Identification Of Inhibitors Of Human Proteins That Promote Tumor Formation May Lead To Novel Anti-Cancer Therapeutics

Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 07 May 2013 - 1:00 PDT Current ratings for:
Identification Of Inhibitors Of Human Proteins That Promote Tumor Formation May Lead To Novel Anti-Cancer Therapeutics

Tumor repressor genes, which inhibit tumor formation, can be "turned off" due to undesirable molecular changes affecting the chromosomes on which the genes reside. Understanding and being able to control these alterations could lead to new approaches for activating or inactivating genes linked to cancer. A novel, high-throughput screening method used to identify agents that can block one chemical modifier that plays a key role in some forms of cancer is described in ASSAY and Drug Development Technologies, a peer-reviewed journal published from Mary Ann Liebert, Inc., publishers. The article is available on the ASSAY and Drug Development Technologies website.*

Jeffrey Simard, Matthew Plant, Renee Emkey, and Violeta Yu, Amgen, Inc. (Cambridge, MA) present an optimized, robust assay for screening large numbers of chemical compounds against EZH2 methyltransferase. This enzyme is part of a multi-protein complex which can alter the methylation state of chromosomal proteins. Increased EZH2 methyltransferase activity has been associated with reduced expression of tumor repressor genes.

In the article "Development and Implementation of a High-Throughput AlphaLISA Assay for Identifying Inhibitors of EZH2 Methyltransferase" the authors describe the use of AlphaLisa technology to detect methylation by EZH2 and emphasize that this approach should accelerate the identification of small molecule inhibitors for use as research tools and for development as novel anti-cancer therapeutics.

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Single-dose Radiation in Early Breast Cancer

A single dose of radiotherapy delivered at the time of surgery may be an effective alternative to external beam radiation delivered over several weeks among selected patients with early breast cancer. Findings of this international Phase III trial were published in The Lancet.

Treatment for early-stage breast cancer often involves breast conserving surgery (lumpectomy), which may be followed by radiation therapy to decrease risk of recurrence. ?Two methods of delivering radiation include:

External beam radiation: High-energy rays are delivered to the breast from a machine outside the body over several weeks. Single dose intraoperative therapy: One dose of radiation is delivered at the time of surgery.

To compare the outcomes of a single dose of targeted radiotherapy delivered at the time of surgery with those of external beam radiation delivered over several weeks, researchers evaluated the two approaches in more than 2,000 women with early breast cancer. Participants were aged 45 or older. Approximately half the patients received a single dose of radiotherapy at the time of surgery, and approximately half received external beam radiation over several weeks. All women underwent breast-conserving surgery.

At four years outcomes of both approaches were similar: There were six local recurrences in the targeted radiation group compared with five in the external beam radiation group. As well, both groups experienced similar side effects and frequency of side effects.

It appears that among some patients with early breast cancer, a single dose of radiotherapy at the time of surgery may be an effective alternative to several weeks of external beam radiation therapy. The researchers caution, however, that these findings may not apply to all patients with early breast cancer, as this study evaluated only women who were 45 or older and considered appropriate candidates for breast-conserving surgery.? In addition, the follow-up remains too short to draw definitive conclusions. It will be important to see if there is any change in the results over time.

Reference: ?Vaidya JS, Joseph DJ, Tobias, JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. The Lancet [early online publication]. June 5, 2010.

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Avancé de Cancer de la Prostate Xofigo de médicament approuvé par la FDA

Editor's Choice
Main Category: Prostate / Prostate Cancer
Also Included In: Regulatory Affairs / Drug Approvals;??Cancer / Oncology
Article Date: 17 May 2013 - 5:00 PDT Current ratings for:
Advanced Prostate Cancer Drug Xofigo Approved By FDA

Xofigo (radium Ra 223 dichloride) has been approved by the US FDA for symptomatic late-stage (metastatic) castration-resistant prostate cancer that has reached bones but not other organs, i.e. with no known visceral metastatic disease.

The Food and Drug Administration (FDA) approved Xifogo under the priority review program, three months ahead of schedule.

According to an online FDA communique published this week, Xofigo is aimed at male patients whose prostate cancer metastasized despite receiving medical or surgical interventions to reduce testosterone levels.

Testosterone, the male sex hormone, stimulates the growth and spread of prostate cancer. Prostate cancer develops in the prostate, a gland in the male reproductive system located below the bladder and in front of the rectum.

Quoting statistics from the NCI (National Cancer Institute), the FDA informs that approximately 238,590 men in the USA will be diagnosed with prostate cancer this years - 29,720 patients will have died of the disease in 2013.

Metastatic prostate cancer commonly affects bone. Approximately 90% of metastatic prostate cancer patients have evidence of bone metastases. When cancer reaches the bone, the patient is much more vulnerable to skeletal events, which are known to be the main cause of morbidity and death in men with castration-resistant prostate cancer.

The FDA was scheduled to make a decision on Xofigo by August 14th, 2013. However, approval came through early because the medications was reviewed under the FDA's priority review program, which allows for a speedier process if the medication appears to provide safe and effective treatment and no alternative therapy is available. Drugs which offer significant improvements compared to currently available options are sometimes processed through the same program.

Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research, FDA, said:

"Xofigo binds with minerals in the bone to deliver radiation directly to bone tumors, limiting the damage to the surrounding normal tissues. Xofigo is the second prostate cancer drug approved by the FDA in the past year that demonstrates an ability to extend the survival of men with metastatic prostate cancer."

In August 2012, the FDA approved Xtandi (enzalutamide) for patients with metastatic castration-resistant prostate cancer that has recurred or spread, including those who received medical or surgical therapy to reduce testosterone. Enzalutamide was approved to be taken in combination with another cancer drug, docetaxel.

When considering whether to approve Xofigo, FDA experts looked at data from one human study, the Phase III ALSYMPCA trial involving 809 patients with symptomatic castration-resistant prostate cancer that spread to bones but not other organs. Patients were randomly selected into one of two groups - the Xofigo or placebo plus best standard of care group.

The main endpoint of the study was overall survival. A pre-planned interim analysis showed that patients given Xofigo lived for an average of 14 months, compared to 11.2 months in the placebo group. Experts also looked at an exploratory updated analysis which was done later - data confirmed extended overall survival among those in the Xofigo group.

Xofigo may cause the following side effects: swelling of a foot, leg or ankle, nausea, vomiting, and diarrhea. Some patients may develop anemia (low level of red blood cells), lymphocytopenia (low level of lymphocytes), leukopenia (low level of white blood cells) and/or neutropenia (low level of infection-fighting white blood cells).

According to Bayer HealthCare, the commercial production of Xofigo is currently underway, initial doses should be on the shelves within a few weeks. Bayer has worldwide exclusive marketing rights for Xofigo. In the United Sates, Xofigo will be co-promoted by Bayer HealthCare and Algeta US, LLC.

Kemal Malik, MD, member of the Bayer HealthCare Executive Committee and Head of Global Development, said:

"Xofigo shows a favorable safety profile and has the potential to improve patient outcomes in a completely novel way. Radium 223 emits alpha particles that affect cancer cells in bone metastases and may contribute to a survival improvement. This FDA approval will provide prostate cancer patients and the physicians who care for them with a new and innovative treatment option."

North American Principal Investigator for the pivotal trial, Dr. Oliver Sartor, medical director of the Tulane Cancer Center, said "Most men with advanced prostate cancer develop bone metastases, which can be life-threatening. Xofigo has demonstrated an anti-tumor effect on bone metastases and an overall survival effect in prostate cancer, making it an important addition to the treatment of CRPC (castration-resistant prostate cancer) patients."

Xofigo's active ingredient, radium 223 dichloride (radium 223) is an alpha particle-emitting radioactive therapeutic agent which undermines the development and growth of tumors on bone metastases. According to Bayer "Radium 223 mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high linear energy transfer of alpha emitters may cause double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha particle range from radium 223 is less than 100 micrometers, which may limit damage to the surrounding normal tissue."

EMA (European Medicines Agency) has not yet approved Radium 223, neither has any other non-US regulatory body. Bayer says it has submitted a Marketing Authorization Application to EMA for Radium 2234 in December 2012 for the treatment of castration-resistant prostate cancer.

Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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Study Evaluates Predictors of DCIS Outcomes

Choice of treatment, choice of surgeon, and surgical margin (a measure of whether the cancer was completely removed) all appear to affect the risk of disease recurrence among women with ductal carcinoma in situ (DCIS) of the breast.? These findings were reported in the Journal of the National Cancer Institute.

Ductal carcinoma in situ refers to a condition in which abnormal cells are found within a breast duct but have not spread outside of the duct to other tissues in the breast. It is most commonly detected by screening mammography. If not treated, some cases of DCIS may progress to invasive breast cancer.

Treatment for DCIS tends to vary. Options include lumpectomy with or without radiation therapy or mastectomy. Data comparing outcomes of different treatment options, as well as how individual outcomes vary by surgeon, have previously been limited.

To compare outcomes of different treatments for DCIS, researchers reviewed the medical records of 994 women who had been diagnosed with DCIS between 1985 and 2000. They evaluated treatment (surgery and radiation therapy), margin status, and the role of surgeons and how these factors affect outcomes. The margin refers to the edges of the tissue that is removed surgically. If cancer cells are found at or near the margin (positive margin), it’s possible that the cancer was not completely removed.

Type of treatment had a significant impact on recurrence risk at five years. Mastectomy was associated with the lowest risk of recurrence, followed by breast-conserving surgery with radiation therapy. Women who received breast-conserving surgery without radiation therapy had the highest risk of recurrence. Margin status was also significantly associated with disease-free survival, with negative margins linked with improved disease-free survival.Disease-free survival also varied by surgeon. Choice of surgeon appeared to account for 15-30% of the variability in outcome.

These findings indicate that treatment type, margin status, and choice of surgeon are important predictors of long-term disease-free survival in DCIS. Recurrence risk is lowest for women with negative surgical margins and for women who are treated with mastectomy or the combination of breast-conserving surgery and radiation therapy.

Reference: Dick AW, Sorbero MS, Ahrendt GM, et al. Comparative effectiveness of ductal carcinoma in situ management and the roles of margins and surgeons. Journal of the National Cancer Institute [early online publication]. January 3, 2011.

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Egg genome is reprogrammed to match to the semen with or without a paternal genome

Main Category: Cancer / Oncology
Also Included In: Biology / Biochemistry;??Genetics
Article Date: May 2013 13 - 1:00 PDT Current ratings for:
Egg Genome Is Reprogrammed To Match Sperm's With Or Without A Paternal Genome

Researchers from Huntsman Cancer Institute (HCI) at the University of Utah have discovered that while the genes provided by the father arrives at fertilization pre-programmed to the state needed by the embryo, the genes provided by the mother are in a different state and must be reprogrammed to match. The findings have important implications for both developmental biology and cancer biology.

In the earliest stages, embryo cells have the potential to develop into any type of cell, a state called totipotency. Later, this potency becomes restricted through a process called differentiation. As a result, as cells continues to differentiate, they give rise to only a subset of the possible cell types.

"In cancer, normal processes of cell differentiation and growth go wrong, and cells either become arrested at an early state of differentiation, or instead go backwards and are 'reprogrammed' to become more like early embryo cells," said Bradley R. Cairns, co-author of the article and Senior Director of Basic Science at HCI. "By understanding how cells are normally programmed to the totipotent state, and how they develop from totipotent that state into specific cell types, we hope to better understand how cancer cells misregulate this process, and to use that knowledge to help us currency strategies to reverse this process." The research results were published online as the cover story in the journal Cell.

Earlier work in the Cairns Lab showed that most genes important for guiding the early development of the embryo are already present in human sperm cells of the father in a "poised" state - turned off, but with attached markers that make gene activation easy. "The logic is that all the important decision-making genes for early development are ready to go," said Cairns. "This poised state is never seen in fully differentiated cells such as skin cells."

In the current study, researchers in the Cairns Lab used high-throughput gene sequencing to dafcomprehensively and precisely analyze DNA methylation patterns in the genomes of zebrafish, which is a common laboratory model both for developmental and cancer biology. Here, they examined egg cells, sperm cells, and four phases of embryonic development: three phases between fertilization and when the embryo's genome becomes active, and one phase after that point. Methylation - in which molecules called methyl groups are selectively attached to certain areas of the DNA and turn off gene activity in those areas - is one of the main markers of gene poising. poised genes lack DNA methylation, enabling gene activity later in embryo development.

Cairns' group found that the methylation pattern of the soon-to-differentiate embryo is identical to that of the sperm cell. In contrast, the pattern of the egg cell was initially quite different, but undergoes a striking set of changes to become exactly matched to that of the sperm DNA. Cairns' work suggests that egg DNA goes through this extensive reprogramming to prepare for the process of differentiation.

"The maternal genes that underwent DNA methylation reprogramming are among the most important loci for determining embryo development," said Cairns. "For example, many hox genes, which determine the body plan and also differentiation during hematopoiesis [the formation of blood cells], are methylated in the mother's genetic contribution and demethylated in the father's, and therefore, also in the embryo."

He said the work added another interesting finding. "We found that the mother's genome takes care of that remodeling on its own, without using the father's genome as a template." Cairns' experiments showed that when the father's genetic contribution was removed, the mother's genome still remodeled itself to the correct state.

"Basically, we re trying to understand how a single cell can make a decision to be any type of cell," said Cairns. "It is a fascinating fundamental question in biology that has implications for all aspects of development and many aspects of diseases such as cancer."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. Cairns is a Howard Hughes Medical Institute investigator, a Huntsman Cancer Institute investigator and a professor in the Department of Oncological Sciences at the University of Utah. He also holds a Jon and Karen Huntsman Presidential Professorship in Cancer Research. Potok is a doctoral candidate in the Cairns Lab at HCI. Co-authors David Nix, PhD, and Timothy Parnell are also affiliated with HCI. Nix is a research assistant professor in the Department of Oncological Sciences at the University of Utah, and Parnell is a research associate in the lab of Cairns.
This work was supported by the Howard Hughes Medical Institute, the Huntsman Cancer Foundation, and NCI CA24014 (for core facilities).
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Tamoxifen and Raloxifene Both Decrease Breast Cancer Risk

?Among postmenopausal women at increased risk of breast cancer, use of either tamoxifen (NolvadexR) or raloxifene (EvistaR) can substantially reduce the risk of breast cancer. The reduction in risk was somewhat greater with tamoxifen (50% versus 38% with raloxifene), but women treated with tamoxifen were also more likely to experience certain serious side effects. These results were published in Cancer Prevention Research.

Drugs that block the effects of estrogen have been shown to reduce the risk of breast cancer in women at high risk of the disease. Two drugs that have been approved for breast cancer risk reduction in certain groups of women are tamoxifen and raloxifene. Tamoxifen is approved for breast cancer risk reduction in women who are at high risk of the disease (including high-risk premenopausal women). Raloxifene—originally approved for the prevention and treatment of osteoporosis—is approved for breast cancer risk reduction in postmenopausal women with osteoporosis or postmenopausal women at high risk of breast cancer.

To directly compare raloxifene to tamoxifen in the prevention of breast cancer in high-risk women, researchers conducted a clinical trial known to as the STAR trial (The NSABP Study of Tamoxifen and Raloxifene [STAR] P-2 Trial). The study enrolled more than 19,000 postmenopausal women at increased risk of breast cancer. Women were assigned to receive either tamoxifen or raloxifene daily for five years. Study participants have now been followed for a median of 6.8 years.

Initial results from the trial indicated that raloxifene and tamoxifen were similarly effective at reducing the risk of invasive breast cancer—both drugs reduced risk by roughly 50%. Raloxifene appeared to be somewhat less effective, however, at reducing the risk of noninvasive breast cancers such as ductal carcinoma in situ (DCIS).

More recent, longer-term results indicate that as women in the study completed five years of the drugs and stopped taking them, tamoxifen continued to reduce the risk of invasive and noninvasive breast cancer by roughly 50% compared with a roughly 38% reduction in risk with raloxifene.

Study participants who took raloxifene had fewer serious side effects than study participants who took tamoxifen, both initially and after longer-term follow-up. Side effects that were less common in women treated with raloxifene than women treated with tamoxifen included uterine cancers, blood clots, and cataracts.

The results of this study demonstrate that both tamoxifen and raloxifene reduce the risk of breast cancer in postmenopausal women at increased risk of the disease. Women at elevated risk of breast cancer as a result of family history or other characteristics may wish to talk with their doctor about the risks and benefits of using one of these drugs to reduce breast cancer risk.

Reference: Vogel VG, Costantino JP, Wickerham DL et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer. Cancer Prevention Research [early online publication]. April 19, 2010.?

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A Patient's Right To Control Genomic Health Information

Main Category: Genetics
Also Included In: Cancer / Oncology;??Alzheimer's / Dementia
Article Date: 13 May 2013 - 0:00 PDT Current ratings for:
A Patient's Right To Control Genomic Health Information

Doctors should not have the right or responsibility to force-feed their patients with genomic information about their future health risks, according to bioethicists writing in Trends in Biotechnology, a Cell Press publication. They write in response to controversial recommendations from the American College of Medical Genetics and Genomics (ACMG) on the reporting of incidental findings in clinical genome sequencing.

"A lot of people in this field would agree that no one has a right to withhold your health information from you," said Megan Allyse from the Stanford University Center for Biomedical Ethics. "But it's problematic to suggest the inverse: that the medical system should give you information you didn't ask for and don't want. No one should be able to interfere with your ability to accept or decline access. We think that's where these recommendations are problematic, because they do suggest that your physician should interfere in that decision by essentially saying, 'You have to accept this information.' And there is certainly evidence that some people do not want information about long-term health risks, especially in children."

The ACMG recommendations were prompted by the increasing use of genome sequencing in medical care. A challenge in sequencing whole genomes or exomes (protein-coding sequences only) is the sheer quantity of information that results. For instance, a patient may undergo sequencing in an effort to individualize their cancer therapy, but their genome sequence might contain information about their risk of developing Alzheimer's disease in old age. The questions are these: Should patients receive those "incidental findings" or not? And who decides?

The ACMG recommends that anyone undergoing genome sequencing for any reason should be tested for a list of clinically actionable conditions, including predispositions to various forms of cancer and to cardiomyopathy (but not to Alzheimer's disease). Furthermore, the recommendations are that physicians have a duty to then pass that information on to the patient, like it or not.

Not only would such an approach to medicine be a challenge for patient autonomy, but it would also be costly, the bioethicists say.

"It's not clear how those costs would be passed along, either to insurers or to patients themselves," Allyse said. "For the moment, from a patient perspective, the affected population is pretty small, because few people currently undergo whole-genome sequencing. But there are definitely signs that this practice is growing, especially in cancer diagnosis, and so we can envision that this issue of how to define and report incidental findings is likely to affect more and more people in the future. The issue of cost will of course affect any patient who has limited resources - along with the hospitals, insurance companies, and government programs that pay for much of the care patients receive."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject. Trends in Biotechnology, Allyse et al.: "Not-so-incidental findings: the ACMG recommendations on the reporting of incidental findings in clinical whole genome and whole exome sequencing."
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