TAG: "Cancer"

Cancer drugs block dementia-linked brain inflammation


Research represents novel approach to lessening impact of Alzheimer’s, Parkinson’s.

Kim Green, UC Irvine

A class of drugs developed to treat immune-related conditions and cancer – including one currently in clinical trials for glioblastoma and other tumors – eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer’s and Parkinson’s, as well as brain injury.

“Because microglia are implicated in most brain disorders, we feel we’ve found a novel and broadly applicable therapeutic approach,” Green said. “This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases.”

The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases – and can harm or kill neurons – the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.

Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.

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UC Davis personalizing outreach to address Asian cancer health disparities


National Minority Cancer Awareness Week is April 13-19.

In an effort to reduce cancer health disparities among Asian-Americans, UC Davis Comprehensive Cancer Center now offers individual, in-language education and culturally sensitive materials for every Asian-American cancer patient.

Debuting during the National Minority Cancer Awareness Week April 13-19, the new brochures and five-minute videos are designed to inform Asian-Americans about the importance of engaging in cancer research. The educational efforts also are part of the Asian-American Cancer Education Study (AACES), a UC Davis program aimed at increasing awareness of clinical trials and the importance of donation of biospecimens such as blood, saliva or tissue.

Asian-Americans’ involvement in clinical trials and biospecimen donation is crucial because Asian-Americans are consistently underrepresented in cancer research. Studies show that language barriers, mistrust of the medical system and cultural differences often create misunderstandings about the nature and purpose of clinical trials and biospecimen donation, discouraging participation.

“Asian-Americans are the only racial group for whom cancer is the leading cause of death, so we are highly motivated to increase their involvement,” said professor Moon Chen, the cancer center’s associate director for cancer control.

UC Davis researchers have found that less than five percent of all clinical trials participants in the U.S. include minorities, less than two percent of clinical cancer research studies focus on non-white ethnic or racial groups, and biospecimen collection among diverse populations lags far behind that of non-Hispanic whites.

The Asian American Network for Cancer Awareness and Training (AANCART), headquartered at the UC Davis Comprehensive Cancer Center, developed the brochures and DVDs based on extensive research using ethnically specific community outreach programs in Honolulu, Los Angeles, Sacramento and San Francisco. Through community focus groups and surveys conducted in Vietnamese, Chinese, Korean, Tagalog and Hmong, AANCART sought to understand existing cultural barriers and misconceptions about participation in cancer research. They found many causes of confusion, from pervasive cultural beliefs to language problems such as inaccurate translation of certain terms and phrases.

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Drug doubles positive effect in hormone-receptor-positive breast cancer


UCLA researchers lead clinical study.

Richard Finn, UCLA

Breast cancer researchers from the Revlon/UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center announced final clinical trial results this week that showed the amount of time patients were on treatment without their cancer worsening (called “progression-free survival”) was effectively doubled in women with advanced breast cancer who took the experimental drug palbociclib.

The results of the phase 2 clinical trial were announced at the American Association for Cancer Research annual meeting in San Diego.

Palbociclib (PD 0332991) is an investigational drug discovered and being developed by Pfizer Inc. The preclinical work testing palbociclib in a panel of human breast cancer cells growing in culture dishes showed very encouraging activity, specifically against estrogen-receptor–positive (ER+) cancer cells.

This led to a clinical study collaboration with Pfizer led by Dr. Richard Finn, associate professor of medicine at the Jonsson Cancer Center. The phase 1 study built on laboratory work from the Translational Oncology Research Laboratory, which is directed by Dr. Dennis Slamon, professor of medicine at the Jonsson Cancer Center and director of the Revlon/UCLA Women’s Cancer Research Program.

The preclinical observations were moved into a phase 1 clinical study led by Finn and Slamon at UCLA. The study was designed to determine the doses and initial safety results of combining palbociclib with letrozole, a commonly used drug for advanced ER+ breast cancer. Once the phase 1 study was completed, the phase 2 study was performed in 165 postmenopausal breast cancer patients with advanced ER+, HER2- disease.

“By combining the test drug, palbociclib, with the standard drug, letrozole, we demonstrated a dramatic and clinically meaningful effect on progression-free survival in women with ER+ advanced breast cancer,” Finn said. “We are gratified and excited that these results confirm the preclinical work we began at the Translational Laboratory.”

As the primary endpoint of the study, progression-free survival was 20.2 months for patients who received palbociclib plus letrozole, and 10.2 months for those who received letrozole only. The progression-free survival results indicated a 51 percent reduction in the risk of disease progression with the addition of palbociclib to letrozole.

“Our final results very much validate the Translational Laboratory approach,” Slamon said. “By identifying the effective treatment targets in the correct patients, we advance personalized cancer treatment that we hope will greatly improve outcomes for this group of women with breast cancer. These results are as exciting as the initial results we saw for trastuzumab (Herceptin) in HER2+ breast cancers but represent a new approach for women with advanced ER+ breast cancer. This group is different from the women with HER2+ breast cancer, and comprises approximately 60 percent of all advanced breast cancer patients, compared with 20 percent with HER2+ cancer.”

This Phase 2 clinical study was sponsored by Pfizer.

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UCLA launches joint venture with Chinese firm to open lab in Shanghai


Clinical laboratory will provide more accurate diagnoses of cancer and other diseases.

Scott Binder, UCLA

The University of California and UCLA Department of Pathology have signed an agreement with Centre Testing International Corp., a Chinese firm, to create a company that will operate a clinical laboratory in Shanghai. The new lab will support clinical trials and enhance medical care for Chinese patients with cancer and other diseases.

The new company, CTI-Pathology/UCLA Health, is jointly owned by CTI and the University of California. The 25,000-square-foot facility — the first of its kind in China — will offer genetic and molecular diagnostics and other sophisticated tests that exceed the scope of the average lab in China, and UCLA pathologists will train Chinese lab specialists to accurately interpret the tests. The lab is expected to open in September.

The partnership is the first between a Chinese company and a U.S. academic medical center to create a specialized laboratory in China. The agreement was signed today at Ronald Reagan UCLA Medical Center in a ceremony that was videocast to China.

“This joint venture is founded on UCLA’s desire to build strong global relationships that, through education, research and service, improve the health of people and communities throughout the world,” said Dr. Tom Rosenthal, chief medical officer for UCLA Health System and co-director of UCLA’s Center for World Health. “UCLA has a genuine interest in elevating the level of medicine around the world. This is one way we can really make a difference in the quality of the Chinese people’s health care and lives.”

UCLA will oversee management of the laboratory to ensure that its operations meet international standards for quality, and CTI will provide capital funding and marketing expertise. The University of California Regents approved the joint venture on Jan. 22.

“We are extremely pleased that the UCLA Health System, UCLA Department of Pathology and the UC Regents agreed to partner with CTI to establish and manage our joint venture laboratory in Shanghai,” said Sangem Hsu, president of CTI. “Our collaboration will offer the people of China oncology, pathology and laboratory medicine services they can trust. Many of these services are not largely available in China and are needed by physicians and health care providers to accurately diagnose and treat their patients.”

The Shanghai laboratory will be electronically and digitally linked with UCLA — enabling physicians and patients to consult with UCLA pathologists — and with hospitals, clinics and other laboratories throughout China.

“CTI will be an outstanding partner in our effort to significantly improve patient care in China,” said Dr. Scott Binder, senior vice chair of pathology and laboratory medicine at the Geffen School of Medicine, and director of pathology laboratory services for UCLA Health System, which performs more than 7 million tests and diagnose more than 90,000 tissue specimens a year.

Jianyu Rao, UCLA

Binder conceived the idea for a UCLA lab in China and made the first of several visits there in 2005. Dr. Jianyu Rao, a UCLA colleague who speaks Mandarin, helped move the plan forward.

“In the past, Chinese medicine focused more on treatment than diagnosis,” said Rao, a professor of pathology and laboratory medicine at the Geffen School of Medicine and director of cytopathology at UCLA Health System. “Due to the rise of a more-informed middle class, the Chinese people are recognizing the importance of accurate diagnoses for their conditions.”

The partnership also has led to teaching exchanges between UCLA and China. UCLA has already hosted Chinese pathologists and technologists for training on specialized diagnostics for skin, blood and brain tissue and other areas. In turn, UCLA pathologists will travel to China to learn about diseases that are common there but rare in the U.S.

“Because pathology has a history of being undervalued in China, the country has a shortage of pathologists trained to diagnose and interpret complex test results in specialized fields of medicine,” Binder said. “Our partnership gives CTI and UCLA the opportunity to save lives by changing that.”

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Double-headed motor protein offers new targets in cancer treatment


UC Davis finding “fills in a major missing piece.”

The structure of a key part of the machinery that allows cells to divide has been identified by researchers at UC Davis — opening new possibilities for throwing a wrench in the machine and blocking runaway cell division in cancer.

“The structure of kinesin-5 is unexpected, and the implications are big — it allows us to target it, for example, in various forms of cancer,” said Jawdat Al-Bassam, assistant professor of molecular and cellular biology at UC Davis, who led the project.

“This fills in a major missing piece, because for the first time we can understand how microtubule filaments can be linked together and slide past each other,” he said.

The work will be published in the online journal eLife and is available at http://elife.elifesciences.org/lookup/doi/10.7554/elife.02217. When a cell divides into two new cells, a structure called the mitotic spindle forms. Microtubules of protein fan out from each end of the cell, capture chromosomes and draw them apart into what will become the two new cells. Precise coordination of this process is crucial for cells to divide properly, and for avoiding birth and developmental defects.

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Pancreatic cancer ‘dream team’ tackles baffling, deadly disease


UCSF is part of national project to accelerate treatment and discoveries for the disease.

Margaret Tempero, UC San Francisco

UC San Francisco has been selected to join a national “dream team” on pancreatic cancer, part of a project designed to accelerate treatment and discoveries for one of the most deadly forms of cancer.

The team was announced on April 7, 2013, during the annual meeting of the American Association for Cancer Research.

The fourth leading cause of cancer death in the United States, according to the National Cancer Institute, progress in treating pancreatic cancer has long been hobbled by a difficulty at detecting it early and by a poor response to therapies by patients. While it is relatively rare, it now kills nearly as many as breast cancer and only about 6 percent of those diagnosed with it live as long as five years.

The goal of the dream team is to turn pancreatic cancer into a treatable disease.

Margaret Tempero, M.D., a UCSF professor of medicine and director of the UCSF Pancreas Center, will lead the UCSF portion of the research. A pioneer in applying radioactively tagged antibodies and accelerating other cancer therapies, Tempero is known internationally for her efforts to improve the care of patients with pancreatic cancer.

In the dream team project, Tempero and UCSF colleagues will collaborate nationally studying vaccines and other immune-based strategies to keep pancreatic cancer in check. The dream team will be funded over three years by an $8 million grant sponsored by Stand Up To Cancer (SU2C), the Lustgarten Foundation and the Fox Family Cancer Research Funding Trust, along with the American Association for Cancer Research, SU2C’s scientific partner.

“We are starting to make real progress, this is the beginning of a new era for pancreatic cancer,” said Tempero who has been involved with research into the disease for 30 years. “The cellular makeup of pancreatic tumors is unique from other cancers, which is partly why pancreatic cancer is such a difficult disease. However, we are beginning to see some very gratifying responses to treatment — and now through surgery and chemotherapy, patients have a much better chance than they did just a decade ago. With its targeted approach, the dream team project will help us move forward in battling this very challenging disease.”

UCSF has special expertise in combatting and treating pancreatic cancer.

In one recent discovery reported in February in the journal Nature Cell Biology, researchers led by Matthias Hebrok, Ph.D., head of the UCSF Diabetes Center, reported the identification in mice of a key gene that normally holds tumor development at bay, but when damaged by mutation, allows pancreatic tumors to develop.

In 2012, UCSF launched a multidisciplinary, patient-centered Pancreas Center designed to advance the care of patients with pancreatic diseases through prevention, early detection, research and treatment. The center’s team includes specialists in medical oncology, gastroenterology, surgery, nursing, psychology and radiology for the diagnosis and treatment of disease and the management of pain.

Compared to other cancers, pancreatic cancer is relatively rare, representing less than 3 percent of all new cancer cases in the United States, but it is particularly lethal. It becomes more common as people age, and occurs slightly more often in men than women.

An estimated 45,000 people in the U.S. were diagnosed with it last year, and more than 38,000 people died from it, reported the National Cancer Institute.

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New breast cancer results illustrate promise, potential of I-SPY 2 trial


Trial identifies breast cancer patients likely to benefit from experimental drug.

Laura Esserman, UC San Francisco

In an innovative clinical trial led by UC San Francisco, the experimental drug neratinib along with standard chemotherapy was found to be a beneficial treatment for some women with newly diagnosed, high-risk breast cancer.

Additionally, researchers learned that an algorithm used in the adaptive, randomized trial known as I-SPY 2 was highly effective at predicting the success of the treatment regimen in the patients who have HER2-positive/HR-negative disease.

The finding marks the second drug “graduation” within the I-SPY 2 trial model, which is designed to accelerate drug development and to reduce the costs of bringing safe and effective new drugs to market.

The phase 2 data was presented in San Diego at the annual meeting of the American Association for Cancer Research (AACR), a premier gathering of scientists presenting cutting edge cancer research.

Launched by UCSF in tandem with a private-public partnership, I-SPY 2 combines personalized medicine with a novel investigational design. Its goals are to improve the efficiency of clinical trials and to streamline the process for developing new drugs and regimens where they are most urgently needed.

“What is so exciting about the graduations is that we’re proving unconditionally that the standing trial mechanism can efficiently evaluate multiple drugs and identify the specific populations for which the agents are most effective,” said Laura Esserman, M.D., M.B.A., professor of surgery and director of the Carol Franc Buck Breast Care Center at the UCSF Helen Diller Family Comprehensive Cancer Center.

Esserman is the co-principal investigator of I-SPY 2, which is under way at 20 cancer research centers in the United States and Canada.

“We are testing the agents in high-risk patients at a time in their disease (primary breast cancer) when we are most likely to make a difference in survival,” Esserman said. “This was the promise of I-SPY 2. It’s what we’ve been waiting to see. As drugs move through the confirmation process, we should be able to accelerate availability of successful agents, see few failures in phase 3 cancer trials and have better options for women.”

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Cancer and the Goldilocks effect


Researchers discover too much or too little of a single enzyme may promote cancer.

Xiang-Dong Fu, UC San Diego

Researchers at the UC San Diego School of Medicine have found that too little or too much of an enzyme called SRPK1 promotes cancer by disrupting a regulatory event critical for many fundamental cellular processes, including proliferation.

The findings are published in the current online issue of Molecular Cell.

The family of SRPK kinases was first discovered by Xiang-Dong Fu, Ph.D., professor in the Department of Cellular and Molecular Medicine at UC San Diego in 1994. In 2012, Fu and colleagues uncovered that SPRK1 was a key signal transducer devoted to regulating alternative pre-mRNA splicing, a process that allows a single gene to produce multiple mRNA isoforms, which in many cases encode functionally distinct proteins. In this pathway, SRPK1 was a downstream target of Akt, also known as protein kinase B. Akt- activated SRPK1 moves to the nucleus to induce its targeted splicing factors.

In their latest paper, Fu and colleagues report that SRPK1 was found to act as a tumor suppressor because when ablated or removed from mouse embryonic fibroblasts, unwanted cell transformation occurred. Unexpectedly, when SRPK1 was overexpressed in mouse cells, tumor development also happened.

“To my knowledge, this is the first time it has been shown that a signal kinase behaves as a tumor suppressor or a promoter, depending upon its abundance in the same cell,” said Fu. “The point is that too much or too little are both bad.”

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Cell metabolism discovery could lead to treatments for cancer, common cold


UCLA study explains how viruses reprogram metabolism of cells they invade.

Heather Christofk, UCLA

Scientists at UCLA’s Jonsson Comprehensive Cancer Center have published the first study explaining in detail how viruses reprogram the metabolism of the cells they invade to promote continued viral growth within an organism.

The findings could have implications for cancer treatments based on similarities between viruses and cancer-cell mechanisms and may even lead to drugs that could inhibit the virus that causes the common cold, the scientists say.

The research, which was led by postdoctoral scholar Minh Thai and assistant professor of molecular and medical pharmacology Heather Christofk, appears today (April 1) in the online edition of the journal Cell Metabolism and will be published in a future print issue of the journal.

A cell’s metabolism — its inner workings — is the group of physical and chemical processes that feed and maintain the cell, allow it to reproduce and eventually decide when it will die off and be replaced by its daughter cells.

When a virus infects a cell, it triggers changes in this metabolism, essentially reprogramming the cell in such a way that it promotes maintenance and reproduction of the virus. Although it has been known that viruses reprogram cells, the molecular mechanisms that a virus uses to accomplish this have remained unknown until now.

Previous research has shown that when normal cells become cancer cells, they are reprogrammed to act in certain ways that are very similar to virus-infected cells; the cells change their metabolism to support the maintenance and reproduction — and thus the spread — of the cancer.

“In our laboratory, we’ve always been interested in how cancer cells acquire metabolic changes, compared to normal cells,” Christofk said. “We decided to look at viruses and how they change the metabolism of cells they invade because we thought they might be using mechanisms similar to those in cancer cells and that there might be some crossover in the way the mechanisms work. We hoped that by finding out how viruses reprogram cell metabolism, we could learn more about how cancer cells do it.”

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Experts question routine mammograms in elderly


UCSF-Harvard study finds tests offer limited benefit to oldest female patients.

Louise Walter, UC San Francisco

Doctors should focus on life expectancy when deciding whether to order mammograms for their oldest female patients, since the harms of screening likely outweigh the benefits unless women are expected to live at least another decade, according to a review of the scientific literature by experts at UC San Francisco and Harvard medical schools.

National guidelines recommend that doctors make individualized screening decisions for women 75 and older. But the analysis, published online in JAMA (March 31), concluded that since this age group was not included in mammography trials, there is no evidence that screening helps them live longer, healthier lives.

The authors said that many women in this age group receive regular mammograms anyway, with no discussion about the uncertain benefit or potential harms of continued testing, which include unnecessary treatment for slow-growing cancers or pre-cancerous lesions that pose no real threat to the women’s lives.

They concluded that women who are expected to live a decade or more should talk with their doctors and weigh the potential benefits of diagnosing a dangerous but treatable cancer through mammography against the possibility of being misdiagnosed or treated aggressively for a cancer that posed no real harm.

“People should be informed that everything we do in medicine can have good and bad effects, and that goes for mammography,” said Louise Walter, M.D., UCSF professor of medicine and chief of the Division of Geriatrics.

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New technique quickly IDs molecular makeup of breast tumor cells


Tool allows researchers to look at many biomarkers at a time.

Richard Levenson, UC Davis

A new technology can simultaneously detect as many as 100 clinically important protein molecules in breast tumor cells – a quantum advance over conventional methods that can pinpoint only two to four at the same time.

The advantages of the new methodology, called multiplexed ion beam imaging (MIBI), is described by a team of scientists at UC Davis and San Francisco and at Stanford, Genentec in the March 23 advance online publication of the journal Nature Medicine.

“This technology enables researchers to identify the molecular makeup of breast tumor cells more quickly and in greater detail than has been possible before,” said Richard Levenson, study co-author and professor and vice chair for strategic technologies in the UC Davis Department of Pathology and Laboratory Medicine. “It’s a powerful tool that allows us to look at many more than one biomarker at a time, which has important implications for research and clinical diagnosis.”

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Mechanical forces driving breast cancer lead to key molecular discovery


UCSF scientists say new finding could lead to more accurate prognosis.

Valerie Weaver, UC San Francisco

The stiffening of breast tissue in breast-cancer development points to a new way to distinguish a type of breast cancer with a poor prognosis from a related, but often less deadly type, UC San Francisco researchers have found in a new study.

The findings, published online March 16 in Nature Medicine, may lead eventually to new treatment focused not only on molecular targets within cancerous cells, but also on mechanical properties of surrounding tissue, the researchers said.

In a mouse model of breast cancer, scientists led by Valerie Weaver, Ph.D., professor of surgery and anatomy and director of the Center for Bioengineering and Tissue Regeneration at UCSF, identified a biochemical chain of events leading to tumor progression. Significantly, this chain of events was triggered by stiffening of scaffolding tissue in the microscopic environment surrounding pre-cancerous cells. The stiffening led to the production of a molecule that can be measured in human breast cancer tissue, and which the researchers found was associated with worse clinical outcomes.

“This discovery of the molecular chain of events between tissue stiffening and spreading cancer may lead to new and more effective treatment strategies that target structural changes in breast cancers and other tumors,” Weaver said.

In the mouse experiments, Janna Mouw, Ph.D., a UCSF associate specialist who works in Weaver’s lab, found that tissue stiffening in microscopic scaffolding known as the extracellular matrix, or ECM, increases signaling by ECM-associated molecules, called integrins. The integrins in turn trigger a signaling cascade within cells that leads to the production of a tumor-promoting molecule called miR-18a.

Unlike most cellular signaling molecules thus far studied by scientists, miR-18a is not a protein or a hormone, but rather a microRNA, another type of molecule recognized in recent years to play an important role in the lives of cells. The miR-18a dials down the levels of a protective, tumor-suppressing protein called PTEN, which often is disabled in cancerous cells, leading to abnormal biochemical signaling that can promote cancer growth.

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