Cholesterol-lowering medicines may be effective against cancer

Millions of people around the world use medicines based on statins to lower their blood cholesterol, but new research from the University of Gothenburg, published in the prestigious journal PNAS, shows that statins may also be effective in the treatment of cancer.

Statins lower cholesterol by blocking certain enzymes involved in our metabolism. However, they have also been shown to affect other important lipids in the body, such as the lipids that help proteins to attach to the cell membrane (known as lipid modification). Because many of the proteins that are lipid-modified cause cancer, there are now hopes that it will be possible to use statins in the treatment of cancer.

Ideal test subject

It is, however, very difficult to study the side-effects of statins in mammals. As a first step, Marc Pilon, researcher at the Department of Cell and Molecular Biology at the University of Gothenburg, has teamed up with Swedish and international colleagues to carry out studies on the nematode C. elegans. This nematode, which is made up of just a thousand or so cells, does not produce cholesterol and is therefore an ideal test subject.

Can treat diabetes

The Gothenburg researchers' studies show that statins can have a dramatic inhibitory effect on growth and development. As the researchers managed to identify the enzyme involved, they can also explain how the effect arises at molecular level.

"Our results support the idea that statins can be used in more ways than just to lower cholesterol," says Pilon. "Not least that they can prevent the growth of cancer cells caused by lipid-modified proteins, but also that they can be effective in the treatment of diabetes and neurological disorders such as Parkinson's."

The article Statins Inhibit Protein Lipidation and Induce the Unfolded Protein Response in the Non-Sterol Producing Nematode C. elegans, published in the journal PNAS, is the result of a research partnership between the University of Gothenburg, Chalmers University of Technology and the University of Southern Denmark.

Contact
Marc Pilon, Department of Cell and Molecular Biology, University of Gothenburg
+46 768 166972
+46 31 786 3279
marc.pilon@cmb.gu.se

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http://www.science.gu.se/english/News/News_detail/Cholesterol-lowering_medicines_may_be_effective_against_cancer.cid898016

Study Finds No Relationship Between PCR Rate and Race in Women with Breast Cancer

Blacks, whites, Hispanics who achieve milestone all have better outcomes.

Locally advanced breast cancer patients who received the same class of neoadjuvant chemotherapy were found to have no evidence of disease at the time of their surgery, or achieved pathological complete response, at the same rate regardless of race, according to researchers at The University of Texas M. D. Anderson Cancer Center.

The study, presented in a poster discussion session at the 2009 Breast Cancer Symposium in San Francisco, is the largest in a homogenous group of breast cancer patients evaluating pathological complete response (pCR) according to race. Only one other study, also conducted at M. D. Anderson but limited to triple negative breast cancer patients (estrogen and progesterone receptor negative, HER2 negative), has analyzed the relationship between the two.

"Our findings confirm pathological complete response is a strong prognostic indicator and a surrogate for good survival, despite a patient's race, and that it's vital we continue to strive towards achieving this milestone for all women with breast cancer," said Mariana Chavez MacGregor, M.D., a medical oncology fellow at M. D. Anderson. "The study also mandates that we continue to research the differences across races in breast cancer."

Racial disparities in breast cancer are known: the American Cancer Society (ACS) estimates that 19,540 blacks and 14,200 Hispanics will be diagnosed with the disease in 2009. While the overall incidence rate is 10% lower in blacks than whites, in 2001-2005, they had a 37% higher death rate. ACS also reports that overall breast cancer mortality rates are lower in Hispanic women than white women.

Understanding the reasons for such disparities - be it access to care and screening, biological differences in tumors and/or breast cancer subtypes - is the focus of ongoing research efforts across the cancer community, explained Chavez MacGregor, the study's first author.

"While these disparities are known, we also understand that breast cancer patients who achieve pathological complete response have better outcomes," said Chavez MacGregor. "What we didn't understand until now was if pathological complete response rates had any relationship with race. If a specific ethnic group had a better or worse response rate, maybe we could then determine which groups may be in need of additional and /or improved therapies."

Using the M. D. Anderson Breast Medical Oncology database, the retrospective study identified 2,074 patients diagnosed with Stages II and III breast cancer and treated at the institution between 1994 and 2008. Of the patients, 1,334 (64.3%) were white, 302 (14.6%) black, 316 (15.2%) Hispanic and 122 (5.9%) were classified as "other" race groups. The median age of the women was 50. All received neoadjuvant anthracycline- and taxane-based chemotherapy; receiving similar class of therapy was an important component in the design of the study, said Chavez MacGregor.

At the time of surgery, the researchers found no difference of statistical significance in pCR rates among racial groups: 12.3% in whites, 12.5% in blacks, 14.24% in Hispanics, 11.5% in "other".

Among all patients, at a median follow-up of 30 months, there were 438 recurrences and 327 deaths. The five-year unadjusted recurrence-free (RFS) and overall survival (OS) rates were 71% and 79% in whites, 60% and 57% in blacks, 76% and 79% in Hispanics and 75% and 84% in "other," respectively. Lack of achieving pCR, HER2-positive and triple-negative subtypes, lymph node involvement were all found to be independent predictors of worse RFS and OS.

In further analysis, the study reconfirmed what had been noted in literature - although not statistically significant, blacks tended to have poorer outcomes, while Hispanics had improved outcomes compared to whites, said Chavez MacGregor.

The study is not without limitations, she noted; in design, it was both retrospective and a single-institution study, and race was self-reported. In addition, the research focus was until the time of surgery, with less attention towards patients' experience post-surgery, such as compliance to hormone therapies or other adjuvant treatments, other than RFS and OS.

In the same cohort of patients, Chavez MacGregor plans further analysis of patients who did not achieve pCR to better understand why they might not have reached this milestone.

The study was funded by grants from the National Cancer Institute and Susan G. Komen for the Cure.

In addition to Chavez MacGregor, M. D. Anderson authors on the study include Gabriel N. Hortobagyi, M.D.; Ana Maria Gonzalez-Angulo, M.D., the study's senior author; Jennifer Litton, M.D.; Vicente Valero, M.D.; and Huiqin Chen, all of the Department of Breast Medical Oncology; Funda Meric-Bernstam, M.D., Department of Surgery; and Melissa Bondy, Ph.D., Department of Epidemiology. Other authors include: Clifford A. Hudis, M.D., Memorial Sloan Kettering; and Antonio C. Wolff, M.D., The Sidney Kimmel Comprehensive Cancer Center. 10/09/09.

Release link :

http://www.mdanderson.org/newsroom/news-releases/2009/study-finds-no-relationship-between-pcr-rate-and-race-in-women-with-breast-cancer.html

KEAP1 Keeps Major Cancer-Promoting Protein at Bay

Researchers find new tumor-suppressor destroys a key link in cancer chain.


A tumor-suppressing protein snatches up an important cancer-promoting enzyme and tags it with molecules that condemn it to destruction, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports this week in the journal Molecular Cell.

“KEAP1 is a recently discovered tumor suppressor, but how it works has not been known. IKKß is a known oncoprotein that promotes cancer in at least two different ways, but we did not know how it was regulated. We think we’ve answered both questions with this research,” said senior author Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson’s Department of Molecular and Cellular Oncology.

The researchers showed that KEAP1, short for the tongue-twisting Kelch-like ECH-associated protein 1, binds to IKKß and attaches molecules known as ubiquitins to the oncoprotein, which targets it for dissolution by the cell’s proteasome complex.

They also showed that underexpression of KEAP1 is associated with poor survival among breast cancer patients, and that it’s mutated and inactivated in some breast, liver, lung and colon tumors.

“KEAP1 underexpression or inactivation is involved in multiple cancers, so we are working now to identify its activation mechanism, which could lead to development of new anti-cancer drugs,” Hung said. He and his colleagues also want to know whether KEAP1 works on other known oncoproteins.

Blocking overexpression of IKKß, short for IkB kinase ß, is crucial for at least two reasons. Hung and colleagues have shown that the protein inhibits at least two other important tumor suppressors. More importantly, IKKß activates the NFκB (nuclear factor Κb) signaling pathway, which regulates expression of genes involved in the immune response, cellular proliferation, growth of new blood vessels, cell survival, tumor invasion and the lethal spreading of cancer known as metastasis.

Hung and colleagues first demonstrated that the presence of KEAP1 inhibits the NFκB signaling pathway and then conducted a series of experiments to find out how that happens. They found that depletion of KEAP1 leads to the accumulation of IKKß, and then discovered that the tumor suppressor binds to a specific site on IKKß, capturing it to feed it to the proteasome.

Hung likens this snatching of IKKß to plucking stuffed animals with a mechanical claw out of an arcade game, imagery that wound up on the cover of Molecular Cell.

KEAP1 is a ubiquitin ligase that attaches to the target protein and works in a complex with another protein, CUL3, that connects the ubiquitins to the bound protein.

The team analyzed both KEAP1 and CUL3 expression in the tumors of 119 breast cancer patients and correlated the findings to overall survival. They found that underexpression of KEAP1 alone was associated with poor survival. Patients with strong expression of both KEAP1 and CUL3 had an 80% survival rate at five years, while those with little expression of either had a 43% five-year survival rate.

Next, they sequenced KEAP1’s genes in 26 cancer lines (18 breast, four liver, four lung) and in 119 primary tumors (17 breast, 78 liver, 13 lung, 11 colon) and found two functional genetic mutations that shut down the protein’s ability regulate IKKß. The mutations affected the portion of the protein that binds to IKKß.

The research in this paper was funded by grants from the National Cancer Institute, including M. D. Anderson’s Specialized Program in Research Excellence (SPORE) grants in breast, pancreatic and ovarian cancers, the Breast Cancer Research Foundation, Kadoorie Charitable Foundations, Patel Memorial Breast Cancer Endowment Fund, the National Breast Cancer Foundation and the Taiwan National Science Council.

Hung noted that first author Dung-Fang Lee, Ph.D., led his lab’s research on IKKß as a doctoral candidate in The University of Texas Graduate School of Biomedical Sciences at Houston, a joint program of M. D. Anderson and The University of Texas Health Science Center at Houston. Lee received the GSBS Alfred Knudson, Jr., Outstanding Dissertation Award when he graduated last year. Lee is now a postdoctoral fellow at Mount Sinai School of Medicine in New York.

Co-authors with Lee and Hung are Hsu-Ping Kuo, Ph.D., Mo Liu, Chao-Kai Chou, Ph.D., Weiya Xia, M.D., Yi Du, Jia Shen, Chun Te Chen, Longfei Huo, Ph.D., Ming-Chuan Hsu, Ph.D., Chia-Wei Li, Ph.D., and Qing-Qing Ding, all of M. D. Anderson’s Department of Molecular and Cellular Oncology; Kuo, Liu, Chou, Du, Shen and Chen are also students in the GSBS. Also, Tsai-Lien Liao, Ann-Chi Lin, Ya-Hui Chang, Shih Feng Tsai, M.D., Ph.D., all of the Division of Molecular and Genomic Science, National Health Research Institutes, Taiwan; Chien-Chen Lai, Ph.D., Division of Molecular and Genomic Medicine, National Health Research Institutes and the Graduate Institute of Chinese Medical Science, China Medical University, both in Taiwan; and Long-Yuan Li., Ph.D.,Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital and Asia University, both in Taiwan.

Release link :

http://www.mdanderson.org/newsroom/news-releases/2009/keap1-keeps-major-cancer-promoting-protein-at-bay.html

Researchers Report Benefits of New Standard Treatment Study for Rare Pediatric Brain Cancer

A team of researchers led by The University of Texas M. D. Anderson Cancer Center unveiled results today from the largest-ever collaborative study addressing the treatment of a rare pediatric brain tumor. The findings suggest a new standard protocol could improve survival nearly two-fold for pediatric patients with choroid plexus tumors, as reported at the 41st Annual Meeting of the International Society of Pediatric Oncology (SIOP).

Johannes Wolff, M.D., professor in the Children’s Cancer Hospital at M. D. Anderson Cancer Center and lead investigator on the study, revealed that the protocol, consisting of three chemotherapy agents and radiation, had projected overall survival rates of 93% at one year, 82% at five years and 78% at eight years.

“This SIOP 2000 study started 10 years ago and has grown to include more than 100 institutions from more than 20 countries,” said Wolff. “With the data we have, we can tell which patients are prone to do better and which ones have a poor prognosis. In addition, we’ve established a promising standard protocol for these patients.”

Choroid plexus carcinomas are malignant brain tumors that originate in the choroid plexus epithelium, which is the gland that produces cerebrospinal fluid. Often the tumors may block the flow of cerebrospinal fluid causing pressure to build in the brain and possibly enlarge the skull. It is a very rare tumor affecting approximately 1,500 children worldwide each year, occurring more often in infants.

Due to the rarity of the disease, there is no standard treatment protocol for the disease, but Wolff and other international researchers hope to change that through their studies. They also developed an innovative statistical module for institutions to use that will ensure quality and efficient data coming out of the study.

One surprising finding Wolff and fellow researchers discovered contradicted historical research, which originally showed the significant advantage of complete surgical resection. The SIOP 2000 study found that patients receiving the intense chemotherapy protocol had similar outcomes as those with complete resection, reducing the need for surgical treatment.

“We think the better outcomes had to do with the fact that physicians will prolong chemotherapy treatment if there is residual tumor,” said Wolff. “If we can prove this hypothesis, this would be an argument for extending treatment in the future.”

Wolff says the next step will be to begin another study that will investigate a four-armed chemotherapy protocol. This would investigate the possibility of adding another chemotherapy to further improve survival rates. The SIOP 2000 study used carboplatinum, etoposide and cyclophosamide in combination with radiation.

The study was funded through the German Children’s Cancer Foundation. 10/09/09


Release link :

http://www.mdanderson.org/newsroom/news-releases/2009/researchers-report-benefits-of-new-standard-treatment-study-for-rare-pediatric-brain-cancer.html

Analyzing Cancer Cells to Choose Treatments

Microfluidics chips allow scientists to study circulating cancer cells and determine their vulnerabilities.

In a new clinical trial for prostate cancer, scientists will capture rare tumor cells circulating in patients' blood, analyze them using a specialized microchip, and use the results to try to predict how well the patient will respond to a drug. The trial reflects a new phase of personalized medicine for cancer, enabled by microfluidics technologies that can isolate scarce cancer cells and detect very small changes in gene expression. Physicians ultimately hope these chips can become a routine part of clinical care for cancer. "We need to be able to profile the tumor at the time we are considering treatment," says Howard Scher, chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center, where the trial will take place.

The study will focus on men with a difficult to treat form of prostate cancer that has failed to respond to other therapies. Changes in gene expression might help determine whether a specific drug will be effective--for example, if a patient has high levels of a receptor for androgen hormones, a drug that inhibits signaling of that receptor is more likely to work well. "We want to know why they don't respond to therapy and what therapies would be best for them," says Martin Fleisher, chairman of the Department of Clinical Laboratories at Sloan. "We collect tumor cells from blood, and do a gene analysis to find out what genes are overexpressed and whether or not they would be candidates for certain types of targeted therapies that would beat down their cancer."

The effectiveness of different cancer drugs can vary based on the molecular characteristics of the cancer, such as the presence of a certain hormone or genetic mutation. Physicians already do some molecular analysis of cancer tissue to select the best drug for a patient. Herceptin, for example, is used to treat breast cancer in women with a particular protein in their tumors. And lung cancer patients with a mutation in the gene for the epidermal growth factor receptor are more likely to respond to a drug called Iressa than patients without it. But these treatments are chosen based on analysis from tumor biopsies, which isn't always possible.

Analyzing tumor cells in blood presents two major challenges. Tumor cells are found at very low concentrations in the blood--about one in ten million cells--making it difficult to isolate them. And the small numbers of cells must be analyzed in very low volumes. In the last year, Sloan scientists and others have developed ways to capture these cells using antibodies that detect a molecular marker present only in cancer cells.

In the new Sloan study, scientists face an even more challenging problem--they must detect differences in gene expression, rather than a specific genetic mutation, such as the mutation linked to Iressa responsiveness in lung cancer. Scher and collaborators will use a microfluidics chip made by Fluidigm, a South San Francisco, CA- based company . DNA from each cell is filtered into one of 96 tiny channels on one side of the chip, while reagents flow in from 96 channels on the other side. A precise plumbing system then combines the molecules in different combinations, generating about 9,000 simultaneous reactions. Each reaction takes a volume of just nanoliters--about the size of a period--rather than the microliter volume typical of most commercial fluidics devices. The chip, which costs about $300, "can detect differences in gene expression that are as subtle as twofold with very good accuracy," says Gajus Worthington, Fluidigm's president, CEO, and co-founder.

Researchers plan to analyze levels of about 30 genes in each patient, including genes involved in production of testosterone and in cell signaling. Expression of these genes has been shown in animal models to predict how well a tumor will respond to a drug called dasatinib, which is approved for treatment of chronic myelogenous leukemia and in late stage clinical trials for prostate cancer.

The microfluidics technology could also be used to examine other properties of tumor cells. Scientists might look for changes in gene expression that suggest a cancer has metastasized, or whether a tumor has evolved specific mutations that make it resistant to specific drugs.

Release link :

http://www.technologyreview.com/biomedicine/23551/

Coruscating currants in a cake : Nanocrystals could make anti-cancer drugs more efficient

Agents employed for the chemotherapy of cancer can have unwanted side-effects. Therefore, a major objective of novel approaches to therapy is to find ways of efficiently targeting the treatment to the tumour, so as to minimize – as far as possible – damage to healthy tissues. In an interdisciplinary study, scientists led by Dr. Manfred Ogris at Ludwig-Maximilians-Universität (LMU) in Munich have developed a method that allows them to monitor the distribution of compounds in whole animals by taking snapshots at different times after injection. The technique relies on the attachment of fluorescent nanocrystals to fragments of DNA. These gene vectors are taken up by the tumour, and the genes they carry direct the synthesis of proteins that attack the tumour. Using light in the near-infrared region to induce the nanocrystals to fluoresce, Ogris and his team were able to track the particles, allowing them to observe the distribution of the vectors associated with them, for periods ranging from seconds to minutes. This novel method could contribute to the development of more efficient, targeted cancer therapeutics in the future (Molecular Therapy Online, 25 August 2009).

Malignant tumours induce the formation of blood vessels that are more permeable than those found in healthy tissues, and allow larger molecules to exit from the bloodstream. In order to treat such tumours effectively, researchers have developed carrier systems that allow the transport of active agents into the tumour itself. This approach makes it possible to attack the tumour directly and consequently reduce the incidence of harmful side-effects. A major factor in the development of efficient delivery systems is the time course of dissemination of the drug in the body. Above all, one wants to avoid rapid clearance of the agent by the liver or speedy excretion by the kidney. Ideally, the active agent should circulate in the bloodstream long enough for it to reach the tumour and should then become concentrated there.

A team made up of pharmacists, biologists and physicists led by Dr. Manfred Ogris of the Department of Pharmacy at LMU Munich, has recently found a way to monitor the distribution of therapeutic agents in the the body with high temporal resolution. Dr. Andrey Rogach and his collaborators at the Physics Department of LMU and the Munich Center for NanoScience (CeNS) have synthesized so-called quantum dots made of the semiconductor cadmium telluride. Quantum dots are tiny crystals with dimensions of between 2 and 8 nanometers (a nanometer is a millionth of a millimeter). When these crystals are exposed to light, they fluoresce in different colours, depending on their size. “In contrast to the quantum dots that have been produced so far, these crystals form in water and are therefore very small”, says Rogach. In addition, they fluoresce not only in the visible, but also in the near-infrared region of the spectrum. This makes them especially suitable for use in living tissue.”

The next step was to couple the quantum dots to gene vectors consisting of a particular fragment of DNA coated with a positively charged macromolecule. “After uptake into the tumour, the DNA fragment induces the production of a specific protein that selectively attacks the tumour cells”, explains Ogris. “The macromolecule, on the other hand, serves to bind the negatively charged quantum dots tightly and to package the DNA. The nanocrystals are incorporated into the complex rather like the currants in a cake”. The scientists call the resulting structures “quantoplexes”: Irradiation of these complexes with near-infrared light induces fluorescence, which can be used to follow the dissemination of the particles in the body in great detail.

Ogris und his colleagues first examined the distribution of free quantum dots, i.e. without attached DNA. They injected the crystals into anaesthesized mice and recorded the fluorescent signal from the whole body every 15 seconds. This enabled them to determine the typical pattern of distribution of the particles in the mouse. Shortly after injection, the particles were found in the bloodstream, the lymphatic system and the liver. After a few hours, most of the particles had been cleared via the liver. When the quantum dots were added to the gene vectors, which are themselves between 100 and 300 nanometers in diameter, the picture was very different. Most of the fluorescing particles were now found in the lung, with smaller amounts localizing to the liver.

“Of course, this distribution is not always what one wants”, notes Ogris. “So we performed further experiments in which we coated the surface of the DNA with a different macromolecule, polyethylene glycol or PEG.” Indeed, this modification reduced the interaction of the particles with blood components, so that significantly more molecules now reached the tumour. And although the vectors were transported from the bloodstream to the liver within minutes of being injected, a clear signal could still be observed in the tumours up to 15 minutes later – showing that the particles that had made it to the tumour could be retained there for some time.

“In future, fluorescent nanocrystals could provide a very useful tool for the study and optimization of carrier systems for the treatment of tumours”, remarks Ogris. At present such studies are only possible in animal models, because the cadmium telluride which we use is toxic in the long term, and very small amounts are retained in tissues. However, a central issue in the development of new drugs is that we must first understand their distribution and modes of action in the whole body”, emphasizes Ogris. The next step is to use quantum dots to investigate the behaviour of gene vectors that can recognize and dock onto tumour-specific receptors and thus have the potential to mount a truly targeted attack on the malignant growth. (ca)

Publication:
“Drug Nanocarriers Labeled With Near-infraredemitting Quantum Dots (Quantoplexes): Imaging Fast Dynamics of Distribution in Living Animals”;
Arkadi Zintchenko, Andrei S. Susha, Massimo Concia, Jochen Feldmann, Ernst Wagner, Andrey L. Rogach, Manfred Ogris;
Molecular Therapy Online Edition, 25 August 2009;
DOI: 10.1038/mt.2009.201

Contact:
Dr. Manfred Ogris
Department of Pharmacy – Center of Drug Research
Pharmaceutical Biology and Biotechnology
Phone: +49 (0) 89 / 2180-77842
E-Mail: manfred.ogris@cup.uni-muenchen.de
Webseite: http://www.cup.uni-muenchen.de/pb/aks/ewagner

Release link :

http://www.en.uni-muenchen.de/news/research/ogris.html

Avastin dramatically improves response, survival in recurrent brain cancers

A new study by UCLA researchers and colleagues shows that the targeted therapy Avastin, alone and in combination with the chemotherapy drug CPT-11, significantly increased response rates, progression-free survival times and survival rates in patients with a deadly form of brain cancer that had recurred.

Patients with recurrent glioblastoma have a grim prognosis, and conventional treatments have typically been limited to largely ineffective and highly toxic chemotherapies. Only about 5 percent of patients respond to further treatment — meaning their tumors shrink by 50 percent or more — and only 15 to 20 percent of patients make it to the six-month mark before their disease progresses again. Survival is limited to six to seven months.

But a randomized Phase II study demonstrates that Avastin alone and Avastin given with CPT-11 improved those statistics. Early results from the study prompted the U.S. Food and Drug Administration to agree to an accelerated approval of Avastin in May 2009 for use in patients with recurrent glioblastomas, said Dr. Timothy Cloughesy, director of the neuro-oncology program at UCLA's Jonsson Comprehensive Cancer Center and senior author of the study. The program allows provisional approval of medicines for cancer or other life-threatening diseases.

The study, conducted at 11 centers across the country, was published this week in the early online version of the Journal of Clinical Oncology.

"This is a huge breakthrough for us. In all the years we've been treating recurrent glioblastomas using conventional and investigational agents, we've never had anything like the responses we're seeing with Avastin," said Cloughesy, who also is a UCLA professor of neurology. "You just don't get these kinds of responses in this patient population. We're seeing dramatic improvements."

The two-armed study enrolled 167 patients with recurrent glioblastoma. One arm evaluated Avastin used as a single agent, the other Avastin given with CPT-11. An independent radiological facility was used to measure tumor responses, Cloughesy said.

In the Avastin-only arm, 28.2 percent of patients responded to the treatment, meaning their tumors shrunk by 50 percent or more, a significant increase from the historic 5 percent response rates. Of the 80 patients, 42.6 percent surpassed the six-month mark without their disease progressing, up from the historic 15 to 20 percent of patients. Survival was 9.2 months, a slight increase from the typical six- to seven-month survival time.

In the arm studying Avastin with CPT-11, 37.8 percent of patients responded to the treatment, while 50.3 percent surpassed the six-month progression-free survival mark. Overall survival was 8.7 months, a little less than the Avastin-only study.

Cloughesy believes the study shows the apparent power of Avastin when used alone in treating deadly brain cancers for which few effective treatments now exist.

"I think what this tells us is that the majority of the effects we're seeing are due to the Avastin," he said.

In addition, Avastin was well tolerated. While some serious side effects were noted — brain hemorrhage, strokes and heart attacks — they were seen in a very small number of patients. Avastin also appeared to reduce brain swelling, allowing patients to significantly lower the steroid dose they had to take, eliminating a number of debilitating side effects.

"Because their brain swelling went down and they could lower their doses of steroids, some patients saw a marked improvement in function," Cloughesy said.

About 20,000 patients will be diagnosed with glioblastoma this year; of those, 14,000 will die.

The last new systemic therapy for recurrent glioblastoma was approved in 1976. Until Avastin, all other experimental therapies tested in this type of cancer failed to meet FDA guidelines for approval.

It's vital that less toxic, more effective therapies are found to fight glioblastoma, Cloughesy said, both when it recurs and when it is first diagnosed. Studies are underway now to see if the study results can be validated in patients with newly diagnosed glioblastomas.

A significant study finding was that Avastin was nearly as effective alone as it was when given with chemotherapy, but was much better tolerated. In consultation with his or her doctor, a patient facing less than a year to live might opt for Avastin alone to promote better quality of life and avoid the toxic side effects of chemotherapy.

Avastin is an angiogenesis inhibitor, meaning it cuts off the independent blood supply a tumor develops to feed and oxygenate itself. A molecularly targeted therapy, Avastin neutralizes vascular endothelial growth factor (VEGF), a chemical signal that stimulates the growth of new blood vessels, or angiogenesis.

In addition to recurrent glioblastoma, Avastin has been approved for use in metastatic colorectal, breast and kidney cancers, as well as non-small-cell lung cancer.

In addition to UCLA's Jonsson Cancer Center, other institutions participating in the study included the University of California, San Francisco; M.D. Anderson Cancer Center; Dana-Farber Cancer Institute; Memorial Sloan-Kettering; Duke University; Henry Ford Hospital; the University of Virginia; the University of Chicago; Evanston Northwestern Healthcare; and the University of Utah Hospital.

The study was funded by Genentech, which manufacturers Avastin.

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 2009, 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 10 consecutive years.


Release link :

http://newsroom.ucla.edu/portal/ucla/avastin-dramatically-improves-101031.aspx

UCLA School of Dentistry to build new cancer research facility : NIH awards $5M for Yip Center for Oral/Head & Neck Oncology Research

The UCLA School of Dentistry consistently ranks among the country's top dental schools in National Institutes of Health funding. During the past three fiscal years, the school has secured nearly $30 million in grants for oral cancer research and research training. Now, the dental school has received a major infusion of construction funding for the creation of the UCLA Yip Center for Oral/Head & Neck Oncology Research.

As a result of funds made available by the American Recovery and Reinvestment Act of 2009, the NIH's National Center for Research Resources (NCRR) has awarded more than $5 million for the state-of-the-art complex, which will consolidate and expand the school's ongoing translational research in the biology, detection and treatment of oral cancer.

According to the National Institute of Dental and Craniofacial Research, oral cancer is the sixth most common cancer in men and the 14th most common cancer in women in the United States. On average, only half of those diagnosed with the disease will survive more than five years. Oral cancer will kill approximately one person every hour this year.

"This visionary funding will enable the dental school to become a nexus of multidisciplinary, collaborative research," said No-Hee Park, dean of the UCLA School of Dentistry and the principal investigator for the construction grant. "Our goal is to make UCLA the home of the premier head and neck and oral oncology research program in the nation, a place where we find new methods for the early diagnosis and treatment of this devastating disease."

Existing outmoded laboratories within the dental school building in UCLA's Center for the Health Sciences will be demolished to construct a 6,660-square-foot facility comprising a large, open wet laboratory, a central core support facility and a conference room. The new lab will include chemical fume hoods, tissue-culture support and a dark room and will be specifically designed for state-of-the-art genomics and proteomics research.

"This is the second time in the UCLA School of Dentistry's history that it has applied for and won an NIH construction grant," said Steve Olsen, UCLA vice chancellor for finance, budget and capital programs. "The first such grant created the Jane and Jerry Weintraub Center for Reconstructive Biotechnology, which also was established under Dean Park's tenure."

The school's new research facility will be named for Felix and Mildred Yip, noted philanthropists within Southern California's Asian American community who have been generous supporters of UCLA and the School of Dentistry.

In 2004, a pledge of support from the Yips was instrumental in the dental school securing a fundable score for this major construction project. However, the NCRR was unable to provide the necessary matching funds to advance the renovation because of federal budget problems. This spring, one of the Obama administration's economic stimulus initiatives breathed new life into the shelved grant.

"The resurrection of our construction grant application — and now the news of this sizable award — are exciting developments at the dental school," said David Wong, the school's associate dean of research and a pioneer in the field of salivary diagnostics who developed the first standardized saliva-based test for oral cancer.

Wong holds the Felix and Mildred Yip Endowed Professorship in Dentistry and will serve as the director of the UCLA Yip Center for Oral/Head & Neck Oncology Research.

"We are energized thinking about what this research facility will mean for oral cancer research and for translational science," Wong said. "We hope the Yip Center will be the site of many discoveries that better inform our understanding of the diagnosis and treatment of many different types of disease."

"Scientists at the UCLA School of Dentistry have been operating at the vanguard of oral biology research, making significant progress in enhancing our understanding of the mechanisms of cancer growth, as well as the promise of salivary diagnostics," Felix Yip said. "My wife, Mildred, and I have a strong commitment to the Yip Center and to the dental school in their efforts to find new ways to improve oral health that can change people's lives."

Construction planning for the Yip Center has already begun. The demolition phase of the project is expected to start in 2011, with a projected conclusion date for the facility sometime in 2013.

The UCLA School of Dentistry is dedicated to improving the oral health of the people of California, the nation and the world through its teaching, research, patient care and public service initiatives. The school provides education and training programs that develop leaders in dental education, research, the profession and the community; conducts research programs that generate new knowledge, promote oral health and investigate the cause, prevention, diagnosis and treatment of oral disease; and delivers patient-centered oral health care to the community and state.

UCLA is California's largest university, with an enrollment of nearly 38,000 undergraduate and graduate students. The UCLA College of Letters and Science and the university's 11 professional schools feature renowned faculty and offer more than 323 degree programs and majors. UCLA is a national and international leader in the breadth and quality of its academic, research, health care, cultural, continuing education and athletic programs. Four alumni and five faculty have been awarded the Nobel Prize.

Release link :

http://newsroom.ucla.edu/portal/ucla/dental-school-to-build-new-cancer-101847.aspx

Researchers examine mechanisms that help cancer cells proliferate

A process that limits the number of times a cell divides works much differently than had been thought, opening the door to potential new anticancer therapies, researchers at UT Southwestern Medical Center report in the Aug. 7 issue of the journal Cell.

Most cells in the human body divide only a certain number of times, via a countdown mechanism that stops them. When the controlling process goes wrong, the cells divide indefinitely, contributing to cancer growth.

The number of times a cell divides is determined by special segments of DNA called telomeres, which are located at the ends of each chromosome. Every time a cell divides, the telomeres get shorter. When they are reduced to a certain length, the cell stops dividing.


In the new study, UT Southwestern researchers used both normal and cancerous human cells to examine closely how telomeres behave during cell division.

As a cell prepares to divide into two new cells, its ladder-shaped DNA “unzips,” creating two halves, each resembling a single upright of a ladder with a set of half-length rungs. Fresh genetic material then fills in the rungs and a second upright. This process creates two identical sets of chromosomes that will be allotted between the two cells.

From earlier studies on model organisms such as yeast, scientists thought that all telomeres replicated late in the stage of overall DNA replication, and by the same processes. The new study suggests that telomeres replicate at various times during this stage, except for a final step that is not completed until the very end, via a different, unknown mechanism.

“Interfering with replication of telomeres might provide a way to halt uncontrolled spread of cancer cells,” said Dr. Woodring Wright, professor of cell biology at
UT Southwestern and co-senior author of the paper.

The researchers also examined an enzyme called telomerase, which “rebuilds” telomeres so they do not get shorter and signals the cell to stop dividing. Normally, telomerase is only active in cells such as stem cells and dividing immune cells, which must reproduce constantly.

But telomerase also has a dark side: When active in cancer cells, it enables unlimited growth, a hallmark of cancer.

It had been thought that telomerase only works on the shortest telomeres in a cell, but in the new study, the UT Southwestern researchers found that telomerase rebuilds most or all of the telomeres in a cell for each division, not just the shortest ones, as had been thought.

“Understanding ways to inhibit this telomerase mechanism might lead to novel anticancer therapies,” said Dr. Jerry Shay, professor of cell biology and co-senior author of the paper.

Clinical trials using a drug that blocks telomerase are already under way at
UT Southwestern for lung cancer and chronic lymphocytic leukemia.

The new study was possible because the researchers developed a way to examine the very ends of telomeres after a single cell division. Previous research in the field required multiple cell divisions to detect such changes.

“Now that we can look at what telomerase is doing in a single cell-division cycle, there is potential for a tremendous number of follow-up studies,” Dr. Wright said.

Other UT Southwestern researchers involved in the study were lead author Dr.Yong Zhao, postdoctoral researcher in cell biology; Dr. Agnel Sfeir, former graduate student in integrative biology; Dr. Ying Zou, former graduate student in genetics and development; graduate student Christen Buseman; and graduate student Tracy Chow.

The research was funded by the National Institutes of Health, the American Federation for Aging Research and the Department of Defense Breast Cancer Program.

Visit www.utsouthwestern.org/cancercenter to learn more about UT Southwestern’s clinical services in cancer.



Release link :

http://www.utsouthwestern.edu/utsw/cda/dept353744/files/546195.html

Depression Increases Cancer Patients’ Risk of Dying

Depression can affect a cancer patient’s likelihood of survival. That is the finding of an analysis published in the November 15, 2009 issue of CANCER, a peer-reviewed journal of the American Cancer Society. The results highlight the need for systematic screening of psychological distress and subsequent treatments.

A number of studies have shown that individuals’ mental attitudes can impact their physical health. To determine the effects of depression on cancer patients’ disease progression and survival, graduate student Jillian Satin, MA, of the University of British Columbia in Vancouver, Canada, and her colleagues analyzed all of the studies to date they could identify related to the topic.

The researchers found 26 studies with a total of 9417 patients that examined the effects of depression on patients’ cancer progression and survival.

“We found an increased risk of death in patients who report more depressive symptoms than others and also in patients who have been diagnosed with a depressive disorder compared to patients who have not,” said Satin. In the combined studies, the death rates were up to 25 percent higher in patients experiencing depressive symptoms and 39 percent higher in patients diagnosed with major or minor depression.

The increased risks remained even after considering patients’ other clinical characteristics that might affect survival, indicating that depression may actually play a part in shortening survival. However, the authors say additional research must be conducted before any conclusions can be reached. The authors add that their analysis combined results across different tumor types, so future studies should look at the effects of depression on different kinds of cancer.

The investigators note that the actual risk of death associated with depression in cancer patients is still small, so patients should not feel that they must maintain a positive attitude to beat their disease. Nevertheless, the study indicates that it is important for physicians to regularly screen cancer patients for depression and to provide appropriate treatments.

The researchers did not find a clear association between depression and cancer progression, although only three studies were available for analysis.

Article: “Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis.” Jillian R. Satin, Wolfgang Linden, and Melanie J. Phillips. CANCER; Published Online: September 14, 2009 (DOI: 10.1002/cncr.24561); Print Issue Date: November 15, 2009.


Release link :

http://www.cancer.org/docroot/MED/content/MED_2_1x_Depression_Increases_Cancer_Patients_Risk_of_Dying.asp?sitearea=MED

Information about the Use and Accuracy of Breast Cancer Tests is Lacking, Study Finds

A new study finds that there is little information available about the use of new testing technologies and targeted therapies in breast cancer, specifically the anti-cancer drug trastuzumab (Herceptin). Published in the November 15, 2009 issue of CANCER, a peer-reviewed journal of the American Cancer Society, the review suggests that many breast cancer patients who may benefit from trastuzumab are not receiving it, and that some women receiving the drug have never been tested for the receptor it targets.

Standard care now dictates that women with early-stage breast cancer should be tested to see if they have tumors that express the HER2 protein. Those who test positive are candidates for treatment with trastuzumab, which is only effective in HER2-positive cancers.

Researchers at the UCSF Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) and led by Kathryn A. Phillips, PhD, of the University of California-San Francisco, reviewed the medical literature to determine how HER2 testing is being used in routine clinical practice. The studies they found reported that up to two-thirds of patients eligible for HER2 testing had no documentation of a test in their health insurance records. About one in five women who received trastuzumab had no documentation of a positive HER2 test in their health insurance records. The studies also revealed that about one in five HER2 test results may be incorrect.

The authors also found that studies looking at the economic issues associated with prescribing trastuzumab often did not explicitly consider the role of HER2 testing, which can have a substantial impact on the cost-effectiveness of the therapy.

Given the increasing use of targeted therapies like trastuzumab, proper testing will become more important to ensure that medications are directed only to the patients who will benefit from them.

“Our review of the literature suggests that there are important knowledge gaps regarding the real-world use of HER2 testing and trastuzumab,” said Dr. Elena Elkin, a researcher at Memorial Sloan-Kettering Cancer Center in New York and one of the study’s authors. “Filling these gaps may help optimize limited health care resources and improve care for women with breast cancer,” she added.

Article: “Clinical practice patterns and cost-effectiveness of HER2 testing strategies in breast cancer patients.” Kathryn A. Phillips, Deborah A. Marshall, Jennifer S. Haas, Elena B. Elkin, Su-Ying Liang, Michael J. Hassett, Ilia Ferrusi, Jane E. Brock, and Stephanie L Van Bebber. CANCER; Published Online: September 14, 2009 (DOI: 10.1002/cncr.24574); Print Issue Date: November 15, 2009.

Contact person :

David Sampson
Director, Medical & Scientific Communications
American Cancer Society
213 368-8523
david.sampson@cancer.org

Release link :

http://www.cancer.org/docroot/MED/content/MED_2_1x_Information_about_the_Use_and_Accuracy_of_Breast_Cancer_Tests_is_Lacking_Study_Finds.asp?sitearea=MED

Diabetes drug kills cancer stem cells in combination treatment in mice

In a one-two punch, a familiar diabetes drug reduced tumors faster and prolonged remission in mice longer than chemotherapy alone, apparently by targeting cancer stem cells, report Harvard Medical School researchers in the Sept. 14 advance online Cancer Research.

"We have found a compound selective for cancer stem cells," said senior author Kevin Struhl, the David Wesley Gaiser professor of biological chemistry and molecular pharmacology at HMS. "What's different is that ours is a first-line diabetes drug."

The findings add to a growing body of preliminary evidence in cells, mice, and people that metformin may improve breast cancer outcomes in people. In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.

The results fit within the cancer stem cell hypothesis, an intensely studied idea that a small subset of cancer cells has a special power to initiate tumors, fuel tumor growth, and promote recurrence of cancer. Cancer stem cells appear to resist conventional chemotherapies, which kill the bulk of the tumor.

"There is a big desire to find drugs specific to cancer stem cells," Struhl says. "The cancer stem cell hypothesis says you cannot cure cancer unless you also get rid of the cancer stem cells. From a purely practical point of view, this could be tested in humans. It's already used as a first-line diabetes drug."

The possible usefulness of a diabetes drug against cancer lends credence to an emerging idea that, in the vast and complex alphabet soup of molecular interactions within cells, relatively few biological pathways will turn out to be most important for many different diseases, Struhl suggested.

In experiments led by postdoctoral fellows Heather Hirsch and Dimitrios Iliopoulos, the combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture. The researchers used four genetically distinct breast cancer cell lines.

In mice, pretreatment with the diabetes drug prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors. In other mice where tumors were allowed to take hold for 10 days, the dual therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone. In the two months between the end of treatment and the end of the experiment, tumors regrew in mice treated with chemotherapy alone, but not in mice that had received both drugs. By itself, metformin was ineffective in treating tumors.

"This is an exciting study," said Jennifer Ligibel, a medical oncologist at Dana-Farber Cancer Institute and an HMS instructor in medicine, who was not involved in the study. Ligibel and colleagues at the National Cancer Institute of Canada Clinical Trials Group are developing a large-scale phase II trial to study metformin's impact on recurrence in women treated for early stage breast cancer.

"There is a lot of interest in studying metformin in breast cancer, but so far we do not have direct evidence that metformin will improve outcomes in patients," Ligibel said. "That's what this trial is for."

So far, observational studies have suggested a lower risk of cancers, including breast cancer, and better response to chemotherapy in diabetics taking metformin, she said. Basic science studies also have suggested plausible biological mechanisms. The study from the Struhl lab suggests a potential new pathway through which metformin could have an effect on breast cancer cells, she said.

In their search for compounds that selectively destroy cancer stem cells, scientists hope to improve cancer outcomes. But the story is never as simple in human cancers, said Kornelia Polyak, a breast cancer researcher at Dana-Farber Cancer Institute and HMS associate professor of medicine, who was not involved in the study

Cancer stem cells are a shifty target, Polyak said. For example, any cancer cell can acquire the properties of a cancer stem cell, and cancer stem cells can change into non-stem cancer cells, which can be just as deadly. Clinical trials in people are needed to test these ideas, Polyak said.

The Struhl paper is an offshoot of a larger project in his lab to systematically track how gene activity changes when cells transform into cancer. These changes were remarkably similar to gene dynamics in diabetes and other inflammatory conditions.

The researchers reasoned that if a common genetic pathway underlies different diseases, drugs that work against one disease might work against another. In a screen, the most effective drug inhibiting the transformation of cells into cancer was metformin, which led to the experiments in this paper.

The team was further encouraged by the low dose of metformin needed for the effect in the laboratory, compared to the amount needed for analogous molecular experiments in basic diabetes research. The relative dosage in people for treating or preventing cancer is unknown and untested.

About Harvard Medical School :

HMS has applied for a patent for a combined therapy of metformin and a lower dose of chemotherapy, which is being tested in animals. The research was funded by the National Institutes of Health and the American Cancer Society.

Written by Carol Cruzan Morton

Full citation:

Cancer Research, Sept. 14 advance online publication

"Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth Q2 and Prolong Remission"

Heather A. Hirsch(1), Dimitrios Iliopoulos(1), Philip N. Tsichlis(2), and Kevin Struhl(1)

1-Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
2-Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts

Harvard Medical School http://hms.harvard.edu has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 17 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.

Ref : http://hms.harvard.edu/hms/home.asp

First results from major European patient survey show devastating impact of living with breakthrough cancer pain

Choosing a more appropriate route of administration for fast acting pain relief could be the key to improvement.

The first results of the first European survey of cancer patients’ experience of breakthrough pain were presented today at the 6th congress of the European Federation of Chapters of the International Association for the Study of Pain (EFIC).

Previous surveys have looked at the overall management of pain in cancer patients but this is the first international study to look in detail at Breakthrough Cancer Pain (BTCP) from a patient perspective. These results for the first 200 patients from the UK, Sweden and Denmark offer valuable insight into cancer patients’ experiences with breakthrough pain management and the impact of the condition on their daily lives.

• The median number of BTCP episodes per patient per day was 3
• Each episode had a median duration of 60 minutes
• 96% of the pain episodes were described as moderate to severe
• For 90% of patients their BTCP interfered with their daily living including their ability to sleep, walk and get on with other people

“The study documents that breakthrough pain has a significant impact on cancer patients’ daily lives,” explained Dr. Andrew Davies, Department of Palliative Medicine, Royal Marsden Hospital, UK and the principal investigator of this survey. “Breakthrough pain is very different to background pain. Background pain is a continuous, chronic pain requiring around-the-clock medication. Breakthrough pain is a fast onset, short duration, intense pain that breaks through the chronic pain even when this is being controlled with medication. It is incapacitating and very distressing to the patient.”

For this kind of pain episode the ideal treatment would be fast acting with a short duration of action to most closely match the nature of BTCP episodes. Moreover, it must be easy to use to improve patient compliance. However, the results of the survey show that:

• At least 95% of patients were using orally administered drugs
• The time to first noticing a reduction in pain had a median time of 20 minutes
• In this survey the median time to peak effect of the current BTCP rescue medications was 30 minutes

“Oral opioids are still commonly used to manage BTCP despite the fact that the way these drugs work does not match the characteristics of a BTCP episode. Opioids given by other routes, for example intranasal, have significant advantages over oral opioids and the interim results from this survey suggest that these routes would be suitable for and welcomed by the majority of cancer patients with breakthrough pain” said Dr. Andrew Davies.

-----------------------------------------------------------------------------------------------

The European Survey of Breakthrough Cancer Pain is continuing to recruit patients in Germany and Ireland and will expand into Austria, Belgium, Czech Republic, Finland, France, Greece, the Netherlands, Norway, Portugal, Spain and Switzerland to provide health care professionals across Europe with patient insights on the management of breakthrough cancer pain.

------------------------------------------------------------------------------------------------

About Nycomed

Nycomed is a privately owned global pharmaceutical company with a differentiated portfolio focused on branded medicines in gastroenterology, respiratory and inflammatory diseases, pain, osteoporosis and tissue management. An extensive range of OTC products completes the portfolio. Its R&D is built to be open for partnerships as in-licensing is a cornerstone in the company’s growth strategy.

Nycomed employs 12,000 associates worldwide, and its products are available in more than 100 countries. It has strong platforms in Europe and in fast-growing markets such as Russia/CIS, and Latin America. While the US and Japan are commercialised through best-in-class partners, Nycomed will further strengthen its position in key Asian markets.

Headquartered in Zurich, Switzerland, the company generated in 2008 total sales of € 3.4 billion and an adjusted EBITDA of € 1.2 billion.

For more information please visit www.nycomed.com

For further information Media: Ulf Jonson, Senior International Brand Manager, Nycomed: +45 46 77 10 78

References
1. Davies A et al. European survey of oncology patient’s experience of breakthrough cancer pain: UK, SE and DK results. Poster presented at EFIC 2009.

About the survey

• First phase of an ongoing, multicentre observational study
• First five countries include: UK, Sweden, Denmark, Germany, Ireland
• 11 palliative care units
• 400 patients with breakthrough cancer pain
• Data collected on breakthrough cancer pain and treatment of breakthrough cancer pain
• First results are based on 200 patients from UK (80), Sweden (80) and Denmark (40)
• The study is supported by an educational grant from Nycomed.

Instanyl sets new standard in management of breakthrough cancer pain

Head-to-head study confirms superiority of the new intranasal treatment for breakthrough cancer pain over OTFC

New data presented today further demonstrate the efficacy of Instanyl in management of breakthrough cancer pain. The data which were presented at the 6th congress of the European Federation of Chapters of the International Association for the Study of Pain (EFIC) are from a multinational, crossover trial comparing Instanyl with oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in patients with cancer. The study concludes that pain relief was significantly greater for Instanyl compared to OTFC at all time points:

• 25% of episodes showed meaningful pain relief already at 5 minutes after treatment with Instanyl, as compared to 7% with OTFC. (p<0.001)>
• 51% of the Instanyl treated patients had a meaningful pain relief at 10 minutes, as compared to 24% with OTFC. (p<0.001)>

"These data confirm the superiority of the intranasal drug administration over OTFC. Rapid pain relief is essential for the management of breakthrough cancer pain and with evidence of onset of pain relief as early as 5 minutes, Instanyl offers patients a much more effective pain control than OTFC," said Professor Sebastiano Mercadante, principal investigator of the comparative study and Director of the Anesthesia and Intensive Care and Pain Relief and Palliative Care Units at La Maddalena Cancer Center, Palermo, Italy.

The study also showed that patients found Instanyl significantly easier to administer than OTFC, with 90% of patients finding Instanyl 'easy' or 'very easy' to use, compared to 40% of OTFC patients (2). Instanyl is the first intranasal treatment for breakthrough cancer pain to be licensed and the study showed that 77% of patients preferred Instanyl to OTFC (2).

"With a preference for Instanyl more than three-fold higher compared to OTFC the study confirms that with Instanyl patients now have a treatment that they feel better matches their need," said Professor Mercadante and concluded: "Instanyl represents a major step forward in the management of breakthrough cancer pain."

Up to 95% of patients with cancer pain experience breakthrough pain (3) of which two-thirds experience inadequate pain control (4). Interim results from the first European survey of breakthrough cancer pain (5) also presented for the first time in Lisbon show that on average a patient will have 3 episodes of BTCP per day, each one lasting on average 60 minutes and 96% of episodes being rated as moderate or severe. 87% of patients reported that their BTCP interfered with their daily living including their ability to sleep, walk and get on with other people.

"Breakthrough cancer pain afflicts a large proportion of cancer patients yet there is a significant under-treatment and sub-optimal treatment of these patients. Time has come for a change in management of breakthrough cancer pain and with Instanyl now approved we have an intranasal product with fast onset of pain relief, short duration which is easy to use. This will enable us to improve the care of cancer patients," commented President of EFIC, Professor Giustino Varrassi, Dept. of Anesthesiology and Pain Medicine L'Aquila University, Italy.

Instanyl is approved for the management of breakthrough cancer pain in adults already receiving maintenance opioid therapy for chronic cancer pain. This first-in class drug was granted marketing authorisation on the 20th July 2009, and will be launched across Europe from September 2009.

About Nycomed:

Nycomed is a privately owned global pharmaceutical company with a differentiated portfolio focused on branded medicines in gastroenterology, respiratory and inflammatory diseases, pain, osteoporosis and tissue management. An extensive range of OTC products completes the portfolio. Its R&D is structured around partnerships and in-licensing is a cornerstone of the company's growth strategy.

Nycomed employs 12,000 associates worldwide, and its products are available in more than 100 countries. It has strong platforms in Europe and in fast-growing markets such as Russia/CIS and Latin America. While the US and Japan are commercialised through best-in-class partners, Nycomed plans to further strengthen its own position in key Asian markets.

Headquartered in Zurich, Switzerland, the company generated total sales of €3.4 billion in 2008 and an adjusted EBITDA of €1.2 billion.

For more information visit www.nycomed.com

For further information
Media: Ulf Jonson, Senior International Brand Manager, Nycomed: +45 46 77 10 78

References
1. Mercadante S, Radbruch L, Popper L, Korsholm L, Davies A; Efficacy of intranasal fentanyl spray (INFS) versus oral transmucosal fentanyl citrate (OTFC) for breakthrough cancer pain: an open-label crossover trial. Abstract presented at EFIC 2009.
2. Mercadante S, Radbruch L, Popper L, Korsholm L, Davies A; Ease of use and preference for intranasal fentanyl spray (INFS) versus oral transmucosal fentanyl citrate (OTFC) for breakthrough cancer pain. Abstract presented at EFIC 2009.
3. Zeppetella G. Ribeiro MD. Pharmacotherapy of cancer-related episodic pain. Expert Opin. Pharmacother. 2003;4:493-502
4. Davis MP, Walsh D, Lagman R, LeGrand SB. Controversies in pharmacotherapy of pain management. Lancet Oncol. 2005;6:696-704.
5. Davies A, Zeppetella G, Sjoland K-F et al. European Survey of Breakthrough Cancer Pain. Poster presented at EFIC 2009.

About the study

• A multinational, open-label, crossover trial comparing Instanyl® and Actiq® for breakthrough cancer pain in patients receiving chronic opioid treatment.
• The trial investigated the efficacy of Instanyl compared to Actiq as well as ease of administration and patient preference.
• Primary efficacy measurement was time to onset of meaningful pain relief.
• Of 196 patients enrolled and 139 randomised, 86 patients completed the trial.

Results showed that:

• 25.3% of episodes showed meaningful pain relief (≥33% reduction in PI score) at 5 minutes after treatment with Instanyl versus 6.8% with Actiq.
• 51% of the Instanyl treated patients had a meaningful pain relief (≥33% reduction in PI score) at 10 minutes versus 23.6% with Actiq.
• 90% of patients found Instanyl was 'easy' or 'very easy' to use versus 40% for Actiq.
• 77% of patients preferred Instanyl to Actiq.
• Both treatments were well tolerated with adverse events experienced being those typical for this group of opioid drugs.

New method monitors early sign of oxidative stress in cancer

The growth of cancerous tumors is fueled, at least in part, by the buildup of free radicals—highly reactive oxygen-containing molecules.

It stands to reason, then, that cancer should respond to treatment with antioxidants, which inhibit the rogue radicals, or with pro-oxidants, which go the opposite direction, increasing "oxidative stress" on cancer cells to the point of vanquishing them.

But experiments with such treatments have had mixed results, possibly because patients differ in their "redox profiles," or oxidative stress levels. Being able to monitor a marker of oxidative stress that is associated with the activation of tumor cell growth pathways, particularly at an early stage, and then tailor treatments accordingly would allow for more targeted studies and might improve the odds of success with antioxidants and pro-oxidants, said University of Michigan chemical biologist Kate Carroll.

A new method developed by Carroll and postdoctoral research fellow Young Ho Seo makes such monitoring possible and reveals that different individuals and even different tumor types have different redox profiles. The method and the research behind it are described in a paper scheduled for online publication in the Proceedings of the National Academy of Sciences during the week of Sept. 7.

The new method detects sulfenic acid in proteins—a tipoff to early oxidative stress and to a specific protein modification associated with cell growth pathways. Sulfenic acid is produced when a particular oxidant, hydrogen peroxide, reacts with the protein building block cysteine. But because the chemical modification involved is so small and transient, it has been difficult to detect. To get around that problem, Carroll and Seo used a chemical probe that "traps" sulfenic acid and tags it for recognition by an antibody. The antibody is labeled with a fluorescent dye that glows when observed with a fluorescence microscope.

The researchers then used the method to assess sulfenic acid levels as a marker of oxidative stress in several systems, including a panel of breast cancer cell lines.

"For each line, we saw a very distinct pattern of sulfenic acid modifications," indicating different oxidative stress levels and hinting at differences in the underlying molecular events associated with tumor growth," said Carroll, assistant professor of chemistry and a research assistant professor in the Life Sciences Institute. "Whether the patterns we see will correlate with response to antioxidant treatment or other therapies that modulate oxidative stress level remains to be seen, but now we at least have a way to investigate that question."

Next, Carroll's group wants to determine which specific proteins in the cell are being modified and what roles, if any, those proteins play in the disease process. "Some of the modified proteins may not play any role, but I'm sure it will turn out that many of them do," Carroll said. "Once we find out which proteins are involved, we can target them directly rather than using global treatments like antioxidants."

The U-M Office of Technology Transfer is working on commercialization of the technology. Patent protection has been applied for, and the compounds used in this research soon will be commercially available.

The researchers received funding from the Life Sciences Institute, the Leukemia & Lymphoma Society and the American Heart Association.

Release link:

http://www.ns.umich.edu/htdocs/releases/story.php?id=7294

Toward a nanomedicine for brain cancer

In an advance toward better treatments for the most serious form of brain cancer, scientists in Illinois are reporting development of the first nanoparticles that seek out and destroy brain cancer cells without damaging nearby healthy cells. The study is scheduled for the Sept. 9 issue of ACS' Nano Letters, a monthly journal.

Elena Rozhkova and colleagues note the pressing need for new ways to treat the disease, glioblastoma multiforme (GBM), which often causes death within months of diagnosis. Recent studies show that titanium dioxide nanoparticles, a type of light-sensitive material widely used in sunscreens, cosmetics, and even wastewater treatment, can destroy some cancer cells when the chemical is exposed to ultraviolet light. However, scientists have had difficulty getting nanoparticles, each about 1/50,000th the width of a human hair, to target and enter cancer cells while avoiding healthy cells.

The scientists' solution involves chemically linked titanium dioxide nanoparticles to an antibody that recognizes and attaches to GMB cells. When they exposed cultured human GMB cells to these so-called "nanobio hybrids," the nanoparticles killed up to 80 percent of the brain cancer cells after 5 minutes of exposure to focused white light. The results suggest that these nanoparticles could become a promising part of brain cancer therapy, when used during surgery, the researchers say.

DOWNLOAD FULL TEXT ARTICLE: http://pubs.acs.org/stoken/presspac/presspac/full/10.1021/nl901610f

Potential skin cancer breakthrough tested at Scottsdale Healthcare published today in New England Journal of Medicine

Hedgehog trial results suggest antitumor activity in basal cell skin cancer

SCOTTSDALE, Ariz. (Sept. 2, 2009) – A study published today in the New England Journal of Medicine reports a potential new investigational therapy for advanced and metastatic basal cell skin cancer tested at the Virginia G. Piper Cancer Center at Scottsdale Healthcare and other sites appears to demonstrate tumor shrinkage and limited side effects in patients.

“Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma” is authored by lead investigator Daniel D. Von Hoff, MD, a world-renowned expert in developing new drugs for patients with cancer. Dr. Von Hoff is an oncologist and chief scientific officer at the Virginia G. Piper Cancer Center at Scottsdale Healthcare, physician-in-chief at Translational Genomics Research Institute (TGen) and chief scientific officer at US Oncology.

The article appears online at NEJM.org and will be included in the Sept. 17 issue of New England Journal of Medicine.

These findings are significant because there is no proven therapy for advanced basal cell carcinoma (BCC). BCC is the most common cancer in the United States with about one million new cases diagnosed each year. Arizona has one of the highest incidences of skin cancer in the world.

Typically diagnosed with a simple biopsy, the risk of BCC increases for individuals with a family history or prolonged exposure to ultraviolet (UV) rays from the sun. Most patients are cured by surgery, but if left untreated or if spread to other organs, then scarring and disfigurement, and even death may result.

In a Phase I clinical trial conducted in Arizona at the Virginia G. Piper Cancer Center at Scottsdale Healthcare, Dr. Von Hoff and colleagues at Johns Hopkins University and Karmanos Cancer Institute demonstrated that GDC-0449, a Hedgehog Pathway Inhibitor, appears to shrink tumors in locally-advanced and metastatic basal cell carcinoma (BCC) while having limited side effects including a loss of sense of taste, and a small amount of hair loss and weight loss. GDC-0449 was discovered by Genentech and was jointly validated through a series of preclinical studies performed under a collaboration agreement between Genentech and Curis, Inc. (Cambridge, MA). Genentech is a wholly-owned subsidiary of the Roche Group.

Known as the “Hedgehog” trial, results suggest a durable clinical benefit, -defined as tumor shrinkage visible on X-ray or other physical exam or improvement in symptoms without tumor growth - was observed in 18 of 33 patients evaluated.

“Until now, we did not have any treatments that can effectively slow the tumor growth in these patients with advanced skin cancer. Using the right drug for each cancer, or precision oncology as we call it, has great potential against other cancers as well,” said Dr. Von Hoff.

Abnormal activation of the Hedgehog signaling pathway appears to be an important mechanism for many different types of cancers to develop, survive or grow. This pathway can be inactivated by a chemical called cyclopamine found in the California corn lily. Initial observation and isolation of cyclopamine from the corn lily was made in 1957. Subsequently, scientists at Genentech developed an oral drug called GDC-0449 which can inhibit key components of the Hedgehog pathway.

Basal cell cancer was chosen as the first cancer to be studied, as most BCCs have abnormalities or mutations of Hedgehog pathway genes named PATCHED and SMOOTHENED.

“Success of this new therapy is another example of applying genetic information to medicine. We are constantly working to improve treatment options for patients with common and rare cancers,” said Dr. Glen J. Weiss, part of Dr. Von Hoff’s team and contributing author for this study.

Patient response to the therapy was assessed through physical examination and imaging. “Integrating genomic data with state-of-the-art clinical and imaging information to develop and apply targeted therapies has certainly taken a major step forward with the encouraging results from the Hedgehog trial," added Dr. Ron Korn, a Scottsdale Healthcare radiologist and director of Scottsdale Medical Imaging Ltd.

Cancer research at Scottsdale Healthcare is administered through its research arm, the Scottsdale Clinical Research Institute.

Dr. Von Hoff’s team sees patients in the TGen Clinical Research Services clinic in the Virginia G. Piper Cancer Center at Scottsdale Healthcare. The cancer center is located on the campus of Scottsdale Healthcare Shea Medical Center.

The trial sponsored by Genentech also included sites at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and Karmanos Cancer Institute in Detroit.

Patients seeking more information on new therapies available through the Virginia G. Piper Cancer Center at Scottsdale Healthcare can email jingold@shc.org or call 480-323-1339 (toll free 1-877-273-3713).

About the Virginia G. Piper Cancer Center at Scottsdale Healthcare

The Virginia G. Piper Cancer Center at Scottsdale Healthcare offers cancer prevention, diagnosis, treatment, research and support services in its facilities at the Scottsdale Healthcare Shea Medical Center, attracting patients from across Arizona and the U.S. Groundbreaking cancer research is conducted through its Scottsdale Clinical Research Institute and TGen Clinical Research Service. It is a primary clinical research site for the Translational Genomics Research Institute and the Stand Up To Cancer Pancreatic Cancer Research Dream Team. Scottsdale Healthcare is the not-for-profit parent organization of the Scottsdale Healthcare Shea Medical Center, Scottsdale Healthcare Osborn Medical Center and Scottsdale Healthcare Thompson Peak Hospital, Virginia G. Piper Cancer Center, Scottsdale Clinical Research Institute and Scottsdale Healthcare Foundation.

For additional information, please visit:

www.shc.org



Release link : http://www.shc.org/content.asp?rnavid=848

HPV vaccine could prevent breast cancer: Australian research

Vaccinating women against the human papillomavirus (HPV) may prevent some forms of breast cancer and save tens of thousands of lives each year, new Australian research suggests.

Using genetic probes, researchers at the University of New South Wales tested cancerous breast cells and found several strains of HPVs known to have a high risk of initiating cancer of the cervix. HPV has a causal role in 90-95 per cent of cervical cancers.

The research was conducted by a team from the UNSW School of Biotechnology and Biomolecular Sciences, led by Visiting Professor James Lawson, and is published in the British Journal of Cancer.

The team confirmed the presence of high-risk HPV in the nuclei of breast cancer epithelial cells in five (39 per cent) of 13 ductal carcinoma in situ and three (21 per cent) of 14 invasive ductal carcinoma (IDC) breast cancer specimens. Non-invasive or in situ cancers are those confined to the milk-making glands and do not spread to other parts of the breast or body. Invasive cancers such as IDC are more serious and account for 70-80 percent of all breast cancers.

"The finding that high risk HPV is present in a significant number of breast cancers indicates they may have a causal role in many breast cancers," says UNSW researcher, Dr Noel Whitaker, a co-author of the new report. "Confirming a cancer-causing role for HPV in some breast cancers establishes the possibility of preventing some breast cancers by vaccination against HPV," he says.

The idea that HPV has an involvement in breast cancer is controversial. Scientific reports from 15 countries around the world have identified the presence of high-risk types of HPV in breast tissue and breast cancer specimens.

But those studies have also showed widely varying results, with the prevalence of HPV-positive breast cancer in ranging from as low as four per cent to as high as 86 per cent, and have been clouded by difficulties in detecting the virus in breast specimens.

As well, the genetic probe technique used – polymerase chain reaction (PCR) – has been criticized for its propensity for contamination.

The technique is based on taking small genetic samples and rapidly copying them to provide a large enough sample to study.

The UNSW researchers addressed these issues by using a technique (in situ PCR) that avoids cross-contamination and that provides evidence about whether HPV genetic material is present in the nuclei of human breast cancer specimens. They validated their findings by looking for "telltale" changes linked to HPV such as enlarged nucleus surrounded by a characteristic "halo". The researchers are working on a new method that will make testing even quicker, cheaper and simpler.

Globally 1.1 million women were diagnosed with breast cancer and more than 500,000 women lost their life to the disease in 2004. Australia data reveals that 12,265 women were diagnosed with breast cancer in 2005, and 2,618 women died from breast cancer in 2006. During the past quarter century 213,658 Australian women were diagnosed with breast cancer (1982 – 2005) and 63,632 died from the disease (1981 – 2006).

Reference :

http://www.eurekalert.org/pub_releases/2009-09/uons-hvc090209.php

DIESEL EXHAUST IS LINKED TO CANCER DEVELOPMENT VIA NEW BLOOD VESSEL GROWTH

Scientists here are the first to demonstrate that the link between diesel fume exposure and cancer lies in the ability of diesel exhaust to induce the growth of new blood vessels that serve as a food supply for solid tumors.

The researchers found that in both healthy and diseased animals, more new blood vessels sprouted in mice exposed to diesel exhaust than did in mice exposed to clean, filtered air. This suggests that previous illness isn’t required to make humans susceptible to the damaging effects of the diesel exhaust.

The tiny size of inhaled diesel particles, most less than 0.1 microns in diameter, potentially enables them to penetrate the human circulatory system, organs and tissues, meaning they can do this damage just about anywhere in the body. A micron is one millionth of a meter.

Diesel exhaust exposure levels in the study were designed to mimic the exposure people might experience while living in urban areas and commuting in heavy traffic. The levels were lower than or similar to those typically experienced by workers who use diesel-powered equipment, who tend to work in mines, on bridges and tunnels, along railroads, at loading docks, on farms and in vehicle maintenance garages, according to the U.S. Department of Labor.

“The message from our study is that exposure to diesel exhaust for just a short time period of two months could give even normal tissue the potential to develop a tumor,” said Qinghua Sun, senior author of the study and an assistant professor of environmental health sciences at Ohio State University.

“We need to raise public awareness so people give more thought to how they drive and how they live so they can pursue ways to protect themselves and improve their health. And we still have a lot of work to do to improve diesel engines so they generate fewer particles and exhaust that can be released into the ambient air.”

The research appears online and is scheduled for later print publication in the journal Toxicology Letters.

The researchers experimented with mice that resembled two conditions that could be present in a human body. In one, the scientists implanted a small platform seeded with normal endothelial cells, the cells that line blood vessels, under the skin of the mice. This was designed to mimic relatively normal conditions in human bodies for cell growth.

In the other, the researchers created an environment that would follow a significant loss of blood flow to a section of a vessel, called ischemia, in the hind limbs of the mice. This generated severe hypoxia, an area with low or no oxygen, a condition that is present in certain diseases.

Both types of mice were then exposed to either whole diesel exhaust containing particles at a concentration of about 1 milligram per cubic meter, or to filtered outdoor air, for six hours per day five days a week. The rest of the time they breathed filtered air in their cages. Effects of the exposure were measured after two weeks, five weeks and eight weeks of the exposures.

Though some blood vessel growth and chemical changes could be seen in the mice after two weeks of exposure, “generally, the longer the exposure, the more effects we could see,” said Sun, also an investigator in Ohio State’s Davis Heart and Lung Research Institute. “It’s difficult to translate outcomes from an animal study directly to the human experience, but the bottom line is, the shorter the exposure to diesel exhaust, the better.”

The exposure to diesel exhaust caused a six-fold increase in new blood vessel formation in the ischemic hind limbs after eight weeks and a four-fold increase in vessel sprouting in the normal hind limbs of the mice in the same amount of time, compared to mice breathing filtered air.

The researchers also saw significantly more blood vessel growth in the implanted cells and in rings of tissue taken from the aortas of mice exposed to the exhaust compared to the control mice exposed to clean air. In fact, the researchers found that three types of blood vessel development occurred in these areas after exposure to the diesel exhaust: angiogenesis, the development of new capillaries; arteriogenesis, the maturation or re-started growth of existing vessels; and vasculogenesis, the formation of new blood vessels.

All of these processes are associated with tumor growth, but unprogrammed angiogenesis in particular can wreak havoc in the human body, Sun said.

“Whenever you talk about a solid tumor, angiogenesis is one of the fundamental mechanisms behind its development. Angiogenesis provides the means for tumor cells to grow because they have to have a blood supply. Without a blood supply, solid tumors will not grow,” he said.

“We want our bodies to generate new blood vessels only when we need them. And then stop producing them when we need them to stop.”

Though the researchers have not defined every mechanism behind these processes, they sought to explain at least a few ways in which blood vessels are able to sprout or mature after exposure to diesel exhaust.

They observed that diesel exhaust exposure activated a chemical signal, vascular endothelial growth factor, which has long been associated with new blood vessel development. The exposure also increased levels of a protein, hypoxia-inducible factor 1, that is essential to blood vessel development when oxygen levels are low. At the same time, the presence of the exhaust lowered the activity of an enzyme that has a role in producing substances that can suppress tumor growth.

The scientists also tracked low-grade inflammation in tissues exposed to the exhaust, which is often associated with tumor development.

Though the tiny size of diesel exhaust particles may contribute to their ability to penetrate all areas of the body, Sun noted that their complex chemical composition, and the way in which those chemicals are released once particles enter the body, also influence how they react with human cells.

Gasoline exhaust particles are larger than diesel fume particles, but it’s premature to suggest that they are any less dangerous to humans, Sun said.

“The bigger particles are known to be harmful primarily for upper respiratory tract illnesses. Larger particles also can’t travel long distances – they tend to fall to the ground,” he said. “Smaller particles hover in the air for a long time and can have long-term impact on humans when inhaled.”

Sun and colleagues are now conducting a study testing whether the exhaust particles promote tumor development and metastasis.

This work is supported by Health Effects Institute awards and grants from the National Institutes of Health.

Co-authors on the study are Xiaohua Xu and Ling Zheng of Ohio State’s Division of Environmental Health Sciences; Nisharahmed Kherada, Aixia Wang and Sanjay Rajagopalan of the Davis Heart and Lung Research Institute; Xinru Hong of the Department of Obstetrics and Gynecology at Fuzhou General Hospital in Fujian Province, China; Chunli Quan, Morton Lippmann and Lung Chi Chen of the Department of Environmental Medicine at the New York University School of Medicine; and Loren Wold of the Center for Cardiovascular and Pulmonary Research at Nationwide Children’s Research Institute.

Release link :

http://researchnews.osu.edu/archive/depexposure.htm