TAG: "Cancer"

New cancer drugs more effective against endometrial tumors when estrogen is low


Findings could lead to one-two-punch therapy to fight most common gynecologic cancer.

Sanaz Memarzadeh, UCLA

Sanaz Memarzadeh, UCLA

Modulating the hormonal environment in which endometrial cancers grow could make tumors significantly more sensitive to a new class of drugs known as PARP inhibitors, UCLA researchers have shown for the first time.

The findings could lead to a novel one-two–punch therapy to fight endometrial cancers and provide an alternative to conventional treatments, which, particularly with advanced disease, have limited efficacy. Endometrial cancer, which starts in the inner lining of the uterus, is the most common gynecologic cancer in the United States.

Studies on endometrial cancer cell lines have shown that PARP inhibition induces cell death when the tumor-suppressor gene PTEN is missing — a defect found in about 80 percent of human endometrial cancers.

However, the UCLA researchers wanted to test the inhibitors in a laboratory model with a tumor microenvironment that closely resembled human endometrial cancer to see if this therapy would be effective, said senior study author Dr. Sanaz Memarzadeh, an assistant professor of obstetrics and gynecology and director of the G.O. Discovery Lab at UCLA.

The findings are published today (Nov. 12) in Molecular Cancer Therapeutics, a peer-reviewed journal of the American Association for Cancer Research.

“A PARP inhibitor was given orally in two hormonal extremes — high and low estrogen,” Memarzadeh said. “The treatment achieved a significant reduction in tumor size in a low estrogenic milieu. In striking contrast, no response to the inhibitor was seen in tumors exposed to high levels of estrogen.”

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UC Santa Cruz team wins cancer genomics competition


Bioniformatics team ranked first in challenge to predict genetic networks in breast cancer.

Members of Josh Stuart's lab group who worked on the breast cancer challenge were (from left): Chris Wong, Artem Sokolov, Kiley Graim, Evan Paull, Adrian Bivol and Dan Carlin.

Members of Josh Stuart's lab group who worked on the breast cancer challenge were (from left): Chris Wong, Artem Sokolov, Kiley Graim, Evan Paull, Adrian Bivol and Dan Carlin.

A team of bioinformatics experts at UC Santa Cruz made the most accurate predictions in a competitive challenge to identify signaling networks in breast cancer cells. The results of the HPN-DREAM breast cancer network inference challenge were announced today at a conference in Toronto.

“Our goal is to understand the underlying biology of cancer cells and, specifically, how genes interact with each other. The DREAM Challenge was an opportunity to test our expertise in a competitive environment,” said Artem Sokolov, a postdoctoral scholar who works with Josh Stuart, the Jack Baskin Professor of Biomolecular Engineering in UCSC’s Baskin School of Engineering. Sokolov led the team of researchers in Stuart’s lab who worked on the challenge.

Such competitions have long been used in the field of bioinformatics to identify the best computational methods for solving complex problems in biology. The specific challenge tackled by the UCSC team involved identifying cellular signaling pathways in cancer cells. Pathway analysis has been a major focus of research in Stuart’s lab, which is involved in several large cancer genomics research projects. Cancer is a disease of the genome, caused by genetic changes that lead to uncontrolled cell growth and proliferation. These genetic changes often disrupt signaling pathways that involve interactions between cellular proteins.

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New therapeutic target ID’d for ALS


New approach also holds promise for developing treatment of frontotemporal degeneration.

A team of scientists led by researchers from the UC San Diego School of Medicine and Ludwig Institute for Cancer Research have identified a novel therapeutic approach for the most frequent genetic cause of ALS, a disorder of the regions of the brain and spinal cord that control voluntary muscle movement, and frontotemporal degeneration, the second most frequent dementia.

Published ahead of print in last week’s online edition of the journal PNAS, the study establishes using segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and selectively degrade the toxic RNA that contributes to the most common form of ALS, without affecting the normal RNA produced from the same gene.

The new approach may also have the potential to treat frontotemporal degeneration or frontotemporal dementia (FTD), a brain disorder characterized by changes in behavior and personality, language and motor skills that also causes degeneration of regions of the brain.

In 2011, scientists found that a specific gene known as C9orf72 is the most common genetic cause of ALS. It is a very specific type of mutation which, instead of changing the protein, involves a large expansion, or repeated sequence of a set of nucleotides – the basic component of RNA.

A normal C9orf72 gene contains fewer than 30 of the nucleotide repeat unit, GGGGCC. The mutant gene may contain hundreds of repeats of this unit, which generate a repeat containing RNA that the researchers show aggregate into foci.

“Remarkably, we found two distinct sets of RNA foci, one containing RNAs transcribed in the sense direction and the other containing anti-sense RNAs,” said first author Clotilde Lagier-Tourenne, M.D., Ph.D., UC San Diego Department of Neurosciences and Ludwig Institute for Cancer Research.

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Hitachi sponsors UC research in cancer genomics, data storage


UC Santa Cruz researchers will do genome sequencing, analysis for UCSF-led breast cancer trial.

Laura van 't Veer, leader of the Breast Oncology Program at UC San Francisco, and Andy Hospodor, executive director of UC Santa Cruz's Center for Research in Storage Systems, with the petabyte-capacity data storage system provided by Hitachi for UCSC cancer genomics and data storage research.

Laura van 't Veer, leader of the Breast Oncology Program at UC San Francisco, and Andy Hospodor, executive director of UC Santa Cruz's Center for Research in Storage Systems, with the petabyte-capacity data storage system provided by Hitachi for UCSC cancer genomics and data storage research.

Two areas of expertise at UC Santa Cruz — genomics and data storage — are brought together under a new research agreement sponsored by Hitachi. The agreement provides funding for cancer genomics research and the development of a “Genomics Medicine Integrated System,” a pilot information system for evaluating clinical and genomic data from cancer clinical trials.

In addition to initial research funding, Hitachi has provided a petabyte-capacity data storage system from Hitachi Data Systems Corp., making a total of more than $1 million in support for the project. UCSC researchers are using the storage system to manage cancer genomics data and study ways to improve the storage and processing of large amounts of genomic data.

The project involves experts in data storage, genome sequencing, and cancer genomics at UCSC’s Baskin School of Engineering. The data storage effort is led by Ethan Miller, professor of computer science and director of the Center for Research in Storage Systems (CRSS); genome sequencing work is led by Nader Pourmand, professor of biomolecular engineering and director of the UCSC Genome Technology Center; and Josh Stuart, professor of biomolecular engineering, is leading the genome analysis effort.

The UCSC team is partnering with cancer researcher Laura van ‘t Veer at UC San Francisco to perform genome sequencing and analysis for the I-SPY 2 breast cancer trial. “The I-SPY2 team is thrilled to work with UCSC experts in genomic data and have access to world-class storage for our patient’s sequence data,” said van ‘t Veer, director of applied genomics and leader of the Breast Oncology Program at the UCSF Helen Diller Family Comprehensive Cancer Center.

I-SPY 2 is an innovative clinical trial for women with newly diagnosed locally advanced breast cancer that is testing the idea of tailoring treatment by using molecular tests to help identify which patients should be treated with investigational drugs. These drugs are administered prior to surgery in order to see the impact of the agent on the tumor. UCSC’s participation, funded by Hitachi, will add genomic data to the biomarkers that will be tested for their ability to predict a patient’s response to specific treatments.

“Results of our research will help enable genomic data analysis that could improve clinical treatment of cancer,” said CRSS director Miller.

Hitachi is an industry sponsor of CRSS and a major manufacturer of data storage and diagnostic healthcare systems. “In our meetings with Hitachi, they expressed a desire to do research with global social impact, and I-SPY 2 came to the top of the list,” said CRSS Executive Director Andy Hospodor, who will oversee the collaborative project.

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Experimental drug shows promise in treating most common lung cancer type


Preliminary results of MK-3475 encouraging.

Edward Garon, UCLA

Edward Garon, UCLA

An experimental cancer drug that has shown promise in the treatment of melanoma also has shown early potential as an effective treatment for patients with non-small cell lung cancer, the leading cause of cancer death among men and women worldwide.

Dr. Edward Garon, director of thoracic oncology at UCLA’s Jonsson Comprehensive Cancer Center, presented the preliminary results of a Phase 1B study of the new drug, called MK-3475, on Oct. 29 at the World Conference on Lung Cancer in Sydney, Australia.

The detailed interim data on safety and activity came from a cohort of 38 patients with non-small cell lung cancer who were treated previously for the disease without positive results. For the study, the patients received MK-3475 every three weeks.

Among the participants, 24 percent responded to the drug, with their tumors shrinking, and the median overall survival rate was 51 weeks. For those who responded, the median response duration — the average amount of time their tumors remained shrunk — had not been reached at the time of this analysis, so it is at least 62 weeks.

Based on this data, a Phase 2/3 trial comparing two different doses of MK-3475 to standard chemotherapy for lung cancer has begun enrolling patients.

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Bioinformatics breakthrough


High-quality transcriptome from as few as 50 cells.

Vipul Bhargava (left) recently completed his Ph.D. at UC San Diego, where he worked in the lab of Shankar Subramaniam (right). Bhargava is the first author on the Nature Scientific Reports paper.

Vipul Bhargava (left) recently completed his Ph.D. at UC San Diego, where he worked in the lab of Shankar Subramaniam (right). Bhargava is the first author on the Nature Scientific Reports paper.

Bioengineers from UC San Diego have created a new method for analyzing RNA transcripts from samples of 50 to 100 cells. The approach could be used to develop inexpensive and rapid methods for diagnosing cancers at early stages, as well as better tools for forensics, drug discovery and developmental biology.

The protocols, which were published in April in the journal Nature Scientific Reports, are now being applied to a wide range of biological and medical research questions from brain cancer, to liver function and stem cell biology.

The approach from the UC San Diego bioengineers is called Designed Primer-based RNA sequencing or “DP-seq.” It’s a new tool for generating comprehensive snapshots of RNA — the “transcriptome” — collected from as little as 50 picograms of RNA. Analysis of the transcriptome provides insights into what biological processes are occurring at a specific moment in time. RNA transcripts serve as a proxy for which genes are being expressed and at what levels.

“In the months since we published the DP-seq protocol, there has been tremendous interest from the scientific community,” said Shankar Subramaniam a bioengineering professor at the UC San Diego Jacobs School of Engineering and the corresponding author on the paper. “When you are not restricted to samples of thousands of cells, there are so many more systemwide gene expression questions you can ask, and answer,” said Subramaniam. Questions like: What transcription factors will determine cell fates, such as cancer versus normal? and what pathways are likely to be activated in a tissue upon treatment with a drug?

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Study documents heavy air pollution in Canadian area with cancer spikes


Carcinogens detected in emissions downwind of “Industrial Heartland.”

The Industrial Heartland of Alberta, Canada, is home to more than 40 companies, including oil refineries, natural gas liquids facilities and chemical plants.

The Industrial Heartland of Alberta, Canada, is home to more than 40 companies, including oil refineries, natural gas liquids facilities and chemical plants.

Levels of contaminants higher than in some of the world’s most polluted cities have been found downwind of Canada’s largest oil, gas and tar sands processing zone, in a rural area where men suffer elevated rates of cancers linked to such chemicals.

The findings by UC Irvine and University of Michigan scientists, published online this week, reveal high levels of the carcinogens 1,3-butadiene and benzene and other airborne pollutants. The researchers also obtained health records spanning more than a decade that showed the number of men with leukemia and non-Hodgkin’s lymphoma was greater in communities closest to the pollution plumes than in neighboring counties. The work is a dramatic illustration of a new World Health Organization report that outdoor air pollution is a leading cause of cancer.

While the scientists stopped short of saying that the pollutants they documented were definitely causing the male cancers, they strongly recommended that the industrial emissions be decreased to protect both workers and nearby residents.

“Our study was designed to test what kinds of concentrations could be encountered on the ground during a random visit downwind of various facilities. We’re seeing elevated levels of carcinogens and other gases in the same area where we’re seeing excess cancers known to be caused by these chemicals,” said UC Irvine chemist Isobel Simpson, lead author of the paper in Atmospheric Environment. “Our main point is that it would be good to proactively lower these emissions of known carcinogens. You can study it and study it, but at some point you just have to say, ‘Let’s reduce it.’ ”

Co-author Stuart Batterman, a University of Michigan professor of environmental health sciences, agreed: “These levels, found over a broad area, are clearly associated with industrial emissions. They also are evidence of major regulatory gaps in monitoring and controlling such emissions and in public health surveillance.”

The researchers captured emissions in the rural Fort Saskatchewan area downwind of major refineries, chemical manufacturers and tar sands processors owned by BP, Dow, Shell and other companies in the so-called “Industrial Heartland” of Alberta. They took one-minute samples at random times in 2008, 2010 and 2012. All showed similar results. Amounts of some dangerous volatile organic compounds were 6,000 times higher than normal.

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Safe delivery system ID’d for tricky yet potent anti-cancer compound


Study overcomes barriers to delivering STS to tumors with use of liposomes.

Santosh Kesari, UC San Diego

Santosh Kesari, UC San Diego

Researchers at the UC San Diego School of Medicine have discovered a way to effectively deliver staurosporine (STS), a powerful anti-cancer compound that has vexed researchers for more than 30 years due to its instability in the blood and toxic nature in both healthy and cancerous cells.  For the first time, the new method safely delivered STS to mouse tumors, suppressing them with no apparent side effects. The results were published online, Oct. 20, in the International Journal of Nanomedicine.

“By itself, staurosporine shows potent activity against a number of cancer cell lines, including chemotherapy-resistant tumors. However, it also harms normal tissue,” said senior author Santosh Kesari, M.D., Ph.D., director of neuro-oncology at UC San Diego Moores Cancer Center. “With this study, we have been able to overcome the pharmacokinetic barriers to delivering staurosporine to tumors with the use of liposomes.”

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UC Davis cancer researcher wins lifetime achievement honor


Ralph de Vere White honored by Society of Urologic Oncology.

Ralph de Vere White, UC Davis

Ralph de Vere White, UC Davis

Ralph de Vere White, associate dean for cancer programs at UC Davis School of Medicine, director of the UC Davis Comprehensive Cancer Center and a distinguished professor of urology, has received the Huggins Medal Award from the Society of Urologic Oncology (SUO).

De Vere White will receive the prestigious medal in recognition of his major contributions and lifetime achievements in research and clinical practice, which have contributed to the progress in the treatment for patients with genitourinary tumors.

De Vere White said he was moved to be chosen for this year’s award.

“There is hardly a nicer feeling than when your peers, who know all your faults, decide to give you an honor like this,” de Vere White said.

Formal presentation of the medal will take place at the society’s 14th annual winter meeting held Dec. 4-6 in Bethesda, Md. De Vere White will give the Huggins lecture preceding the award presentation on the importance of team science to accomplish research and bring new knowledge in the fight against cancer.

“If I have done one thing well in my career it is having leveraged resources available to the UC Davis Comprehensive Cancer Center and to do it by encouraging and allowing people to work in teams,” de Vere White said.

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Genetic discovery could help guide doctors’ treatment of bladder cancer


Finding highlights potential of precision medicine to personalize clinical care.

During cell division, seen here in a bladder cancer cell, STAG2 plays a crucial role in properly allocating chromosomes to the two newly formed cells. (Image by David Solomon, UC San Francisco)

During cell division, seen here in a bladder cancer cell, STAG2 plays a crucial role in properly allocating chromosomes to the two newly formed cells.

A UC San Francisco-led team of scientists has discovered that a gene mutation found in some bladder cancers is indicative of low-risk tumors that are unlikely to recur or progress after surgery.

The finding could help doctors spare many patients from uncomfortable, expensive follow-up tests.

The study, reported online in the journal Nature Genetics on Oct. 13 offers a glimpse into the potential of precision medicine, which aims to use genetic information to make an accurate analysis of an individual’s disease and target it with precise therapy.

The fifth most common malignancy in the U.S., bladder cancers claim about 15,000 lives each year.

A majority of bladder cancers known as papillary tumors can be successfully treated with surgery, but about 20 percent recur and invade the muscle wall of the bladder or spread to nearby organs and lymph nodes. Thus far, physicians have not had an accurate method to determine which papillary tumors are potentially lethal, so most patients undergo frequent endoscopic examinations of their bladder using a technique known as cystoscopy to look for signs of recurrence.

In 2011, while at Georgetown University School of Medicine, David A. Solomon, M.D., Ph.D.; his mentor Todd Waldman, M.D., Ph.D.; and colleagues published research in Science showing that mutations that deactivate a gene called STAG2 – which regulates the separation of duplicate chromosomes during cell division – are present in a range of human cancers.

Now a UCSF resident in anatomic pathology in the Department of Pathology, Solomon built on that work for the new Nature Genetics study.

Along with colleagues C. David James, Ph.D.; Tomoko Ozawa, M.D., Ph.D.; and Joanna J. Phillips, M.D., Ph.D., all of UCSF’s Department of Neurological Surgery, and other scientists from around the U.S. and from Germany, Solomon showed that inactivating mutations in the STAG2 gene are present in 36 percent of noninvasive papillary bladder tumors, but in only 16 percent of the recurrent, invasive variety.

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Leukemia researcher receives $6.25M grant


Thomas Kipps one of four recipients of Leukemia & Lymphoma Society Award.

Thomas Kipps, UC San Diego

Thomas Kipps, UC San Diego

The Leukemia & Lymphoma Society has awarded Thomas J. Kipps, M.D., Ph.D., Distinguished Professor of Medicine at the UC San Diego School of Medicine, with a 5-year, $6.25 million Specialized Center of Research program grant to support research on chronic lymphocytic leukemia (CLL), the most common adult leukemia in the United States.

Kipps, the Evelyn and Edwin Tasch Chair in Cancer Research and UC San Diego Moores Cancer Center deputy director for research, is a recipient of The Leukemia & Lymphoma Society’s grant for the “Specific Targets for Therapy of Patients with Chronic Lymphocytic Leukemia,” a four-part project. After nearly three decades of investigating and treating CLL, Kipps is considered among the nation’s leading experts in the disease. According to the National Cancer Institute, 1 in 192 people will be diagnosed with CLL during their lifetime.

“Although the research proposal is directed toward improving therapy for patients with CLL, the research may impact other leukemias, lymphomas and cancers in general,” said Kipps. “The Leukemia & Lymphoma Society’s Specialized Center of Research grant plays an important part in moving this research forward.”

CLL is a cancer of the blood and bone marrow, characterized by the growth of abnormal white blood cells that ultimately crowd out healthy cells. Treating this slow-growing cancer is challenging because malignant cells are resistant to drugs used to treat other leukemias. Past research has been unable to uncover a common mutation; instead, alterations in CLL occur through different survival pathways.

Kipps and colleagues reported that a protein used by embryo cells during early development, called Receptor-tyrosine-kinase-like Orphan Receptor 1 or ROR1, serves as a switch regulating the spread of cancer, known as metastasis.

The Leukemia & Lymphoma Society grant will permit Kipps to advance the development of potential new therapies that would target identified pathways that support leukemia-cell survival such as ROR1 (Project 1). Because the activation or silencing of one pathway could lead to the expression of another, William Wierda, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center, will take the findings and implement a Phase I clinical trial (Project 2).

Dennis Carson, M.D., UC San Diego emeritus professor of medicine, will investigate the suppression of Wnt-signaling, which can stimulate leukemia-cell growth, and the ability to sensitize these cells to agents currently in clinical trials at UC San Diego (Project 3). And Michael Karin, Ph.D., UC San Diego School of Medicine, Distinguished Professor of Pharmacology and Pathology, will examine the regulation of signaling and regulatory molecules IKKbeta, NF-KappaB, JAK2 and STAT3 in CLL cells (Project 4).

The project is funded by grant award number 7005-14 from the Leukemia & Lymphoma Society.

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Cell growth discovery has implications for targeting cancer


UCSF findings may lead to new ways to fight cancer.

Davide Ruggero, UC San Francisco

Davide Ruggero, UC San Francisco

The way cells divide to form new cells — to support growth, to repair damaged tissues, or simply to maintain our healthy adult functioning — is controlled in previously unsuspected ways UC San Francisco researchers have discovered. The findings, they said, may lead to new ways to fight cancer.

The steps leading a quiet cell to make and divvy up new parts to form daughter cells rely on some of the cell’s most complex molecular machines. Different machines play key roles at different stages of this cell cycle. Each of these cellular machines consists of many proteins assembled into a functioning whole. They carry out such tasks as repairing DNA in the newly replicated gene-bearing chromosomes, for instance, or helping pull the chromosomes apart so that they can be allocated to daughter cells.

In a study published online on Oct. 10 in the journal Molecular Cell, UCSF researchers led by molecular biologist Davide Ruggero, Ph.D., associate professor of urology, and computational biologist Barry Taylor, Ph.D., assistant professor of epidemiology and biostatistics, found that the production of entire sets of proteins that work together to perform such crucial tasks is ramped up together, all at once — not due to the transcription of genes into messenger RNA, a phenomenon scientists often study to sort out cellular controls — but at a later stage of gene expression that occurs within the cell’s protein-making factories, called ribosomes.

“We have found that these proteins are regulated specifically and exquisitely during the cell cycle,” Ruggero said. When this regulation falters, it wreaks havoc in the cell, he added. “Cell-cycle control is a process that is most often misregulated in human disease,” he said.

More specifically, the researchers found that this coordinated timing of protein production during the cell cycle is largely governed at the tail end of gene expression, within the ribosome, where cellular machinery acts on messenger RNA to churn out the chains of amino acids that eventually fold into functional form as proteins.

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