Author: Shaun Mason

UCLA’s Jonsson Comprehensive Cancer Center and the department of urology at the David Geffen School of Medicine at UCLA have been notified that their standing as a National Cancer Institute Specialized Program of Research Excellence (SPORE) site in prostate cancer has been renewed for another five years. 

 

The UCLA program is under the leadership of principal investigator Dr. Robert Reiter, Bing Professor of Urologic Research and a member of the Jonsson Cancer Center. 

 

This renewal marks the beginning of a third five-year cycle of funding that will support UCLA scientists’ efforts to improve the prevention, detection and treatment of prostate cancer. Thirty-thousand American men are expected to die from the disease this year, and the NCI estimates that more than 238,000 men will be diagnosed with prostate cancer in 2013.

 

The SPORE program is a central component of NCI’s efforts to spur collaborative, interdisciplinary cancer research at academic centers throughout the U.S., with the goal of translating basic research from the laboratories into patient care more quickly and effectively. The five-year, $11.6 million grant will help UCLA expand its renowned prostate cancer program, which engages researchers and clinicians from many disciplines across campus to uncover the mysteries of the disease.

 

“The SPORE grant will robustly continue the outstanding programs we have developed over the last two cycles of the grant and give us the resources to bring investigators together for new innovative and multidisciplinary projects with the goal of improving the way we diagnose and treat prostate cancer,” said Dr. Mark Litwin, professor and chair of UCLA’s department of urology.

 

“This renewal of the UCLA prostate SPORE is indicative of the world-class research we have on this campus,” said Dr. James Economou, UCLA vice chancellor for research and professor of microbiology, immunology and molecular genetics; molecular and medical pharmacology; and surgical oncology.

 

“The renewal of this SPORE grant is affirmation of the leadership role UCLA continues to play in groundbreaking research on prostate cancer,” said Dr. Eugene Washington, vice chancellor for health sciences and dean of the Geffen School of Medicine.

 

“Over the past 10 years, the UCLA prostate SPORE has had some great successes,” Reiter said. “Among them have been the development of the drug enzalutamide by Dr. Charles Sawyers and Dr. Michael Jung, the identification of prostate stem cells by Dr. Owen Witte and colleagues, and the discovery and development of antibodies against the prostate stem-cell antigen gene, which have all gone from discovery through to clinical trials. Other highlights include Dr. Hong Wu’s work on the PTEN tumor suppressor gene, demonstrating that the gene negatively regulates prostate cancer stem cell self-renewal, proliferation and survival, and the work of Dr. Bill Aronson and colleagues demonstrating that dietary changes can affect the growth rate of prostate tumors.”

 

According to the NCI, SPORE grants are designed to promote collaboration among the best scientific minds. The grants bring together researchers who might not otherwise have a chance to work together. The UCLA prostate SPORE is the only one in California and one of a handful in the U.S.

 

The specific aims of the renewed grant are:

• Conducting translational research to investigate what makes prostate cancer spread and become castration resistant, meaning that it does not respond to hormone therapy. 
• Targeting cancer stem cells and signaling pathways.
• Evaluating the effects and mechanisms of dietary change in preventing prostate cancer. 
• Providing organizational infrastructure and novel technologies to support SPORE objectives. 
• Developing new research areas and supporting the careers of new researchers.

The SPORE grant will primarily fund four projects at UCLA:

• Dr. Robert Reiter and Dr. Anna Wu will focus on translating N-cadherin-targeted antibody therapy into the clinic. N-cadherin, a protein expressed widely across prostate cancers, is required for castration-resistant prostate cancer to emerge and survive, and it therefore is considered a credentialed target treatment for prostate cancer by the NCI. 

Jonsson Cancer Center director Dr. Judith Gasson, a professor of medicine and senior associate dean for research, said that UCLA’s prostate cancer program is a shining example of the campus’s excellence in interdisciplinary research. 

 

“We’ll be able to move forward more quickly now to develop new and better ways to prevent, diagnose and treat prostate cancer with the goal of saving tens of thousands of lives every year,” she said.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter. 

Researchers at UCLA’s Jonsson Comprehensive Cancer Center have successfully combined cellular therapy and gene therapy in a mouse-model system to develop a viable treatment strategy for breast cancer that has spread to a patient’s brain.

 

The research, led by Carol Kruse, a professor of neurosurgery and member of the Jonsson Cancer Center and the UCLA Brain Research Institute, was published Aug. 1 in the journal Clinical Cancer Research.

 

Breast cancer is the most common form of cancer in women, and metastasis is a major cause of health deterioration and death from the disease. Managing metastasis is difficult for several reasons: The circulatory network known as the blood–brain barrier prevents many anti-cancer drugs from reaching areas of the brain to which cancer has spread, and metastases have a tendency to spring up in multiple brain locations simultaneously, making current treatments such as radiation challenging.

 

Cellular therapy is a type of immunotherapy that uses T cells, the foot soldiers of the immune system, that have been sensitized in the laboratory to kill breast cancer cells. These sensitized T cells are injected into the parts of the brain to which cancer has spread. The research shows that the T cells can move through tissue and recognize and directly kill the tumor cells.

 

With the gene therapy, genetically modified cancer cells are killed by a drug called 5-flurocytosine (5-FC). To get the gene into the cancer cells, the researchers first insert it into a virus that can infect the tumor cells. After the virus has infected the cells, non-toxic 5-FC is given to the patient. Tumor cells infected by the virus convert the non-toxic drug to a toxic form that kills the cancer cells. Dr. Noriyuki Kasahara, a professor in the department of medicine at UCLA, developed the gene therapy method in his laboratory.

 

While the two methods alone each show efficacy in mouse models, the greatest reduction in metastatic brain tumor size occurred when the cellular and gene therapies were combined, the researchers said.

 

“There is a significant lack of federally funded research addressing translational studies on brain metastases of systemic cancers, even though metastatic brain tumors occur 10 times more frequently than primary brain tumors in humans,” Kruse said. “These patients have a dismal prognosis because the brain represents a ‘sanctuary site’ where appropriate access by many chemotherapeutics is ineffective. Our research addresses this unmet need.”

 

Both experimental therapies are being tested individually in ongoing clinical trials for primary malignant brain tumors; this presents a unique opportunity for the rapid translation of these technologies from the laboratory to the clinic for breast and other types of cancer that metastasize to the brain, the researchers said.

 

This study was supported by the U.S. Army Research Materiel Command; the California Breast Cancer Research Program; the National Center for Advancing Translational Sciences of the National Institutes of Health: the UCLA Clinical Translational Science Institute; the Joan S. Holmes Memorial Research Fund; the Joan S. Holmes Memorial Postdoctoral Fellowship; and Tocagen Inc.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

UCLA scientists, in collaboration with teams in China, have used the powerful technology of single-cell RNA sequencing to track the genetic development of a human and a mouse embryo at an unprecedented level of accuracy. 

 

The technique could lead to earlier and more accurate diagnoses of genetic diseases, even when the embryo consists of only eight cells. 

 

The study was led by Guoping Fan, professor of human genetics and molecular biology and member of both the Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. The findings were published in the online edition of the journal Nature and will appear later in the print edition.

 

Single-cell RNA sequencing allows researchers to determine the precise nature of the total gene transcripts, or all of the genes that are actively expressed in a particular cell.

 

“The advantages of this technique are twofold,” Fan said. “It is a much more comprehensive analysis than was achievable before and the technique requires a very minimal amount of sample material — just one cell.”

 

Besides its implications for genetic diagnoses — such as improving scientists’ ability to identify genetic mutations like BRCA1 and BRCA2, which predispose women to breast cancer and ovarian cancer, or genetic diseases that derive from protein dysfunction, such as sickle cell disease — the technology may also have important uses in reproductive medicine. 

 

The technique marks a major development in genetic diagnoses, which previously could not be conducted this early in embryonic development and required much larger amounts of biological material.

 

“Previous to this paper we did not know this much about early human development,” said Kevin Huang, the study’s co-first author and a postdoctoral scholar in Fan’s laboratory. “Now we can define what ‘normal’ looks like, so in the future we will have a baseline from which to compare possible genetic problems. This is our first comprehensive glance at what is normal.”

 

With single-cell RNA sequencing, much more gene transcription was detected than before. “The question we asked is, ‘How does the gene network drive early development from one cell to two cells, two cells to four cells, and so on?’” Fan said. “Using the genome data analysis methods developed by co-author Steve Horvath at UCLA, we have uncovered crucial gene networks and we can now predict possible future genetic disorders at the eight-cell stage.”

 

The research was supported by the Chinese Ministry of Science and Technology, the International Science and Technology Cooperation Program of China, and the National Natural Science Foundation of China.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years.

 

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. 

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

Researchers from UCLA’s Jonsson Comprehensive Cancer Center have discovered that specific types of bacteria that live in the gut are major contributors to lymphoma, a cancer of the white blood cells.

 

Published online ahead of press today in the journal Cancer Research, the study was led by Robert Schiestl, member of the Jonsson Cancer Center and professor of pathology and laboratory medicine, environmental health sciences, and radiation oncology.

In rodents, intestinal bacteria influence obesity, intestinal inflammation and certain types of epithelial cancers. (Epithelial cancers affect the coverings of the stomach, liver or colon.) However, little is known about the identity of the bacterial species that promote the growth of, or protect the body from, cancer — or about their effect on lymphoma. 

 

Up to 1,000 different species of bacteria (intestinal microbiota) live in the human gut. Intestinal microbiota number 100 trillion cells; over 90 percent of the cells in the body are bacteria. The composition of each person’s microbiome — the body’s bacterial make-up — is very different, due to the types of bacteria people ingest early in their lives, as well as the effects of diet and lifestyle. 

 

Schiestl’s group wanted to determine whether differences in peoples’ microbiomes affect their risk for lymphoma, and whether changing the bacteria can reduce this risk. They studied mice with ataxia-telangiectasia (A-T), a genetic disease that in humans and mice is associated with a high rate of B-cell lymphoma. They discovered that, of mice with A-T, those with certain microbial species lived much longer than those with other bacteria before developing lymphoma, and had less of the gene damage (genotoxicity) that causes lymphoma.

 

“This study is the first to show a relationship between intestinal microbiota and the onset of lymphoma,” Schiestl said. “Given that intestinal microbiota is a potentially modifiable trait, these results hold considerable promise for intervention of B-cell lymphoma and other diseases.”

 

The scientists also were able to create a detailed catalog of bacteria types with promoting or protective effects on genotoxicity and lymphoma, which could be used in the future to create combined therapies that kill the bacteria that promote cancer (as antibiotics do) and increase the presence of the bacteria that protect from cancer (as probiotics do).

 

The work was supported by the National Institutes of Health, Jonsson Cancer Center, the Crohn’s and Colitis Foundation of America, the Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, the Austrian Federal Ministry of Science and Research, NASA, University of California Toxic Substances Research and Teaching Program, and the UCLA Graduate Division.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

 

Researchers at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have successfully established the foundation for using hematopoietic (blood-producing) stem cells from the bone marrow of patients with sickle cell disease to treat the disease. The study was led by Dr. Donald Kohn, professor of pediatrics and of microbiology, immunology and molecular genetics.

 

Sickle cell disease causes the body to produce red blood cells that are formed like the crescent-shaped blade of a sickle, which hinders blood flow in the blood vessels and deprives the body’s organs of oxygen.

 

Kohn introduced an anti-sickling gene into the hematopoietic stem cells to capitalize on the self-renewing potential of stem cells and create a continual source of healthy red blood cells that do not sickle. The breakthrough gene therapy technique for sickle cell disease is scheduled to begin clinical trials by early 2014. The study was published online today ahead of press in the Journal of Clinical Investigation.

 

Kohn’s gene therapy approach, which uses hematopoietic stem cells from a patient’s own blood, is a revolutionary alternative to current sickle cell disease treatments as it creates a self-renewing normal blood cell by inserting a gene that has anti-sickling properties into hematopoietic stem cells. This approach also does not rely on the identification of a matched donor, thus avoiding the risk of rejection of donor cells. The anti-sickling hematopoietic stem cells are transplanted back into the patient’s bone marrow and multiply the corrected cells that make red blood cells without sickling.

 

“The results demonstrate that our technique of lentiviral transduction is capable of efficient transfer and consistent expression of an effective anti-sickling beta-globin gene in human sickle cell disease bone marrow progenitor cells, which improved the physiologic parameters of the resulting red blood cells,” Kohn said.

 

Kohn and colleagues found that in the laboratory the hematopoietic stem cells produced new non-sickled blood cells at a rate sufficient for significant clinical improvement for patients. The new blood cells survive longer than sickled cells, which could also improve treatment outcomes. 

 

Sickle cell disease mostly affects people of Sub-Saharan African descent, and more than 90,000 patients in the U.S. have been diagnosed. It is caused by an inherited mutation in the beta-globin gene that makes red blood cells change from their normal shape, which is round and pliable, into a rigid, sickle-shaped cell. Normal red blood cells are able to pass easily through the tiniest blood vessels, called capillaries, carrying oxygen to organs such as the lungs, liver and kidneys. But due to their rigid structure, sickled blood cells get stuck in the capillaries. 

 

Current treatments include transplanting patients with donor hematopoietic stem cells, which is a potential cure for sickle cell disease, but due to the serious risks of rejection, only a small number of patients have undergone this procedure and it is usually restricted to children with severe symptoms. 

 

This study was supported in part by a Disease Team I Award from the California Institute for Regenerative Medicine, the state’s stem cell research agency, which was created by a voter initiative in 2004. The purpose of the disease team program is to support research focused on one particular disease that leads to the filing of an investigational new drug application with the FDA within four years. The program is designed to speed translational research — research that takes scientific discoveries from the laboratory to the patient bedside. This requires new levels of collaboration between basic laboratory scientists, medical clinicians, biotechnology experts and pharmacology experts, to name a few.

 

Other support came from UCLA’s Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center, and from the Ruth L. Kirschstein National Research Service Award.

 

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. 

 

Researchers at UCLA’s Jonsson Comprehensive Cancer Center led by Dr. Karim Chamie have found that more intense surveillance and treatment of bladder cancer in the first two years after diagnosis could reduce the number of patients whose cancer returns after treatment and lower the disease’s death rate. The study was published online ahead of press today in the journal Cancer.

 

Based on the team’s previous research showing underutilization of care for patients with bladder cancer, this study is the first to examine the burden of the disease on the population. To date no one had examined the morbidity of recurrence of the disease in the U.S. 

 

Chamie, assistant professor-in-residence in the UCLA department of urology, and his colleagues found that nearly three quarters of patients with high-grade, non–muscle-invasive bladder cancer suffered a return of the disease within 10 years. In 33 percent of patients, the cancer progressed to a more advanced form requiring removal of the bladder, radiation therapy or systemic chemotherapy. And in an additional 41 percent, the cancer recurred without further spread of the disease.

 

“Even though 80 percent of bladder cancer patients don’t die of their disease within five years, most patients will either die of other causes or bladder cancer, require aggressive treatment — removal of the bladder, radiation and/or chemotherapy — or have a recurrence of the disease,” Chamie said. “This study highlights the need to comply with treatment guidelines to prevent recurrences by instilling anticancer agents inside the bladder and following patients more closely within the first two years of diagnosis.”

 

The study was based on a nationwide sample of Medicare beneficiaries who had high-grade, non–muscle-invasive bladder cancer. “We have Level I evidence that demonstrates that a single instillation of chemotherapy into the bladder can minimize recurrences, and that six instillations can minimize recurrence and progression,” Chamie said. “Efforts should be increased to offer patients intravesical therapy with the goal of minimizing the burden of this disease.”

 

The researchers also found that the burden of bladder cancer on the population is very high, and that the elderly, women and African-American patients had a higher likelihood of dying of bladder cancer than younger patients, men and white patients, respectively.

 

This study was supported by the American Cancer Society, the Ruth L. Kirschstein National Research Service Award Extramural, UCLA’s Jonsson Comprehensive Cancer Center, the National Institutes of Health, and the National Institute of Diabetes and Digestive and Kidney Diseases.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter. 

Researchers from UCLA’s Jonsson Comprehensive Cancer Center report that a new drug in preliminary tests has shown promising results with very manageable side effects for treating patients with melanoma, the deadliest form of skin cancer.

 

The results were presented at the 2013 meeting of the American Society of Clinical Oncology today in Chicago by Dr. Antoni Ribas, professor of medicine in the UCLA division of hematology-oncology, who led the research. Following Ribas’ presentation, the study was published online ahead of press in the New England Journal of Medicine. 

 

The results are from the first clinical trial of the drug lambrolizumab (MK3475), which was discovered and developed by Merck. Researchers analyzed 135 patients with advanced metastatic melanoma who were divided into three groups with different treatment regimens.

 

Overall, 38 percent of patients taking lambrolizumab saw confirmed improvement of their cancer across all dose levels. Of those taking the lowest dose of lambrolizumab, 25 percent showed improvement, while 52 percent of those who received the highest dose improved. The rate of any tumor response across all patients was 77 percent. Researchers have not yet determined the average duration of response to the drug, because only five patients who had initial responses were taken off the study after their cancers got worse. To date, the longest response has been over one year.

 

Side effects with lambrolizumab are usually mild and easily managed. These include fatigue, fever, skin rash, loss of skin color and muscle weakness. Thirteen percent of patients had side effects that were more severe, including inflammation of the lung or kidney, and thyroid problems.

 

“This study is showing the highest rate of durable melanoma responses of any drug we have tested thus far for melanoma, and it is doing it without serious side effects in the great majority of patients,” Ribas said.

 

Serving as the immune system’s soldiers, T cells find and destroy invaders that cause infections and diseases. Cancers like melanoma are usually not detected by the immune system, and they spread without T cells destroying them. One problem may be that a protein called PD-L1 on the surface of cancer cells allows them to hide from T cells that express the protein PD-1 on their surfaces.

 

Lambrolizumab is an antibody that blocks PD-1 and reactivates an immune response to the cancer cells.

 

“Lambrolizumab turns on the body’s immune system to attack the cancer, and the immune system seems to remember that the melanoma is the enemy and continues to control it long term,” Ribas states.

 

These data have led to a series of additional studies testing lambrolizumab in patients with melanoma and other cancers, including lung cancer.

 

Lambrolizumab received “breakthrough therapy” designation from the U.S. Food and Drug Administration in April. Enacted as part of the 2012 FDA Safety and Innovation Act, the breakthrough therapy designation was created by the agency to expedite the development and review of a potential new medicine if it is “intended, alone or in combination with one or more other drugs, to treat a serious of life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.”

 

This research was supported by Merck Sharp & Dohme Corp. The UCLA authors have no financial ties to disclose.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

Led by Dr. Peiyee Lee and Dr. Richard Gatti, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have used induced pluripotent stem (iPS) cells to advance disease-in-a-dish modeling of a rare genetic disorder, ataxia telangiectasia (A-T).

 

Their discovery shows the positive effects of drugs that may lead to effective new treatments for the neurodegenerative disease. iPS cells are made from patients’ skin cells, rather than from embryos, and they can become any type of cells, including brain cells, in the laboratory. The study appears online ahead of print in the journal Nature Communications.

 

People with A-T begin life with neurological deficits that become devastating through progressive loss of function in a part of the brain called the cerebellum, which leads to severe difficulty with movement and coordination. A-T patients also suffer frequent infections due to their weakened immune systems and have an increased risk for cancer. The disease is caused by lost function in a gene, ATM, that normally repairs damaged DNA in the cells and preserves normal function.

 

Developing a human neural cell model to understand A-T’s neurodegenerative process — and create a platform for testing new treatments — was critical because the disease presents differently in humans and laboratory animals. Scientists commonly use mouse models to study A-T, but mice with the disease do not experience the more debilitating effects that humans do. In mice with A-T, the cerebellum appears normal and they do not exhibit the obvious degeneration seen in the human brain.

Lee and colleagues used iPS cell–derived neural cells developed from skin cells of A-T patients with a specific type of genetic mutation to create a disease-in-a-dish model. In the laboratory, researchers were able to model the characteristics of A-T, such as the cell’s lack of ATM protein and its inability to repair DNA damage. The model also allowed the researchers to identify potential new therapeutic drugs, called small molecule read-through (SMRT) compounds, that increase ATM protein activity and improve the model cells’ ability to repair damaged DNA.

 

“A-T patients with no ATM activity have severe disease but patients with some ATM activity do much better,” Lee said. “This makes our discovery promising, because even a small increase in the ATM activity induced by the SMRT drug can potentially translate to positive effects for patients, slowing disease progression and hopefully improving their quality of life.”

 

These studies suggest that SMRT compounds may have positive effects on all other cell types in the body, potentially improving A-T patients’ immune function and decreasing their susceptibility to cancer.

Additionally, the patient-specific iPS cell–derived neural cells in this study combined with the SMRT compounds can be an invaluable tool for understanding the development and progression of A-T. This iPS cell–neural cell A-T disease model also can be a platform to identify more potent SMRT drugs. The SMRT drugs identified using this model can potentially be applied to most other genetic diseases with the same type of mutations.

 

This research was supported by training and research grants from the California Institute of Regenerative Medicine, the National Institutes of Health, APRAT, A-T Ease and Scott Richards Foundation.

 

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

 

Pluripotent stem cells can turn, or differentiate, into any cell type in the body, such as nerve, muscle or bone, but inevitably some of these stem cells fail to differentiate and end up mixed in with their newly differentiated daughter cells. 

 

Because these remaining pluripotent stem cells can subsequently develop into unintended cell types — bone cells among blood, for instance — or form tumors known as teratomas, identifying and separating them from their differentiated progeny is of utmost importance in keeping stem cell–based therapeutics safe.

 

Now, UCLA scientists have discovered a new agent that may be useful in strategies to remove these cells. Their research was published online April 15 in the journal Developmental Cell and will appear in an upcoming print edition of the journal.

 

The study was led by Carla Koehler, a professor of chemistry and biochemistry at UCLA, and Dr. Michael Teitell, a UCLA professor of pathology and pediatrics. Both are members of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA and UCLA’s Jonsson Comprehensive Cancer Center.

 

In work using the single-celled microorganism known as baker’s yeast, or Saccharomyces cerevisiae, as a model system, Koehler, Teitell and their colleagues had discovered a molecule called MitoBloCK-6, which inhibits the assembly of cells’ mitochondria — the energy-producing “power plants” that drive most cell functions. The research team then tested the molecule in a more complex model organism, the zebrafish, and demonstrated that MitoBloCK-6 blocked cardiac development. 

 

However, when the scientists introduced MitoBloCK-6 to differentiated cell lines, which are typically cultured in the lab, they found that the molecule had no effect at all. UCLA postdoctoral fellow Deepa Dabir tested the compound on many differentiated lines, but the results were always the same: The cells remained healthy. 

 

“I was puzzled by this result, because we thought this pathway was essential for all cells, regardless of differentiation state,” Koehler said. 

 

The team then decided to test MitoBloCK-6 on human pluripotent stem cells. Postdoctoral fellow Kiyoko Setoguchi showed that MitoBloCK-6 caused the pluripotent stem cells to die by triggering apoptosis, a process of programmed cell suicide.

 

Because the tissue-specific daughter cells became resistant to death shortly after their differentiation, the destruction of the pluripotent stem cells left a population of only the differentiated cells. Why this happens is still unclear, but the researchers said that this ability to separate the two cell populations could potentially reduce the risk of teratomas and other problems in regenerative medicine treatment strategies.

 

“We discovered that pluripotent stem cell mitochondria undergo a change during differentiation into tissue-specific daughter cells, which could be the key to the survival of the differentiated cells when the samples are exposed to MitoBloCK-6,” Teitell said. “We are still investigating this process in mitochondria, but we now know that mitochondria have an important role in controlling pluripotent stem cell survival.”                        

 

MitoBloCK-6 is what is known as a “small molecule,” which can easily cross cell membranes to reach mitochondria. This quality makes MitoBloCK-6 — or a derivative compound with similar properties — ideal for potential use as a drug, because it can function in many cell types and species and can alter the function of mitochondria in the body for therapeutic effects.

 

“It is exciting that our research in the one-cell model baker’s yeast yielded an agent for investigating and controlling mitochondrial function in human pluripotent stem cells,” Koehler said. “This illustrates that mitochondrial function is highly conserved across organisms and confirms that focused studies in model systems provide insight into human stem-cell biology. When we started these experiments, we did not predict that we would be investigating and controlling mitochondrial function in pluripotent stem cells.”

 

The research was supported by the California Institute for Regenerative Medicine, the National Institutes of Health, the United Mitochondrial Disease Foundation, and the Development and Promotion of Science and Technology Talents Project of the Royal Thai Government.

 

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the past 13 years.

For more news, visit the UCLA Newsroom and follow us on Twitter.

For many years, breast cancer patients have reported experiencing difficulties with memory, concentration and other cognitive functions following cancer treatment. Whether this mental “fogginess” is psychosomatic or reflects underlying changes in brain function has been a bone of contention among scientists and physicians.

 

Now, a new study led by Dr. Patricia Ganz, director of cancer prevention and control research at UCLA’s Jonsson Comprehensive Cancer Center, demonstrates a significant correlation between poorer performance on neuropsychological tests and memory complaints in post-treatment, early-stage breast cancer patients — particularly those who have undergone combined chemotherapy and radiation.

 

“The study is one of the first to show that such patient-reported cognitive difficulties — often referred to as ‘chemo brain’ in those who have had chemotherapy — can be associated with neuropsychological test performance,” said Ganz, who is also a professor of health policy and management at UCLA’s Fielding School of Public Health and a professor of medicine at the David Geffen School of Medicine at UCLA.

 

The study was published April 18 in the online edition of the Journal of the National Cancer Institute and will appear in an upcoming print edition of the journal.

 

Ganz and her colleagues looked at 189 breast cancer patients, who enrolled in the study about one month after completing their initial breast cancer treatments and before beginning endocrine hormone-replacement therapy (70 percent planned to undergo hormone therapy). Two-thirds of the women had had breast-conserving surgery, more than half had received chemotherapy, and three-quarters had undergone radiation therapy. The average age of study participants was 52.

 

Because cognitive complaints following cancer treatment have often been associated with anxiety and depressive symptoms, limiting confidence that “chemo brain” and similar difficulties reflect a cancer treatment toxicity, the researchers excluded women with serious depressive symptoms. They also took careful account of the cancer treatments used and whether or not menopause and hormonal changes could be influencing the cognitive complaints. A sample of age-matched healthy women who did not have breast cancer was used as a control group.

 

The researchers provided a self-reporting questionnaire to the women and found that those with breast cancer reported, on the whole, more severe complaints than normal; 23.3 percent of these patients had higher complaints about their memory, and 19 percent reported higher complaints about higher-level cognition (problem-solving, reasoning, etc.). Significantly, those breast cancer patients who reported more severe memory and higher-level cognition problems were more likely to have undergone both chemotherapy and radiation.

 

While earlier studies had not identified a consistent association between cognitive complaints and neuropsychological testing abnormalities, the UCLA research team found that even when patients reported subtle changes in their memory and thinking, neuropsychological testing showed detectable differences.

 

In particular, they discovered that poorer performance on the neuropsychological test was associated both with higher levels of cognitive complaints and with combined radiation-and-chemotherapy treatment, as well as with symptoms related to depression.

 

“In the past, many researchers said that we can’t rely on patients’ self-reported complaints or that they are just depressed, because previous studies could not find this association between neuropsychological testing and cognitive complaints,” Ganz said. “In this study, we were able to look at specific components of the cognitive complaints and found they were associated with relevant neuropsychological function test abnormalities.”

 

The findings are part of an ongoing study that seeks to examine the extent to which hormone therapy contributes to memory and thinking problems in breast cancer survivors, and this pre-hormone therapy assessment was able to separate the effects of initial treatments on these problems. Earlier post-treatment studies of breast cancer patients were difficult to interpret, as they included women already taking hormone therapy.

 

“As we provide additional reports on the follow-up testing in these women, we will track their recovery from treatment, as well as determine whether hormone therapy contributes to worsening complaints over time,” Ganz said.

 

This research was supported by the National Cancer Institute and the Breast Cancer Research Foundation, and by funding from the National Institutes of Health to the Cousins Center for Psychoneuroimmunology.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the past 13 years.

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An experimental drug being investigated for the treatment of advanced breast cancer by researchers from the Revlon/UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center this week received “breakthrough therapy” designation from the U.S. Food and Drug Administration.

 

In a clinical trial, patients with advanced breast cancer that was estrogen-receptor positive (ER+) and HER2-negative (HER2-), and who were given palbociclib (PD 0332991, Pfizer Inc.) in addition to the standard anti-estrogen treatment of letrozole had significantly higher progression-free survival — the length of time a patient is on treatment without tumor growth — than patients taking letrozole alone.

 

Enacted as part of the 2012 FDA Safety and Innovation Act, the breakthrough therapy designation was created by the agency to expedite the development and review of a potential new medicine if it is “intended, alone or in combination with one or more other drugs, to treat a serious of life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.”

 

Dr. Richard S. Finn, associate professor of medicine at the Jonsson Cancer Center, initially reported the phase 2 clinical data supporting the designation in December 2012 at the CTRC-AACR San Antonio Breast Cancer Symposium. The clinical study was built on laboratory work from the Translational Oncology Research Laboratory directed by Dr. Dennis Slamon, professor of medicine at UCLA and director of the Jonsson Cancer Center’s Revlon/UCLA Women’s Cancer Research Program.

 

In preclinical work, palbociclib was tested in a panel of human breast cancer cells growing in culture dishes and showed very encouraging activity, specifically against ER+ cancer cells. These preclinical observations were then moved into phase 1 clinical studies. Led by Finn and Slamon at UCLA, the studies were designed to determine the doses and safety of a combination with letrozole, a commonly used drug for ER+ breast cancer.

 

Once the phase 1 studies were completed, the phase 2 studies were performed in 165 patients with breast cancer with ER+ disease. The drug was designated as a breakthrough therapy by the FDA based on the preliminary analysis of the phase 2 data showing that the median progression-free survival of patients given the palbociclib-letrozole combination was 26.1 months, compared with 7.5 months for those given letrozole alone. Among patients with measurable disease, 45 percent receiving the combination had confirmed responses, compared with 31 percent for letrozole alone, and the clinical benefit rates (tumor shrinkage and/or stable disease for a minimum of six months) were 70 percent for those receiving the combination therapy, versus 44 percent for letrozole only.

 

“This drug combination demonstrated a dramatic and clinically meaningful effect on progression-free survival in women with ER+ breast cancer,” Finn said. “These results confirm the preclinical work we began at the Translational Lab.”

Finn and colleagues have initiated a randomized, multicenter, double-blind phase 3 study to evaluate palbociclib combined with letrozole, compared with letrozole alone, as a first-line treatment for post-menopausal patients with ER+, HER2-, locally advanced or metastatic breast cancer. The researchers will continue to work closely with Pfizer and the FDA to better understand the implications of the breakthrough therapy designation with the hope that further study will support potential regulatory submission.

 

Slamon said the phase 2 study results validate the Translational Laboratory’s approach.

 

“By identifying the correct targets for treatment in the right patient population, we move forward with personalized oncology that we hope will greatly improve the outcomes for this group of breast cancer patients,” he said. “These results are as exciting as the initial results we saw for trastuzumab (Herceptin) in HER2+ breast cancers but represent a new approach for a different and larger subset of breast cancers, namely those that are ER+.”

 

Slamon said the researchers are working diligently to enroll the phase 3 validation study as quickly and safely as possible.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the past 13 years.

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Scientists from UCLA’s Fielding School of Public Health led by Julia Heck, an assistant researcher in the school’s epidemiology department and a member of UCLA’s Jonsson Comprehensive Cancer Center, have found a possible link between exposure to traffic-related air pollution and several childhood cancers.

 

The results of their study — the first to examine air pollution from traffic and a number of rarer childhood cancers — were presented on April 9 in an abstract at the annual meeting of the American Association for Cancer Research in Washington, D.C.

 

For the study, the UCLA researchers utilized data on 3,950 children who were enrolled in the California Cancer Registry and who were born in the state between 1998 and 2007. They estimated the amount of local traffic the children had been exposed to using California LINE Source Dispersion Modeling, version 4 (CALINE4).

 

Pollution exposure was estimated for the area around each child’s home for each trimester of their mother’s pregnancy and during their first year of life. The estimates included information on gasoline and diesel vehicles within a 1,500-meter radius buffer, traffic volumes, roadway geometry, vehicle emission rates and weather. Cancer risk was estimated using a statistical analysis known as unconditional logistic regression.

 

The researchers found that heightened exposure to traffic-related air pollution was associated with increases in three rare types of childhood cancer: acute lymphoblastic leukemia (white blood cell cancer), germ-cell tumors (cancers of the testicles, ovaries and other organs) and retinoblastoma (eye cancer), particularly bilateral retinoblastoma, in which both eyes are affected.

 

The pollution-exposure estimates were highly correlated across pregnancy trimesters and the first year of life, meaning that even in areas of high exposure, no particular period stood out as a higher-exposure time. This, the scientists said, made it difficult to determine if one period of exposure was more dangerous than any other.

 

“Much less is known about exposure to pollution and childhood cancer than adult cancers,” Heck said. “Our innovation in this study was looking at other, more rare types of childhood cancer, such as retinoblastoma, and their possible connection to traffic-related air pollution.”

 

Because these are rare diseases, Heck cautions that the findings need to be replicated in further studies.

 

The UCLA Fielding School of Public Health is dedicated to enhancing the public’s health by conducting innovative research; training future leaders and health professionals; translating research into policy and practice; and serving local, national and international communities.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

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A new study of genetically modified immune cells by scientists from UCLA and the California Institute of Technology could help improve a promising treatment for melanoma, an often fatal form of skin cancer.

 

The research, which appears March 21 in the advance online edition of the journal Cancer Discovery, was led by James Heath, a member of UCLA’s Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research and UCLA’s Jonsson Comprehensive Cancer Center. Heath is a professor of molecular and medical pharmacology at UCLA and also holds the Elizabeth W. Gilloon Chair in Chemistry at Caltech.

 

The melanoma treatment uses T cells — immune cells that play a major role in fighting infection — taken from patients with melanoma. The cells are then genetically modified in the laboratory so that when they are reintroduced into a patient’s bloodstream, they specifically attack melanoma tumors. In early clinical trials, this treatment was shown to shrink tumors dramatically in many patients, but the positive effects were often short-lived.

 

The UCLA and Caltech researchers found that after the engineered T cells were returned to patients, their efficacy faded within two to three weeks. Surprisingly, however, once the engineered cells were no longer effective, a new group of non-engineered T cells arose that had a similar tumor-killing effect that lasted even longer, the scientists discovered.

 

Using newly developed nanotechnology chips to perform multidimensional and multiplexed immune-monitoring assays, the researchers were able to examine at high resolution single engineered T cells taken at different times from patients undergoing the therapy, each of whom had a different level of response to the treatment.

 

“The engineered T cells did not recover their tumor-killing effect,” Heath said, “but after one month, another group of T cells appeared that did have tumor-killing effects for another 90 days. Those were not the genetically engineered T cells, and they appeared to be a byproduct of a process called ‘antigen spreading’ by the original engineered cells. After 90 days, those cells lost their tumor-killing ability as well.”

 

Antigen spreading is a process by which a T cell that has been engineered to attack a particular tumor expands its immune response to other T cells in the body, which then attack the same tumor but are focused on different antigens. (Antigens are substances that trigger a response by the body’s immune system.) Scientists may be able to use this process, Heath stressed, to improve T cell–based treatments for melanoma.

 

“Our results have led us to possible ways to improve the T cell therapy to extend its positive effect,” Heath said. “We need to incorporate strategies that maintain the functional properties of the engineered T cells used for therapy. This might include modifying how we grow the T cells in the laboratory to make their tumor-killing effect last longer or make them resistant to the effects of the patient’s T cells as they recover from pretreatment chemotherapy conditioning and possibly increase the antigen spreading of anti-tumor T cells.”

 

UCLA professor of medicine Dr. Antoni Ribas was one of Heath’s key collaborators on the research.

“One of the possible approaches to resolve the problem identified by this study is to use engineered blood stem cells — instead of the peripheral blood used in the original trials — with this therapy in the hope that the engineered blood stem cells will provide a renewable source of engineered T cells,” said Ribas, a member of UCLA’s Broad Stem Cell Research Center and Jonsson Cancer Center.

 

Caltech’s Chao Ma, the study’s first author, said the findings and the use of the new nanotechnology assay process hold promise for treatments of other disease as well.

 

“This study points to the value of these single-cell functional analyses for probing the successes and failures of a sophisticated immunotherapy,” he said. “I am excited to see its use as a monitoring tool to understand a spectrum of other cellular immunotherapies in the near future.”

 

This research was funded by the National Cancer Institute, the Jean Perkins Foundation, The California Institute for Regenerative Medicine, UCLA’s Broad Stem Cell Research Center, the Seaver Institute, the PhaseOne Foundation, the Garcia-Corsini Family Fund, the Caltech/UCLA Joint Center for Translational Medicine, the Melanoma Research Alliance, a Rosen Fellowship and UCLA’s Jonsson Comprehensive Cancer Center.

 

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

For more news, visit the UCLA Newsroom and follow us on Twitter.

 

Researchers at UCLA report that they have refined a method they previously developed for capturing and analyzing cancer cells that break away from patients’ tumors and circulate in the blood. With the improvements to their device, which uses a Velcro-like nanoscale technology, they can now detect and isolate single cancer cells from patient blood samples for analysis.

 

Circulating tumor cells, or CTCs, play a crucial role in cancer metastasis, spreading from tumors to other parts of the body, where they form new tumors. When these cells are isolated from the blood early on, they can provide doctors with critical information about the type of cancer a patient has, the characteristics of the individual cancer and the potential progression of the disease. Doctors can also tell from these cells how to tailor a personalized treatment to a specific patient.

 

In recent years, a UCLA research team led by Hsian-Rong Tseng, an associate professor of molecular and medical pharmacology at the Crump Institute for Molecular Imaging and a member of both the California NanoSystems Institute at UCLA and UCLA’s Jonsson Comprehensive Cancer Center, has developed a “NanoVelcro” chip. When blood is passed through the chip, extremely small “hairs” — nanoscale wires or fibers coated with protein antibodies that match proteins on the surface of cancer cells — act like Velcro, traping CTCs and isolating them for analysis.

 

CTCs trapped by the chip also act as a “liquid biopsy” of the tumor, providing convenient access to tumor cells and earlier information about potentially fatal metastases.

 

Histopathology — the study of the microscopic structure of biopsy samples — is currently considered the gold standard for determining tumor status, but in the early stages of metastasis, it is often difficult to identify a biopsy site. By being able to extract viable CTCs from the blood with the NanoVelcro chip, however, doctors can perform a detailed analysis of the cancer type and the various genetic characteristics of a patient’s specific cancer.

 

 

Tseng’s team now reports that they have improved the NanoVelcro chip by replacing its original non-transparent silicon nanowire substrate inside with a new type of transparent polymer nanofiber-deposited substrate, allowing the device’s nanowires to better “grab” cancer cells as blood passes by them.

 

Tseng and his colleagues were able to pick single CTCs immobilized on the new transparent substrate by using a miniaturized laser beam knife, a technique called laser micro-dissection, or LMD.

 

The researchers’ paper on their improvement to the chip was published online Feb. 22 in the peer-reviewed journal Angewandte Chemie and is featured on the cover of the journal’s March 2013 print issue.

 

“This paper summarizes a major milestone in the continuous development of NanoVelcro assays pioneered by our research group,” Tseng said. “We now can not only capture cancer cells from blood with high efficiency but also hand-pick single CTCs for in-depth characterization to provide crucial information that helps doctors make better decisions.”

 

 

Using the new assay on patients’ blood containing circulating melanoma cells (CMCs), Tseng’s team was able to isolate and preserve single CMCs. Melanoma is a deadly type of skin cancer that is prone to spreading quickly throughout the body. The ability to capture and preserve single CMCs allows doctors to analyze melanoma cells’ DNA structure, determine the genetic characteristics of the patient’s cancer and confirm that the circulating cells remain genetically similar to the tumor they came from.

 

The preservation of single captured CMCs in this proof-of-concept study also allowed researchers to conduct an analysis — called single-cell genotyping — to find within the cell a specific target (BRAF V600E) for a drug called vemurafenib. BRAF V600E is a mutation in the BRAF protein that appears in approximately 60 percent of melanoma cases. Drugs that inhibit BRAF are able to slow and often reverse the growth of melanoma tumors.

 

“With this technology, we are getting closer to the goal of a widely clinically applicable liquid biopsy, where we can sample cancer cells by a simple blood draw and understand the genes that allow them to grow,” said Dr. Antoni Ribas, a professor of medicine in the division of hematology–oncology, a Jonsson Cancer Center member and one of Tseng’s key collaborators. “With the NanoVelcro chips, we will be able to better personalize treatments to patients by giving the right treatment to stop what makes that particular cancer grow.”

 

Dr. Roger Lo, another key Tseng collaborator and an assistant professor in UCLA’s department of medicine, division of dermatology, and department of molecular and medical pharmacology, was also optimistic about the new method.

 

“This scientific advancement — being able to capture the melanoma cells in transit in the blood and then perform genetic analysis on them — will in principle allow us to track the genomic evolution of melanoma under BRAF-inhibitor therapy and understand better the development of drug resistance,” said Lo, who is also a member of the Jonsson Cancer Center.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

Two cardiology investigators from the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA have been awarded grants totaling more than $6 million from the California Institute of Regenerative Medicine (CIRM), the state’s stem cell agency.

 

The young physician–scientists, Dr. Reza Ardehali and Dr. Ali Nsair, will use the CIRM funds to conduct leading-edge research into the developmental and molecular biology of stem cells in their efforts to advance regenerative medicine for heart disease. Their studies will help form the foundation for translational and clinical advances, enabling human stem cells to be used for potential therapies and as tools for biomedical innovation.

 

The CIRM grants, known as New Faculty Physician Scientist Translational Research Awards, are given to clinician–scientists in the first six years of their first independent faculty appointments. The awards were announced Dec. 12 during the regular meeting of the CIRM Independent Citizens Oversight Committee at the Luxe Hotel in Los Angeles.

 

Dr. Reza Ardehali, an assistant professor of cardiology and a member of the Broad Stem Cell Research Center, was awarded more than $2.9 million for research to isolate heart stem cells derived from human embryonic stem cells — cells that can  become any cell in the body — to determine if these heart cells can be integrated successfully into the environment of a living heart or if they will function in isolation at a different pace.

 

Ardehali uses an analogy: “The performance of a symphony can go into chaos if one member plays in isolation from all surrounding cues. Therefore, it is important to determine if the transplanted cells can beat in harmony with the rest of the heart and if these cells will provide functional benefit to the injured heart.”

 

Ardehali will transplant the heart stem cells into injured hearts in an animal model to determine if the cells improve heart function. He also will perform detailed analysis of the electrical activities of the heart to determine how well the stem cells grow and integrate into new heart tissue. The success of this proposed project could lead to future clinical trials of stem cell therapy for heart disease.

 

Dr. Ali Nsair, an assistant professor of medicine and cardiology and a member of the Broad Stem Cell Research Center, was awarded more than $3 million for research using induced pluripotent stem cells — tissue-specific blood or skin cells that have been reprogrammed to become like human embryonic stem cells — to develop heart tissue cells known as cardiac progenitor cells. Once these cardiac progenitor cells are grown in the laboratory, they will be used to regenerate heart muscle damaged by heart attack.

 

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

Liposarcoma, the most common type of sarcoma, is an often lethal form of cancer that develops in fat cells. It is particularly deadly, in part, because the tumors are not consistently visible with positron emission tomography (PET) scans that use a common probe called FDG and because they frequently do not respond to chemotherapy.

 

Now, using a strategy that tracks cancer cells’ consumption of nucleosides, a team of researchers at UCLA’s Jonsson Comprehensive Center has identified a group of liposarcoma tumors that can be imaged by PET scanning using a tracer substance known as FAC. Furthermore, they have found that these tumors are sensitive to chemotherapy.

 

The team’s findings are published online in the journal Cancer Discovery and will appear in an upcoming print edition.

 

Led by Jonsson Cancer Center researcher Heather Christofk, an assistant professor of molecular and medical pharmacology at UCLA, the scientists employed a metabolomic strategy that detected nucleoside salvage activity in liposarcoma cells taken from patient samples, cells grown in the laboratory and cells grown in mouse models. The nucleoside activity was visible using PET with the UCLA-developed FAC probe (FAC PET), which measures the activity of the DNA salvage pathway, a fundamental cell biochemical pathway that acts as a sort of recycling mechanism to help with DNA replication and repair.

 

FAC was created by slightly altering the molecular structure of the standard chemotherapy drug gemcitabine, and in the current study, the UCLA research team discovered that the liposarcoma cells with high nucleoside salvage activity were sensitive to gemcitabine chemotherapy.

 

In clinical practice, this strategy might be used to identify liposarcoma patients, at the time of diagnosis, who would respond well to gemcitabine chemotherapy, saving time on other treatments and possibly extending the lives of this sub-group of patients.

 

“It was a satisfying study because it has translational potential for liposarcoma patients now — and this is a deadly disease,” Christofk said. “Our metabolomic strategy is also generalizable to treatment strategies for other cancers, and that is something we hope to do.”

 

The study was a collaboration between basic scientists and clinicians, following the translational paradigm of bench-to-bedside discoveries.

 

“This was an outstanding transdisciplinary project between a diverse group of physician scientists and basic scientists that translates molecular oncology from the laboratory to the clinic in a rapid and clinically relevant manner,” said Dr. Fritz Eilber, an associate professor of surgery and of molecular and medical pharmacology at UCLA and an investigator on the study. “The findings from this work can be used to directly impact the care of patients with this morbid and lethal malignancy.”

 

The research was supported in part by NIH grant P50CA0863062. Christofk is a Damon Runyon–Rachleff Innovation awardee, supported in part by the Damon Runyon Cancer Research Foundation, the Searle Scholars Program, the NIH Director’s New Innovator Award (DP2 OD008454-01) and the Caltech/UCLA Nanosystems Biology Cancer Center (NCI U54 CA151819).

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

A combination therapy using an experimental new drug shows significant promise for women with a common type of breast cancer in which estrogen causes their tumors to grow, researchers with the Revlon/UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center report.

 

The treatment, which incorporates the standard anti-estrogen therapy letrozole and the experimental drug PD 0332991, developed by pharmaceutical company Pfizer Inc., was found to increase progression-free survival time — the length of time a patient is on treatment without tumor growth — in women with estrogen receptor–positive, HER2-negative cancer, compared with letrozole alone.

 

The results of a two-part, phase 2 clinical trial testing the new combination therapy were announced Dec. 5 at the 2012 CTRC–AACR San Antonio Breast Cancer Symposium in San Antonio, Texas, by Dr. Richard S. Finn, an associate professor of medicine at UCLA and a member of the Jonsson Cancer Center, who led the trial.

 

The clinical study built on pre-clinical work from the Translational Oncology Research Laboratory directed by Dr. Dennis Slamon, a professor of medicine at the Jonsson Cancer Center and director of the Revlon/UCLA Women’s Cancer Research Program.

 

For the first part of the study, in which 66 patients were enrolled, preliminary results showed significant improvement in median progression-free survival for individuals who were given the new drug combination. The second part of the study enrolled 99 more patients — but only those whose tumors revealed selected biomarkers known as CCND1 amplification and p16 loss.

 

Retrospective analysis from Part 1 of the suggested there was a clinical benefit from PD 0332991 regardless of the women’s biomarker status. All the other demographic features of the patients were similar, so for final trial analysis, the results of the study’s two parts were combined for presentation at the San Antonio Breast Cancer Symposium.

 

The researchers’ analysis showed that the median progression-free survival time for patients on the combination therapy was 26.1 months, compared with 7.5 months for those on letrozole alone. Of the patients with measurable disease, 45 percent of those given the combination treatment had confirmed responses, compared with 31 percent on letrozole alone.

 

And the clinical benefit rates — tumor shrinkage and/or stable disease for a minimum of six months — were 70 percent with the combination therapy and 44 percent with only letrozole, the researchers report.

 

“This drug combination demonstrated a dramatic and clinically meaningful effect on progression-free survival in women with estrogen receptor–positive breast cancer,” said Finn. “These results confirm the pre-clinical work we began at the Translational Oncology Research Laboratory.”

 

Finn and his colleagues published their initial pre-clinical data in 2009, which showed that PD 0332991 blocked two important proteins in cancer cells — cyclin D kinase 4 (CDK 4) and cyclin D kinase 6 (CDK 6) — thus prohibiting the growth of estrogen receptor–positive and HER2-amplified cancer cells in the lab.

 

With the goal of identifying important targets for cancer therapy in the lab and promptly developing them into patient treatments using the translational paradigm, the investigators then conducted a phase 1 clinical trial in collaboration with Pfizer in which the safety of the drug was tested.

 

The results of that trial confirmed the safety of PD 0332991, which was taken as a pill and was found to have manageable side effects. This prompted the phase 2 trial comparing the combination of PD 0332991 and letrozole to the standard treatment of letrozole alone.

 

Critical to the clinical studies were the synergistic interactions observed in the laboratory between PD 0332991 and standard breast cancer drugs tamoxifen and trastuzumab, which are used in treating estrogen receptor–positive and HER2-positive breast cancers, respectively.

 

“The results of this phase 2 study validate the Translational Oncology Research Laboratory approach,” said Slamon, the study’s senior author.

 

“By identifying these targets for treatment, we move forward with personalized oncology that greatly improves the chances for this group of patients,” Slamon added. “These results are as exciting as the initial results we saw for trastuzumab (Herceptin) in HER2-positive breast cancers but represent a new approach for a different and larger subset of breast cancers – those that are estrogen receptor–positive.”

 

The core laboratory research for this project was funded primarily through the Revlon/UCLA Women’s Cancer Research Program and the longtime philanthropic support of Ronald O. Perelman. Additional resources were provided by a U.S.  Department of Defense Innovator Award (W81XWH-05-1-0395) and the Noreen Frazier Foundation. The clinical trial itself was supported entirely by Pfizer Inc.

 

 UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.

Researchers led by Tanya Stoyanova and Dr. Owen Witte of UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have determined how a protein known as Trop2 drives the growth of tumor cells in prostate and other epithelial cancers.

 

This discovery is important because it may prove essential for creating new therapies that stop the growth of cancer, the researchers said. The study is featured on the cover of the Oct. 15 issue of the journal Genes and Development.

 

The Trop2 protein is expressed on the surface of many types of epithelial cancer cells — cells that form tumors that grow in the skin and the inner and outer linings of organs — but little was known about the protein’s role in the growth and proliferation of cancer cells. The UCLA researchers discovered that Trop2 controls those processes through a mechanism that leads to the protein being cleaved into two parts, one inside the cell and one outside. This Trop2 division promotes self-renewal of the cancer cells, resulting in tumor growth.

 

“Determining the mechanism of this protein is important for planning treatments that stop the growth of prostate cancer, but it is also overexpressed in so many other types of cancer that it might be a treatment target for many more patients beyond that population,” said senior author Witte, director of the Broad Center and a professor in the department of microbiology, immunology, and molecular genetics at UCLA.

 

The finding may have a critical clinical impact, the researchers said, since preventing the cleavage of Trop2 by mutating those sites on the protein where it splits eliminates the protein’s ability to promote tumor cell growth. Using this knowledge, they said, new therapy strategies can be developed that block Trop2 molecular signaling, thus stopping its ability to enhance tumor growth in a variety of epithelial malignancies, including prostate, colon, oral cavity, pancreatic and ovarian cancers, among others.

 

“The reason I became interested in Trop2 was that it is highly expressed in many epithelial cancers but no one knew precisely how the protein worked to promote the disease,” said Stoyanova, the study’s first author and a postdoctoral scholar in the department of microbiology, immunology and molecular genetics at UCLA.

 

Funding for the study was provided by the California Institute for Regenerative Medicine Training Grant (TG2-01169), the U.S. Department of Defense Prostate Cancer Research Program (PC110638) and the Howard Hughes Medical Institute.

 

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

 

For more news, visit the UCLA Newsroom and follow us on Twitter. 

Researchers at UCLA’s Jonsson Comprehensive Cancer Center have discovered the mechanism by which an experimental drug known as GCS-100 removes from lymphoma cells a protein that prevents the cells from responding to chemotherapy.

 

The discovery revives hope in a drug that had been tested in clinical trials years before but had been delayed indefinitely. The researchers hope GCS-100 can be combined with chemotherapy to create an effective treatment for diffuse large B-cell lymphoma (DLBCL), the most common and aggressive form of non-Hodgkin lymphoma, a cancer of the immune system.

 

The findings are published in the advance online issue of the journal Blood and will appear in a forthcoming print issue of the journal.

 

The UCLA researchers found that a protein called galectin-3 binds to an enzyme called CD45 on the surface of lymphoma cells. This protein–enzyme combination regulates the cancer cells’ susceptibility to chemotherapy, essentially protecting them from chemotherapy drugs.

 

Derived from citrus pectin, GCS-100 works outside the cancer cells to remove the protective galectin-3. Once the galectin-3 is removed, a lymphoma cell can be effectively killed by chemotherapy drugs, part of a chain reaction of programmed cancer-cell death known as apoptosis.

 

Although the researchers knew the drug had shown action against lymphoma cells, the finding that GCS-100 literally removed the barrier to the initiation of cell death by removing galectin-3 from the cell surface was unexpected.  

 

“We let the results guide our ideas, and we were able to establish a mechanism for GCS-100,” said the study’s first author, Mary Clark, a graduate student researcher in pathology and laboratory medicine. “I am excited to follow the progress of GCS-100 and hope to see its use in the clinic as an adjunct therapy for lymphoma in the near future.”

 

Dr. Linda Baum, a professor of pathology and laboratory medicine and senior researcher on the study, said, “This drug had been abandoned because of the vagaries of the economy. My hope would be to restart this drug in clinical trials and, using this new knowledge, to include it in a more targeted lymphoma therapy.” 

Early clinical trials of GCS-100 had shown no known side effects of the drug other than a mild rash in some patients, which other research has demonstrated is the result of the drug also promoting the development of T cells, which are created by the immune system to fight disease.

 

Funding for the research was provided by the Ron and Maddie Katz Family Foundation and the National Institutes of Health.

 

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation’s top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years.

 

For more news, visit the UCLA Newsroom and follow us on Twitter.