TAG: "Cancer"

Grant to fund work to develop new class of drugs for treating breast cancer


UC Santa Cruz’s Seth Rubin receives Breast Cancer Research Program Breakthrough Award.

Seth Rubin, UC Santa Cruz

UC Santa Cruz cancer researcher Seth Rubin has received a $350,000 grant to fund his work toward the development of a new class of drugs for treating breast cancer. The grant is a Breast Cancer Research Program Breakthrough Award from the congressionally directed medical research programs of the U.S. Department of Defense.

Rubin, an associate professor of chemistry and biochemistry, will use the grant to build on his recent discoveries regarding a key tumor suppressor protein that is inactivated in most breast cancer cells. The retinoblastoma tumor suppressor protein (Rb) helps regulate the cycle of cell growth and division, putting the brakes on cell proliferation when it is active. In normal cells, Rb coordinates cellular growth signals, turning on and off to ensure that cells divide at the right time. Genetic changes in cancer cells disrupt this regulatory pathway and allow cells to multiply out of control.

Rubin’s research has revealed important details of the molecular mechanisms involved in turning Rb on and off. These findings suggested the possibility of a new class of therapeutic molecules that target the retinoblastoma protein directly. Most attempts to target the retinoblastoma pathway with drugs have focused on blocking the action of other proteins that inactivate Rb.

“A common analogy is to think of cancer cells as being like a car with a jammed accelerator and broken brakes, so the cells can’t stop proliferating. Most drugs target the jammed accelerator and knock down proteins that are too active. We want to target the broken brakes and restore the tumor suppressor activity,” Rubin said.

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New mouse model points to therapy for liver disease


UC San Diego findings could have impacts on obesity, organ transplantation.

Non-alcoholic fatty liver disease (NAFLD) is a common affliction, affecting almost 30 percent of Americans, with a significant number suffering from its most severe form, called non-alcoholic steatohepatitis or NASH, which can lead to cirrhosis and liver cancer. In recent years, NASH has become the leading cause of liver transplantation.

Development of effective new therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In a paper published online in Cancer Cell, scientists at the UC San Diego School of Medicine describe a novel mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.

“These findings strongly call for clinical testing of relevant drugs in human NASH and its complications,” said senior author Michael Karin, Ph.D., Distinguished Professor of Pharmacology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction. “Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high-fat diet.”

The increasing prevalence of NAFLD is linked to the nation’s ongoing obesity epidemic. In the past decade, the rate of obesity has doubled in adults and tripled in children, in large part due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma (HCC), the major form of liver cancer, and loss of function. Often, the only remedy is organ transplantation.

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FDA approves cervical cancer treatment based on UC Irvine-led study


Clinical trial found therapy effective in recurrent and metastatic cancer.

The U.S. Food and Drug Administration today (Aug. 14) approved bevacizumab, also known as Avastin, to treat persistent, recurrent or metastatic cervical cancer.

The approval is based on a clinical trial led by UC Irvine Health gynecologic oncologist Dr. Krishnansu S. Tewari and conducted by the Gynecological Oncology Group, now known as NRG Oncology.

The phase three randomized trial enrolled 452 women, including UC Irvine Health patients, and found that combining chemotherapy with bevacizumab extended median survival to 17 months, compared to 13.3 months for those receiving chemotherapy without it. The FDA approval allows its use in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

Treatment with bevacizumab — an anti-angiogenesis agent that inhibits a tumor’s ability to form new blood vessels — caused no significant deterioration in patients’ quality of life, Tewari said. Trial results appeared in the Feb. 20 issue of the New England Journal of Medicine.

“This trial showed for the first time that a targeted agent could improve overall survival in a gynecologic cancer,” said Tewari, a professor of obstetrics & gynecology at UC Irvine. “Women with metastatic or recurrent cervical cancer don’t have many options. Now we finally have a therapy that helps them live longer.”

The findings already have changed U.S. treatment for advanced cervical cancer. Within a month of the study’s presentation at the June 2013 meeting of the American Society of Clinical Oncology, the National Comprehensive Cancer Network listed the cisplatin-paclitaxel-bevacizumab triplet in the NCCN Cervical Cancer Treatment Guidelines Update.

Although a difference of three to seven months may not seem like a long time, Tewari said it is important to understand that this patient population responds very poorly to even one line of therapy and that those minimal responses tend to be short-lived.

“We do not have the luxury of treating women who have advanced cervical cancer with multiple lines of therapy over many years, as we do with more [chemotherapy] sensitive malignancies such as ovarian or breast cancer,” Tewari said. “However, these findings show that we may be on the cusp of converting this disease from a terminal to a chronic condition where the 3.7 months provides a window of opportunity in which patients might benefit from new therapies, including other anti-angiogenesis drugs and immunotherapies that are now being studied.”

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MRI is a ‘game-changer’ in diagnosing prostate cancer


UC San Diego Health System is first to use new tool in San Diego.

Oncologists at UC San Diego Moores Cancer Center are the first in San Diego to meld magnetic resonance imaging (MRI) technology with a traditional ultrasound prostate exam to create a three-dimensional map of the prostate that allows physicians to view growths that were previously undetectable.

An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, M.D., M.H.S., the UC San Diego Health System urologic oncologist who, along with Christopher Kane, M.D., chair of the Department of Urology and Karim Kader, M.D., Ph.D., urologic oncologist, is pioneering the new technology at Moores Cancer Center.

“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”

Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.

An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.

Lopez is thankful he will be able to celebrate his 58th wedding anniversary with his wife.

“Life is going on as normal,” said Lopez. “This is the wave of the future. I see this new technology as the way to save thousands of lives. I commend Dr. Parsons for taking the lead in San Diego in this area.”

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Bone drugs may not protect women from breast cancer


New analysis of clinical trial data suggests earlier evidence was misleading.

Trisha Hue, UC San Francisco

Osteoporosis drugs known as bisphosphonates may not protect women from breast cancer as had been thought, according to a new study led by researchers at UC San Francisco.

The drugs’ protective effect was widely assumed after several observational studies showed that women who took them were less likely to get breast cancer.

But when researchers assessed the effect of two of the most widely used osteoporosis drugs – sold under the brand names, Fosamax and Reclast – in two large randomized clinical trials, neither drug protected women with osteoporosis from getting breast cancer. The results were published today (Aug. 11) in JAMA Internal Medicine.

The researchers said the link found in the previous observational studies between taking the drugs and having a lower incidence of breast cancer may be due to a third factor, low estrogen.

Since having low estrogen both weakens bones and protects against most breast cancers, the women most likely to be prescribed drugs for osteoporosis are usually also at lower risk for breast cancer.

“They may have seen a lower risk of breast cancer in women using bisphosphonates in the earlier observational studies because those women had a lower risk of breast cancer to begin with,” said Trisha Hue, Ph.D., lead author of the study.

“Post-menopausal women with osteoporosis usually have low estrogen levels,” said Hue, an epidemiologist with the San Francisco Coordinating Center, a partnership between the CPMC Research Institute and the UCSF Department of Epidemiology & Biostatistics. “Lower levels of estrogen are strongly associated with a lower risk of breast cancer.”

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Researchers discover how a drug specifically kills cancer cells


Finding culminates nearly a decade of research into the role of arginine.

Hsing-Jien Kung

Researchers at UC Davis, City of Hope, Taipai Medical University and National Health Research Institutes in Taiwan have discovered how a drug that deprives the cells of a key amino acid specifically kills cancer cells.

Their paper, published today (Aug. 11) in Proceedings of the Academy of Sciences, is the culmination of nearly a decade of research into the role of arginine – and its deprivation – in the generation of excessive autophagy, a process in which the cell dies by eating itself.

Study co-author Hsing-Jien Kung, a renowned cancer biologist and UC Davis professor emeritus who now leads the National Health Research Institutes in Taipei, Taiwan, first discovered the mechanism by which arginine deprivation works in 2009, when he led basic science research at the UC Davis Comprehensive Cancer Center.

“Traditional cancer therapies involve ‘poisoning’ by toxic chemicals or ‘burning’ by radiation cancer cells to death, which often have side effects,” Kung said. “An emerging strategy is to ‘starve’ cancer cells to death, taking advantage of the different metabolic requirements of normal and cancer cells. This approach is generally milder, but as this study illustrates, it also utilizes a different death mechanism, which may complement the killing effects of the conventional therapy.”

The discovery led to the further development of a drug now being tested in several clinical trials against melanoma, prostate, liver, sarcoma and other cancers that lack an enzyme that helps synthesize arginine, an amino acid with an essential role in cell division, immune function and hormone regulation.

The study published today describes how arginine starvation specifically kills tumor cells by a novel mechanism involving mitochondria dysfunction, reactive oxygen species generation, nuclear DNA leakage and chromatin autophagy, where leaked DNA is captured and “eaten” by giant autophagosomes.

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How breast cancer usurps powers of mammary stem cells


Finding provides insight into how aggressive breast cancer might be treated.

Mammary cells found during pregnancy that express integrin beta3 (CD61) act as stem cells, capable of reconstituting a new mammary gland in mice. This property may be to blame for the more aggressive nature of beta3-expressing breast cancer cells. Shown is a section from a mammary “outgrowth” harvested at lactation and immuno-stained for the epithelial markers E-cadherin (brown) and alpha-SMA (red).

During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the UC San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer.

Writing in today’s (Aug. 11) issue of Developmental Cell, David A. Cheresh, Ph.D., Distinguished Professor of Pathology and vice chair for research and development, Jay Desgrosellier, Ph.D., assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy.

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated,” said Cheresh. “This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.”

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Grant awarded to test ‘smart’ chemotherapy drug for bladder cancer


Clinical trial may improve survival rates, transform the standard of care.

Chong-Xian Pan, UC Davis

UC Davis Comprehensive Cancer Center oncologist Chong-Xian Pan has received a $650,000 grant from the VA Northern California Health Care System to conduct the first clinical trial of a novel chemotherapy-delivery drug he developed for bladder cancer patients.

Bladder cancer is one of the 10 most common cancers in the United Sates, however, there has been very little improvement in treatment outcomes during the past three decades said Pan, a genitourologist, the study’s principal investigator, and  leader of the Urothelial Carcinoma Initiative at the Comprehensive Cancer Center.

The researchers hope the trial will result in a more effective therapy and improved treatment outcomes and possibly a cure for bladder cancer.

Standard treatment for non-muscle invasive bladder cancer, which accounts for 80 percent of cases, currently is “intravesical therapy,” which involves a transurethral resection of bladder tumor, a procedure in which a scope is inserted into the patient’s bladder through the urethra and the cancerous cells are removed with a cutting tool.  Most patients then are given a vaccine commonly used to prevent tuberculosis, which stimulates immune cells that can kill bladder cancer cells.

“And that is not good enough,” said Pan, associate professor in the UC Davis Division of Hematology and Oncology.

In 60 percent of cases the cancer returns within two years, Pan said. When it does, oncologists reach for valrubicin, the only Food and Drug Administration-approved drug for recurrent bladder cancer. But valrubicin only works 20 percent of the time.

So Pan and Kit Lam, study co-investigator and chair of the UC Davis Department of Biochemistry and Molecular Medicine, developed a micelle that targets bladder cancer cells and loads them with Paclitaxel, a chemotherapy agent commonly used to treat bladder cancer. The micelle is coated with a PLZ4 ligand, developed by Lam and Pan. Together the ligand-coated micelle enhances Paclitaxel’s effectiveness while decreasing its toxicity.

“It’s like a guided missile,” Pan said.

“Without creating much toxicity, the cancer-targeting micelle has proven effective in killing human bladder cancer cells when injected into a mouse model,” he said. “The goal is to now determine the drug’s safety and effectiveness in humans.”

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Cancers classified in new system


Reclassification could lead to different treatment options for up to 10 percent of patients.

Josh Stuart, UC Santa Cruz

New research involving UC San Francisco-affiliated and UC Santa Cruz scientists suggests that 1 in 10 cancer patients would be more accurately diagnosed if their tumors were defined by cellular and molecular criteria rather than by the tissues in which they originated, and that this information, in turn, could lead to more appropriate treatments.

In the largest study of its kind to date, scientists analyzed molecular and genetic characteristics of more than 3,500 tumor samples of 12 different cancer types using multiple genomic technology platforms.

Cancers traditionally have been categorized by their “tissue of origin”— such as breast, bladder, or kidney cancer. But tissues are composed of different types of cells, and the new work indicates that in many cases the type of cell affected by cancer may be a more useful guide to treatment than the tissue in which a tumor originates.

The study, published today (Aug. 7) in the online edition of Cell, was conducted as part of The Cancer Genome Atlas (TCGA) initiative spearheaded by the National Cancer Institute and National Human Genome Research Institute, both part of the National Institutes of Health.

“It’s only 10 percent that were classified differently, but it matters a lot if you’re one of those patients,” said senior author Josh Stuart, a professor of biomolecular engineering at UC Santa Cruz.

Stuart helped organize the study as part of the Pan-Cancer Initiative of the Cancer Genome Atlas project. A large team of researchers from multiple institutions performed a comprehensive analysis of molecular data from thousands of patients representing 12 different types of cancer. This was the most comprehensive and diverse collection of tumors ever analyzed by systematic genomic methods. Each tumor type was characterized using six different “platforms” or methods of molecular analysis — mostly genomic platforms such as DNA and RNA sequencing, plus a protein expression analysis.

“This genomic study not only challenges our existing system of classifying cancers based on tissue type, but also provides a massive new data resource for further exploration, as well as a comprehensive list of the molecular features distinguishing each of the newly described cancer classes,” said co-senior author Christopher Benz, M.D., professor at the Buck Institute for Research on Aging, adjunct professor of medicine at UCSF, and a member of UCSF’s Helen Diller Family Comprehensive Cancer Center.

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Single-cell analysis holds promise for stem cell, cancer research


UCSF researchers use microfluidic technology to probe human brain development.

Arnold Kriegstein, UC San Francisco

UC San Francisco researchers have identified cells’ unique features within the developing human brain, using the latest technologies for analyzing gene activity in individual cells, and have demonstrated that large-scale cell surveys can be done much more efficiently and cheaply than was previously thought possible.

“We have identified novel molecular features in diverse cell types using a new strategy of analyzing hundreds of cells individually,” said Arnold Kriegstein, M.D., Ph.D., director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. “We expect to use this approach to help us better understand how the complexity of the human cortex arises from cells that are spun off through cell division from stem cells in the germinal region of the brain.”

The research team used technology focused on a “microfluidic” device in which individual cells are captured and flow into nanoscale chambers, where they efficiently and accurately undergo the chemical reactions needed for DNA sequencing. The research showed that the number of reading steps needed to identify and spell out unique sequences and to successfully identify cell types is 100 times fewer than had previously been assumed. The technology, developed by Fluidigm Corp., can be used to individually process 96 cells simultaneously.

“The routine capture of single cells and accurate sampling of their molecular features now is possible,” said Alex Pollen, Ph.D., who along with fellow Kriegstein-lab postdoctoral fellow Tomasz Nowakowski, Ph.D., conducted the key experiments, in which they analyzed the activation of genes in 301 cells from across the developing human brain. Their results were published online August 3 in Nature Biotechnology.

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Spicy chemical may reduce risk of gut tumors


Capsaicin activates receptor on cells lining intestines of mice, study finds.

Researchers at the UC San Diego School of Medicine report that dietary capsaicin – the active ingredient in chili peppers – produces chronic activation of a receptor on cells lining the intestines of mice, triggering a reaction that ultimately reduces the risk of colorectal tumors.

The findings are published in today’s (Aug. 1) issue of The Journal of Clinical Investigation.

The receptor or ion channel, called TRPV1, was originally discovered in sensory neurons, where it acts as a sentinel for heat, acidity and spicy chemicals in the environment. “These are all potentially harmful stimuli to cells,” said Eyal Raz, M.D., professor of medicine and senior author of the study. “Thus, TRPV1 was quickly described as a molecular ‘pain receptor.’ This can be considered to be its conventional function, which all takes place in the nervous system.”

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Depression associated with lower survival rates in men with prostate cancer


UCLA study finds patients are often diagnosed later, receive less effective therapies.

Jim Hu, UCLA

Depressed men with localized prostate cancer are more likely to be diagnosed with more aggressive cancer, receive less effective treatments and survive for shorter times than prostate cancer patients who are not depressed, a UCLA study has found.

The study’s lead author, UCLA professor Dr. Jim Hu, said the negative outcomes may be the result of several factors, including bias against people with mental illness, depression’s impact on cancer’s biological processes, the patient’s lack of investment in his general health and disinterest in more effective care, and missed opportunities by physicians to educate patients about prostate cancer screening and treatment.

The population-based observational study used data from the Surveillance, Epidemiology and End Results Medicare database. Researchers focused on 41,275 men diagnosed with localized prostate cancer between 2004 and 2007 and observed through 2009, of whom 1,894 had a depressive disorder that had been discovered in the two years before the cancer was diagnosed.

“Men with intermediate- or high-risk prostate cancer and a recent diagnosis of depression are less likely to undergo definitive treatment and experience worse overall survival,” said Hu, UCLA’s Henry E. Singleton Professor of Urology and director of robotic and minimally invasive surgery at the David Geffen School of Medicine at UCLA. “The effect of depressive disorders on prostate cancer treatment and survivorship warrants further study, because both conditions are relatively common in men in the United States.”

The study was published online by the Journal of Clinical Oncology, a peer-reviewed journal of the American Society of Clinical Oncology.

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