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/