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PostPosted: Tue Apr 20, 2010 10:12 am 
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A Multidisciplinary Approach to Cancer Detection and Treatment: What’s On the Horizon

Newswise — Cancer is a multifaceted disease that requires multiple approaches to diagnosis and management.

At the American Association for Cancer Research 101st Annual Meeting 2010, scientists and clinicians will present more than 6,300 abstracts dealing with innovative aspects of biology, technology and emerging therapies.

On Sunday, April 18, 2010, at 3:30 p.m. ET, Laura J. van 't Veer, Ph.D., visiting associate professor in the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, School of Medicine, will host a press conference on selected abstracts that will be presented at the Annual Meeting.

The press conference will take place in room 142 of the Walter E. Washington Convention Center. Reporters who cannot attend in person can participate by using the following information:

U.S. and Canada: (888) 282-7404
International: (706) 679-5207
Access Code: 59333765

The following abstracts will be included:

LB-319. A novel cancer-testis antigen, BORIS-based vaccine delivered by dendritic cells is effective against metastatic disease

The therapeutic potency of Brother of the Regulator of Imprinted Sites (BORIS) against breast cancer suggests efficacy as a target antigen for a cancer vaccine, according to study results presented here.

A member of the cancer testis-antigen gene family, BORIS is an epigenetically-acting tumor-promoting transcription factor that is normally expressed in male germ cells, but can be activated in various malignancies, including breast cancer.

“BORIS is capable of inducing strong and effective antitumor immunity, but the efficacy of this immunotherapeutic strategy could be even better if one could eliminate immune suppressor cells, such as myeloid dervived suppressor cells and T regulatory cells,” said lead researcher Michael G. Agadjanyan, Ph.D., D.Sc., head of the department of immunology and professor at the Institute for Molecular Medicine, and adjunct professor at the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine.

Ample data indicate that the immune system could significantly inhibit cancer development and growth, leading to anticancer immunotherapy strategies in clinical settings. However, data also suggest that, to be effective, an antitumor vaccine should generate strong cellular immune responses to the target tumor-associated antigens.

Recent success in understanding the molecular biology of cancer provides new targets for immunotherapy of tumors, so called cancer-testis antigens.

Using a breast cancer mouse model, the researchers tested the immunotherapeutic potency of a mutated BORIS (mBORIS) vaccine delivered by dendritic cells. Dendritic cells are immune cells; they function as antigen-presenting cells that can bring target antigen to naïve T cells and induce cancer-specific cellular immunity.

“Recombinant mBORIS antigen delivered by dendritic cells into the body elicited strong antitumor cellular immune responses in tumor-free mice,” said Agadjanyan. “More importantly, therapeutic vaccination dramatically inhibited both tumor growth and the number of metastases in the lungs of tumor-bearing mice.”

Results showed that 18.75 percent of the mice remained tumor-free, while 50 percent remained metastases-free. Additionally, higher numbers of CD4- and CD8-positive T cells, which are responsible for antitumor immunity, infiltrated into the tumors of the vaccinated mice.

Levels of myeloid-derived suppressor cells and T regulatory cells detected in spleens isolated from vaccinated and control mice were similar, suggesting no change as a result of the vaccine. Importantly, these tumor-activated suppressor cells vigorously inhibited activation of CD4- and CD8-positive T cells.

“Although our data are encouraging, it is clear that even a vaccine based on a strong cancer-testis antigen, BORIS, does not completely inhibit tumor growth or eliminate metastatic disease in this model, which closely resembles human breast cancer,” said Agadjanyan. “With increasing understanding of the interactions between the host immune system and tumors, traditional vaccines are inadequate for eliciting effective antitumor immune responses. Novel, multipronged approaches will be required. The BORIS-based vaccine or any other strong target antigen should be combined with strategies to limit the degree of tumor-associated immune suppression.”

3716. Targeted therapy of high-grade gliomas using TGF-beta2 inhibitor trabedersen (AP 12009): Results of the Phase IIb study as basis for the Phase III SAPPHIRE Study

Results of a Phase IIb study showed a clear clinical benefit from trabedersen, a TGF-beta inhibitor, in patients with high-grade glioma; the Phase III study SAPPHIRE (NCT00761280) is currently enrolling.

“Current therapies for this patient population include surgery, radiation and chemotherapy with temozolomide,” said Piotr Jachimczak, M.D., senior scientific advisor at Antisense Pharma. “Trabedersen performed better than these therapy standards on all levels in anaplastic astrocytoma.”

Antisense Pharma is developing trabedersen, a TGF-beta-2 specific phosphorothioate antisense oligonucleotide administered intratumorally using convection-enhanced delivery. The company is funding its own research through a venture capital conglomerate.

Researchers enrolled 145 patients with recurrent or refractory high-grade glioma. These patients were randomly assigned to receive either trabedersen at 10 microM or 80 microM or standard chemotherapy.

Results showed that the lower dose of trabedersen performed most optimally in anaplastic astrocytoma. At 24 months, 83.3 percent had survived compared with 53.3 percent on the higher dose and 41.7 percent on standard chemotherapy. Duration of response was 29.1 months compared to the standard chemotherapy group of eight months and the median overall survival benefit of 10 microM trabedersen over chemotherapy was 17.4 months.

“This is clearly a novel therapeutic option for patients with this disease,” said Jachimczak.

In young patients suffering from glioblastoma (WHO Grade 4), specifically those younger than 55 years, the two-year survival rate was 44 percent, compared with 13.3 percent with standard chemotherapy.

1136. Detection and characterization of circulating tumor cells in localized and metastatic prostate cancer patients using CTC-Chip microfluidic technology

Analyzing prostate cancer using the CTC-chip, which measures the level of circulating tumor cells in blood, provides important insights into prognosis and potential rates of recurrent disease, according to data from a developing study at Massachusetts General Hospital.

Sunitha Nagrath, Ph.D., an instructor of surgery and bioengineering at Harvard Medical School and Massachusetts General Hospital, said her research team found circulating tumor cells in patients with localized cancers, low-grade cancers and in those who had undergone surgery three months prior.

“These are patient groups in whom we would normally not expect to see circulating tumor cells, so it gives us a tremendous amount of information about their risk,” said Nagrath.

Circulating tumor cells are the root cause of metastasis in a number of cancers, which occurs when the cancer spreads beyond its tumor site. The identification of these circulating tumor cells can help identify patients at risk for metastasis early on, but, unfortunately, circulating tumor cells are extremely rare — scientists estimate one per one billion normal cells — and identifying them is a challenge.

One method of identification that shows promise is the CTC-chip, which in May 2009 received a Stand Up To Cancer Dream Team grant for scientists to continue its development. Stand Up To Cancer, the charitable initiative supporting groundbreaking research aimed at getting new cancer treatments to patients in an accelerated timeframe, awarded five Dream Team grants to investigators conducting promising research in a variety of areas. The American Association for Cancer Research is the sole scientific partner of Stand Up To Cancer.

The CTC-chip can capture approximately 200 circulating tumor cells from a teaspoon of blood taken from a cancer patient, according to researchers.

Nagrath and colleagues performed their analysis on 20 patients with early-stage prostate cancer and found circulating tumor cells in 42 percent of the patients. In patients with advanced prostate cancer, circulating tumor cells were found in 64 percent of the patients.

The research team was also able to identify circulating tumor cells nine days after surgery and also more than three months post-surgery. Nagrath and colleagues plan to continue this research and these circulating tumor cells would provide important prognostic information.

“The field is still emerging because while circulating tumor cells have been studied in patients with metastatic cancer, the idea of localized cancer is still new,” said Nagrath. “We haven’t had the right tools before; with the CTC-chip we potentially have the necessary tool.”

LB-174. Use of massively parallel, next-generation sequencing to identify gene mutations beyond KRAS that predict response to panitumumab in a randomized, Phase III, monotherapy study of metastatic colorectal cancer (mCRC)

Using next-generation sequencing technology, researchers have identified multiple gene mutations that may alter a patient’s response to panitumumab for metastatic colorectal cancer.

“One of the pressing goals is to identify predictive biomarkers for drugs such as panitumumab. This technique provides a method to simultaneously evaluate multiple genes within a tumor,” said David M. Reese, M.D., executive medical director in medical sciences and head of the oncology early development group at Amgen, Thousand Oaks, Calif.

Reese and colleagues used the Roche 454 pyrosequencing technology to investigate whether mutation of genes, beyond the KRAS gene mutation, altered colorectal cancer response to panitumumab. KRAS gene mutation is an established biomarker for a lack of response to anti-epidermal growth factor receptor antibodies. Using tumor samples from 288 patients with metastatic colon cancer, they investigated mutations in nine genes: KRAS (exon 3), BRAF, NRAS, AKT1, CTNNB1, EGFR, PIK3CA, PTEN and TP53.

On average, eight genes were evaluable per patient. More than one mutation was found in 109 tumors and 20 tumors had more than one mutation in a single gene. Two tumor samples yielded KRAS and BRAF mutations, suggesting that the presence of these mutations together is not always mutually exclusive, which has been previously reported, according to Reese.

Further, this study confirmed that simultaneously testing multiple biomarkers in one tumor sample is possible.

“The ability of this sequencing technology to assess multiple genes in parallel may permit the more rapid development of truly personalized medicine,” said Reese.

There is still much work to be done though, according to the researchers. Two large Phase III trials have been completed and the next step is to see if the predicative ability of these genetic profiles is influenced when patients undergo combination chemotherapy.

4335. Imaging of cancer stem cells with radiolabeled Hedgehog

A new imaging agent — radiolabeled hedgehog — detects cancer stem cells, potentially allowing for imaging of “stem cell-like” cancer cells by positron emission tomography (PET) in patients with breast cancer, according to results of a pilot study.

Cancer stem cells are resistant to chemotherapy and radiotherapy and can lead to tumor regrowth after treatment. Tumors that are rich in stem cell-like cancer cells are more likely to recur after treatment and to metastasize. Detecting these cells early means timely initiation of aggressive treatments to minimize relapse and improve therapeutic outcome. It may also be useful in evaluating new stem-cell targeted cancer therapies.

Jennifer Sims-Mourtada, Ph.D., director of molecular research and development at RadioMedix, Inc., Houston, Texas, and colleagues tested the ability to detect breast cancer stem cell-like populations using a protein, sonic hedgehog that was radiolabeled with the positron emitting isotope Gallium-68.

Increased activation of the hedgehog pathway is observed in cancer stem cells and aggressive tumors.

Binding of the radiolabeled hedgehog to the Patched-1 hedgehog receptor on the surface of breast cancer cells occurred, suggesting potential for molecular imaging of breast cancer by PET. A significant increase in binding was observed in cultures enriched for breast cancer stem-like cells.

“Our study is the first to show that radiolabeled hedgehog is capable of differentiating stem-like cancer cells compared to the entire tumor population,” she said. “Additionally, this agent can potentially identify aggressive tumors.”

These results are being validated in further laboratory work and microPET imaging studies are underway to assess the value of this agent for imaging tumors that are rich in cancer stem cell populations, according to Sims-Mourtada.

Download interviews with cancer researchers and recordings of the teleconferences by subscribing to the AACR Scientific Podcasts via iTunes ( or an RSS Reader (

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes 31,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowship and career development awards. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy. ... he-horizon

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PostPosted: Sat Apr 24, 2010 1:43 pm 
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Subtle Changes in PTEN Tumor Suppressor Gene Can Determine Cancer Susceptibility

ScienceDaily (Apr. 23, 2010) — It is an accepted fact that genetics play a key role in a person's susceptibility to cancer, and that throughout life, mutations can cause damage to tumor suppressor genes (TSGs) further increasing the chances of developing cancerous tumors.

Now a new study led by scientists at Beth Israel Deaconess Medical Center (BIDMC) demonstrates that even subtle changes in expression of the PTEN tumor suppressor gene can significantly increase cancer susceptibility in specific tissues, suggesting that environmental factors, such as diet or exposure to carcinogens, may have a more dramatic influence on tumor development than previously recognized. Appearing in this week's Advance On-line issue of Nature Genetics, the findings propose a new model for the role of tumor suppressor genes in the onset of cancer and could prove valuable in the development of diagnostic tests targeted to these gene alterations.

"More than 30 years ago, it was proposed that a person's susceptibility to cancer was dependent on a 'two-hit' model," explains Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Genetics Program at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. This meant that there had to be two genetic alterations of a single tumor suppressor gene (TSG) to activate tumor development - one gene would be missing from birth, while the second would be lost to other factors during one's lifetime.

"Our study adds another dimension to this Knudsonian model [so-named for its creator, cancer geneticist Alfred Knudson] demonstrating that cancer susceptibility can be driven in specific tissues by a progressive -- but slight -- continuum reduction in tumor suppressor levels," explains Pandolfi. "Consequently, subtle modulation of TSG levels can result in increased cancer susceptibility. This implies that any factor that affects PTEN levels - chemicals, diet, other carcinogens - could increase tumor susceptibility, even in the absence of a full blown genetic mutation."

Tumor suppressor genes function to slow down cell division, repair DNA and help alert damaged cells when it is time to die, and PTEN is one such example. (In addition to preventing uncontrolled cell growth, PTEN is also responsible for controlling cell movement or migration, controlling the adhesion of cells to surrounding tissues and helping to control the formation of new blood cells.) But, when TSGs are absent or malfunctioning - as is the case of a genetic mutation - cells can multiply too quickly, growing out of control and leading to the development of cancerous tumors.

In recent years, with the advent of functional genomics, the idea that subtle changes in TSG levels could influence tumor development had been proposed but not formally investigated. To test this hypothesis, the Pandolfi team created a mouse model of PTEN that expressed the gene at approximately 80 percent of total levels. Next, they used a gene targeting approach which drives a transcriptional interference of the PTEN gene, resulting in inefficient protein production. The authors report that the presence of one targeted allele resulted in approximately 80 percent of PTEN expression relative to the normal level of PTEN expressed in specific tissues - in this case, mammary gland tissue. And, as predicted, the scientists subsequently identified an increased incidence of mammary tumors in these mice, and through a careful histopathological and molecular analysis were able to demonstrate that mammary tumors maintained both the targeted and wild-type PTEN alleles intact.

"These mice showed mammary cancer at a high incidence and in the absence of further alterations to the PTEN gene," explains Pandolfi. "This confirms that the PTEN gene is a 'quasi-insufficient' tumor suppressor, such that even a subtle 20 percent decrease in gene expression is sufficient to impair its full tumor-suppressive activity."

This discovery, say the authors, is tremendously relevant for how genetic alterations in cancer are detected, studied, evaluated and treated. "From a diagnostic perspective, our findings encourage the implementation of quantitative methods to evaluate cancer gene expression levels, and the design of therapies oriented to target these alterations," they write. Adds Pandolfi, "Our immediate aim is to develop a genetic test to be used for the screening of patients at risk of developing breast cancer. Such a test might also be useful in predicting the outcome of certain treatments [i.e. Trastuzumab] for breast cancer patients." ... 113827.htm

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PostPosted: Sat Apr 24, 2010 1:45 pm 
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Novel Regulation Of The Common Tumor Suppressor PTEN

ScienceDaily (Jan. 12, 2007) — PTEN is one of the most commonly mutated tumor suppressor genes. It is an antagonist for many cellular growth, proliferation and survival processes. When mutated or deleted, it causes cancers of the prostate, breast, colon, and brain. Researchers led by scientists at Memorial Sloan-Kettering Cancer Center have now identified fundamentally novel regulatory mechanisms of PTEN function. The findings from two related studies are published in the January 12 issue of Cell.

The first is research by Dr. Xuejen Jiang's laboratory at Sloan-Kettering which identified a novel component that regulates PTEN. This protein, NEDD4-1, controls protein stability in cells. Researchers found that NEDD4-1 is a key component in eliminating PTEN from cells by adding a molecular tag, ubiquitin, to PTEN causing degradation in the cellular machinery called proteasome. In a mouse model for prostate cancer, the researchers found that areas with aggressive tumor contained low PTEN levels and high NEDD4-1. They concluded that NEDD4-1 could promote cancer development by down-regulating PTEN.

The second study by Dr. Pier Paolo Pandolfi of Memorial Sloan-Kettering and colleagues found that the ubiquitination of PTEN by NEDD4-1 also regulates another important aspect of PTEN, its cellular localization.

PTEN has been found mostly in the cytoplasm but has been known to also be in cell nuclei. While the cytoplasmic function of PTEN is now quite well understood, its nuclear functions have been elusive. Looking at a family with an inherited PTEN mutation that caused them to have the cancer-susceptibility condition, Cowden Syndrome, researchers found that the patients' colon cancer strikingly lacked nuclear PTEN.

The Pandolfi and Jiang labs showed that the PTEN mutation in these patients prevented the addition of ubiquitin by NEDD4-1, providing a molecular mechanism for the detrimental effect of the mutant PTEN protein. They showed that the single ubiquitin tagging is necessary to import PTEN into the cell nucleus where it is protected from degradation and cancer is initiated.

According to the researchers, the uncovered key role of PTEN degradation provides a new therapeutic strategy. Since ubiquitination has both positive (single tag) and negative (repetitive tagging) effects, a class of drugs, the proteasome inhibitors, that selectively blocks the degrading effects of ubiquitination, should now be studied as possible treatments for cancers with PTEN mutations. ... 121906.htm

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