers by 20 percent compared to screening with chest X-rays. Data from the trial were published in the New England Journal of Medicine in 2011.

Lung cancer is the third most common cancer and the leading cause of cancer death in the United States. Smoking is the leading cause of lung cancer; about 85 percent of all U.S. lung cancer cases are smoking related. Lung cancer is most commonly diagnosed in people 55 and older.

The American College of Radiology represents more than 37,000 diagnostic radiologists, radiation oncologists, interventional radiologists, nuclear medicine physicians and medical physicists. The organization works to improve, promote and protect the practice of radiology to ensure the quality and safety of patient care.

The UC Davis lung cancer screening program uses a multidisciplinary team of radiologists, thoracic surgeons, pulmonologists, pathologists, medical oncologists and radiation oncologists to develop a patient-centered plan for leading-edge lung cancer care. Individuals interested in lung cancer screening should discuss the pros and cons of the test with their primary care physician, who will, after a shared decision to participate has been reached, refer them to the UC Davis Department of Radiology.

Referrals can be faxed to (916) 703-2254, and screenings can be scheduled by calling (916) 734-0655.

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