In a research article published in this week’s PLoS Medicine, Ann Killary
(from the University of Texas M. D. Anderson Cancer Center) and colleagues
describe a new gene called DEAR1 that is genetically altered by mutation
and deletion in breast tumors, and that may provide a new breast cancer
prognostic marker.

Each year, more than one million women discover that they have breast
cancer. Although breast cancer is usually diagnosed in women in their 50s
or
60s, some women develop breast cancer much earlier. Cancer in younger
women tends to be more likely to recur or spread, and young women with
breast
cancer have a lower overall survival rate than older women with cancer. It
would therefore be particularly useful to be able to identify those young
women who are specifically at the greatest risk of cancer recurrence, so
that they could be offered intensive surveillance.

In this study, the researchers used a genetic technique termed
“suppression subtractive hybridization” to identify a new gene that is
located on
Chromosome 1 in a region where loss of heterozygosity (a specific type of
genetic alteration) regularly occurs. They called the gene ductal
epithelium-associated RING Chromosome 1, or DEAR1. Further analysis of a
series of 14 samples showed that DEAR1 protein expression was reduced or
lost
in 71% of ductal carcinomas in situ (abnormalities that can develop into
breast cancer). Sequence analysis of 55 primary breast tumors obtained
from
The University of Texas M. D. Anderson Cancer tumor bank also showed that
13% contained genetic alterations in DEAR1.

In addition, Ann Killary and colleagues found that DEAR1 expression was
frequently lost in women with early-onset breast cancer and the loss of
DEAR1
expression correlated with a strong family history of breast cancer and
with a breast cancer subtype that has a poor outcome. At 5-year follow-up
of a
cohort of 123 pre-menopausal women with onset of breast cancer between the
ages of 25 and 49 years, DEAR1-positive expression correlated
significantly
with a 95% local recurrence-free survival.

Although laboratory experiments may not necessarily reflect what happens
in people, the authors say that these findings “indicate that DEAR1
expression is an independent predictor of local recurrence in early-onset
breast cancers and suggest that DEAR1-negative staining on
immunohistochemistry could be an important marker to stratify early-onset
breast cancer patients for increased vigilance in follow-up and adjuvant
therapy.”

In a related expert commentary on the new study, Senthil K. Muthuswamy
from the Ontario Cancer Institute, Toronto, Canada, who was not involved
with
the original study, says “these observations identify DEAR1 as an
excellent predictive biomarker for early onset breast cancers”.

Funding: This research was supported by grants from the Texas Advanced
Research Program, the US Department of Defense, and the US National Cancer
Institute Early Detection Research Network to AMK. STL and DSC were
supported by the US National Cancer Institution training grant (T32
CA09299), STL
by the US National Kidney Foundation, and DSC by the Ladies Auxiliary to
the Veterans of Foreign Wars. The M. D. Anderson core facilities for DNA
sequencing, peptide synthesis, nucleic acid extraction, and histopathology
are supported by a grant from the US National Cancer Institute (NCI
CA-16672). Funding agencies had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Three of the authors (Steven T. Lott, Dawn S.
Chandler and Ann McNeill Killary) are co-inventors named in the US Patent
#6,943,245 granted 9/13/2005 and US Patent #7,169,384 granted 1/30/2007 to
the University of Texas M. D. Anderson Cancer Center regarding the novel
gene DEAR1 described herein.

Citation:
“DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer.”
Lott ST, Chen N, Chandler DS, Yang Q, Wang L, et al. (2009)
PLoS Med 6(5): e1000068. doi:10.1371/journal.pmed.1000068

Source
PLoS Medicine

FDA and Congress “should protect physicians’ and patients’ right” to use FDA-approved drugs for off-label uses “and for the first time allow drugmakers to promote off-label uses that prove beneficial,” Richard Epstein, a law professor at the University of Chicago and a senior fellow at the Hoover Institution, writes in a Wall Street Journal opinion piece. He continues, “Right now these drugs provide immense lifesaving opportunities for many sick patients, particularly those threatened by cancer.”

Epstein writes, “Cancer patients are often in desperate straits” and “when existing treatments fail, patients and physicians alike can rationally conclude that they lose nothing by rolling the dice.” He continues, “Clinical trials sometimes give way to educated guesses that a drug approved for one kind of tumor might treat a second,” adding, “In many instances the result is failure.” However, “when early results from clinical trials suggest favorable results on which the FDA is unwilling to act, off-label use begins in earnest,” Epstein writes.

Epstein writes, “Any reliable information about what drugs work has the potential to save lives — but the FDA’s slow and ponderous system can’t respond in real time to new data.” He adds, “As matters now stand, no off-label use is possible for any drug that has not been certified for some particular on-label use,” which “reduces the number of drugs available on the market for off-label experimentation.”

Epstein continues, “No one thinks that unapproved cancer drugs should be freely available to patients in the over-the-counter market.” However, making drugs that pass Phase I clinical trials available for general distribution is an option. He concludes, “This may sound radical. But when lives are at stake, we should consider drastic measures” (Epstein, Wall Street Journal, 5/2).

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation.

© 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

SuperGen Inc., (NASDAQ: SUPG), a pharmaceutical company dedicated to the discovery and development of novel cancer therapies, today announced that Phase Ib data for MP-470, its multi-targeted, tyrosine kinase inhibitor and RAD51 suppressor, demonstrated an overall clinical benefit rate of 54 percent when the drug is given in combination with standard of care (SOC) anti-cancer therapies in patients with non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The data was presented at a poster session on Saturday at the European Multidisciplinary Conference in Thoracic Oncology (EMCTO) in Lugano, Switzerland.

The Phase Ib dose escalation study enrolled thirteen poor prognosis patients: nine with NSCLC and four with SCLC as of August 31, 2008. Of eleven evaluable patients, only one showed progressive disease, five showed stable disease, and five showed partial response. MP-470 did not alter the pharmacokinetics of SOC agents.

“We continue to be very encouraged by the clinical data resulting from our MP-470 trials. A 54 percent overall clinical benefit rate is a positive step forward for these poor prognosis patients for whom current therapies have limited effectiveness,” said Gavin Choy, PharmD, SuperGen’s Vice President, Clinical Operations. “These results support the pursuit of Phase II clinical trials in lung cancer once we have determined the optimal dose.”

About the Study

The primary objectives were to estimate the maximum tolerated dose (MTD) in combination with SOC regimens, as well as define safety profiles of specific MP-470 combinations. Secondary objectives included estimating the therapeutic response rate (RECIST), and defining the effect of MP-470 on the PK profile of SOC. MP-470 doses were started at 100 mg orally once per day, increasing to twice daily dosing based on the modified Fibonacci sequence. The MTDs have not been reached and no dose limiting toxicities have been identified.

A copy of the 2009 EMCTO Meeting poster presentation is available in the pipeline section of SuperGen’s website, http://www.supergen.com.

Source
SuperGen

A panel of experts and citizens convened to review recent studies on the link between DDT and human health expressed concern that the current practice of spraying the pesticide indoors to fight malaria is leading to unprecedented - and insufficiently monitored - levels of exposure to it.

Although DDT has been largely abandoned as an agricultural pesticide worldwide, its use to combat malaria was endorsed in 2006 by the World Health Organization (WHO) and by officials in the President’s Malaria Initiative, a program led by the U.S. Agency for International Development, which was launched by former President George W. Bush in 2005. According to WHO, in 2006 alone there were 247 million cases of and 880,000 deaths from malaria. Most of the deaths were of young children in Africa.

In regions where malaria is endemic, the organochlorine pesticide is now sprayed inside buildings and homes to repel and kill the mosquitoes that spread the disease. This is being done despite a paucity of data on the human health impacts of DDT exposure at such high levels in currently exposed populations, according to the experts from fields ranging from environmental health to cancer biology.

After a review of nearly 500 epidemiological studies, to be published online Monday, May 4, ahead of print in the journal Environmental Health Perspectives, the researchers developed a consensus statement calling for increased efforts to reduce exposure to DDT, to understand the health effects of exposure to DDT, and to develop alternatives to using DDT so that other methods could ultimately be relied upon for malaria control.

Examples of non-chemical measures to control malaria include the use of bed nets, draining sources of standing water or filling them up with soil, and the rapid diagnosis and treatment of malaria cases.

“We have to put our concerns in the context of people dying of malaria,” said lead author Brenda Eskenazi, UC Berkeley professor of epidemiology and of maternal and child health at the School of Public Health. “We know DDT can save lives by repelling and killing disease-spreading mosquitoes. But evidence suggests that people living in areas where DDT is used are exposed to very high levels of the pesticide. The only published studies on health effects conducted in these populations have shown profound effects on male fertility. Clearly, more research is needed on the health of populations where indoor residual spraying is occurring, but in the meantime, DDT should really be the last resort against malaria rather than the first line of defense.”

The researchers noted that the majority of studies on DDT have focused on the impact on wildlife and the environment. Of the studies published on human health, almost all have dealt with populations exposed to low, background levels of DDT. Nevertheless, some of those studies have suggested links between DDT and cancer risk, diabetes, developmental problems in fetuses and in children, and decreased fertility.

“Any studies conducted up to now on the human health effects from DDT exposure may not be relevant to the populations currently exposed to the pesticide through indoor residual spraying,” said Eskenazi, who has published research on the negative impact of DDT exposure to a child’s neurodevelopment.

Moreover, most of the studies on DDT and human health were done in developed countries where the pesticide was banned in the 1970s, the researchers said.

“DDT is now used in countries where many of the people are malnourished, extremely poor and possibly suffering from immune-compromising diseases such as AIDS, which may increase their susceptibility to chemical exposures,” said co-author Jonathan Chevrier, UC Berkeley post-doctoral researcher in epidemiology and in environmental health sciences.

DDT has been banned in the United States since 1972. To date, more than 160 countries have signed the Stockholm Convention on Persistent Organic Pollutants, an international treaty banning DDT and 11 other persistent organic pollutants, except when needed for malaria control.

In cases where DDT must be used, the Stockholm Convention requires an implementation and management plan to minimize the pesticide’s exposure to humans and its release into the environment. However, the authors noted, little oversight exists to ensure that those plans are being carried out properly.

“There are anecdotal reports of people failing to remove their clothes and cooking utensils from their homes before DDT spraying,” said Chevrier. “More training and monitoring is needed to prevent such instances.”

The consensus statement emerged from a March 2008 conference jointly organized by the Pine River Superfund Citizen Task Force, the Center for Responsible Leadership and the Public Affairs Institute of Alma College. More than 200 participants attended the conference, which was held near the site in St. Louis, Mich., where a chemical plant leached massive levels of DDT into Pine River. In 1983, the area was named a Superfund site by the U.S. Environmental Protection Agency.

Source:
Sarah Yang

University of California - Berkeley

One can have a dream, two can make that dream so real, goes a popular song. Now a Weizmann Institute study has revealed that it takes two to perform an essential form of DNA repair.

Prof. Zvi Livneh of the Weizmann Institute’s Biological Chemistry Department has been studying DNA repair for some two decades: ‘Considering that the DNA of each cell is damaged about 20,000 times a day by radiation, pollutants and harmful chemicals produced within the body, it’s obvious that without effective DNA repair, life as we know it could not exist. Most types of damage result in individual mutations - genetic ’spelling mistakes’ - that are corrected by precise, error-free repair enzymes. Sometimes, however, damage results in more than a mere spelling mistake; it can cause gaps in the DNA, which prevent the DNA molecule from being copied when the cell divides, much like an ink blot or a hole on a book page interferes with reading. So dangerous are these gaps that the cell resorts to a sloppy but efficient repair technique to avoid them: It fills in the missing DNA in an inaccurate fashion. Such repair can save the cell from dying, but it comes at a price: this error-prone mechanism, discovered at the Weizmann Institute and elsewhere about a decade ago, is a major source of mutations.’

In a recent study he conducted with graduate students Sigal Shachar and Omer Ziv, as well as researchers from the US and Germany, Livneh revealed how the error-prone repair works. The team found that such repair proceeds in two steps and requires two types of enzymes, belonging to the family of enzymes called DNA polymerases, which synthesize DNA. First, one repair enzyme, ‘the inserter,’ does its best to fit in a genetic ‘letter’ into the gap, opposite the damaged site in the DNA molecule; several enzymes can perform this initial step, which often results in the insertion of an incorrect genetic letter. Next, another enzyme, ‘the extender,’ helps to restore regular copying of DNA by attaching additional DNA letters after the damaged site; only one repair enzyme is capable of performing this vital second step. These findings were published recently in the EMBO Journal.

Understanding how this major form of DNA repair works can have significant clinical implications. Since defects in this process increase the risk of cancer, clarifying its nuts and bolts might one day make it possible to enhance it in people whose natural DNA repair is deficient. In addition, manipulating this mechanism can improve the effectiveness of cancer drugs. Cancer cells can resist chemotherapy by exploiting their natural repair mechanisms, and blocking these mechanisms may help overcome this resistance, leading to a targeted destruction of the cancerous tumor.

Prof. Zvi Livneh’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research; the estate of Lore F. Leder; and Esther Smidof, Geneva, Switzerland. Prof. Livneh is the incumbent of the Maxwell Ellis Professorial Chair in Biomedical Research.

For the scientific paper, please see: http://www.nature.com/emboj/journal/v28/n4/full/emboj2008281a.html

Source:
Yivsam Azgad

Weizmann Institute of Science

Eighty-seven percent of Black women say late-stage diagnosis is the major factor contributing to poorer outcomes for Black women with breast cancer, according to a survey released today by the Black Women’s Health Imperative (Imperative).

While death rates for most cancers have declined overall, racial and ethnic disparities in breast cancer morbidity and mortality continue to persist. Black women under age 40 have a greater incidence of invasive breast cancer than white women in the same age range. Despite a 10 percent lower incidence, Black women have a 37 percent higher breast cancer death rate than white women. Triple-negative breast cancer - an aggressive and hard to treat form of the disease - is three times more common in Black women.

Additional factors that contribute to breast cancer disparities in Black women, according to survey respondents, include a lack of access to treatment and care (75 percent) and poor quality of care (65 percent).

“The results of the survey provide a snapshot of what Black women believe are the most pressing issues for them related to breast cancer,” said Eleanor Hinton Hoytt, president and CEO of the Imperative.

A link to the online survey was sent to 2,280 Black women across the country. More than 280 responded saying that fear (70 percent) and lack of access to quality care and treatment (69 percent) are major issues affecting Black women’s survival. Ninety percent of respondents believe that breast cancer awareness and education should be a priority for the Imperative. Advocacy and social support are also important priority areas according to women who participated in the survey.

“There remains a critical unmet need for breast cancer education among Black women. The findings from the survey show that Black women recognize the vital need for additional information while noting the absence of leadership to address breast cancer disparities among Black women,” said Hinton Hoytt.

A preview of the survey findings were presented at the Imperative’s first Breast Cancer Leadership Summit held earlier this month. The groundbreaking meeting opened with remarks from Congresswoman Debbie Wasserman Schultz (D-FL), a breast cancer survivor.

“There are great disparities in survival rates based on race, ethnicity and age. I am a true believer in the mission of the Black Women’s Health Imperative,” said Representative Wasserman Schultz. “We don’t want to alarm people but we can and we must reduce the number of young women dying from breast cancer. We can do that by passing legislation to educate young women and providers of the risks.”

The survey and leadership summit are part of the Imperative’s year-long effort to understand the scope and scale of breast cancer disparities among Black women. The leadership summit, held on April 3 in Washington, D.C., brought together a cadre of experts, survivors and organizational leaders to collectively examine the knowledge base on breast cancer among Black women and identify strategies for supporting national and community leadership on breast health policies and programs.

Included among these experts were two national organizations-National Coalition of 100 Black Women and Zeta Phi Beta Sorority and three community-based groups-the Center for Black Women’s Wellness in Atlanta, GA, Boston Black Women’s Health Institute and Philadelphia Black Women’s Health Alliance-that have agreed to serve as advisors to the development of a national agenda for mobilizing Black women in support of breast cancer education, early detection, treatment and survivorship for Black women.

“This is the beginning of a national movement for Black women. Our vision is for Black women across the country to be engaged in breast health as community advocates, leaders, clinicians, researchers and survivors,” said Hinton Hoytt. “We are fortunate to have the support of some of the leading researchers, clinicians and advocates in the country.”

Source
The Black Women’s Health Imperative

It has long been known that heat is an effective weapon against tumor cells. However, it’s difficult to heat patients’ tumors without damaging nearby tissues.

Now, MIT researchers have developed tiny gold particles that can home in on tumors, and then, by absorbing energy from near-infrared light and emitting it as heat, destroy tumors with minimal side effects.

Such particles, known as gold nanorods, could diagnose as well as treat tumors, says MIT graduate student Geoffrey von Maltzahn, who developed the tumor-homing particles with Sangeeta Bhatia, professor in the Harvard-MIT Division of Health Sciences and Technology (HST) and in the Department of Electrical Engineering and Computer Science, a member of the David H. Koch Institute for Integrative Cancer Research at MIT and a Howard Hughes Medical Institute Investigator.

Von Maltzahn and Bhatia describe their gold nanorods in two papers recently published in Cancer Research and Advanced Materials. In March, von Maltzahn won the Lemelson-MIT Student Prize, in part for his work with the nanorods.

Cancer affects about seven million people worldwide, and that number is projected to grow to 15 million by 2020. Most of those patients are treated with chemotherapy and/or radiation, which are often effective but can have debilitating side effects because it’s difficult to target tumor tissue.

With chemotherapy treatment, 99 percent of drugs administered typically don’t reach the tumor, said von Maltzahn. In contrast, the gold nanorods can specifically focus heat on tumors.

“This class of particles provides the most efficient method of specifically depositing energy in tumors,” he said.

Wiping out tumors

Gold nanoparticles can absorb different frequencies of light, depending on their shape. Rod-shaped particles, such as those used by von Maltzahn and Bhatia, absorb light at near-infrared frequency; this light heats the rods but passes harmlessly through human tissue.

In a study reported in the team’s Cancer Research paper, tumors in mice that received an intravenous injection of nanorods plus near-infrared laser treatment disappeared within 15 days. Those mice survived for three months with no evidence of reoccurrence, until the end of the study, while mice that received no treatment or only the nanorods or laser, did not.

Once the nanorods are injected, they disperse uniformly throughout the bloodstream. Bhatia’s team developed a polymer coating for the particles that allows them to survive in the bloodstream longer than any other gold nanoparticles (the half-life is greater than 17 hours).

In designing the particles, the researchers took advantage of the fact that blood vessels located near tumors have tiny pores just large enough for the nanorods to enter. Nanorods accumulate in the tumors, and within three days, the liver and spleen clear any that don’t reach the tumor.

During a single exposure to a near-infrared laser, the nanorods heat up to 70 degree Celsius, hot enough to kill tumor cells. Additionally, heating them to a lower temperature weakens tumor cells enough to enhance the effectiveness of existing chemotherapy treatments, raising the possibility of using the nanorods as a supplement to those treatments.

The nanorods could also be used to kill tumor cells left behind after surgery. The nanorods can be more than 1,000 times more precise than a surgeon’s scalpel, says von Maltzahn, so they could potentially remove residual cells the surgeon can’t get.

Finding tumors

The nanorods’ homing abilities also make them a promising tool for diagnosing tumors. After the particles are injected, they can be imaged using a technique known as Raman scattering. Any tissue that lights up, other than the liver or spleen, could harbor an invasive tumor.

In the Advanced Materials paper, the researchers showed they could enhance the nanorods’ imaging abilities by adding molecules that absorb near-infrared light to their surface. Because of this surface-enhanced Raman scattering, very low concentrations of nanorods - to only a few parts per trillion in water [gf1]- can be detected.

Another advantage of the nanorods is that by coating them with different types of light-scattering molecules, they can be designed to simultaneously gather multiple types of information - not only whether there is a tumor, but whether it is at risk of invading other tissues, whether it’s a primary or secondary tumor, or where it originated.

Bhatia and von Maltzahn are looking into commercializing the technology. Before the gold nanorods can be used in humans, they must undergo clinical trials and be approved by the FDA, which von Maltzahn says will be a multi-year process.

Other authors of the Advanced Materials paper are Andrea Centrone, postdoctoral associate in chemical engineering; Renuka Ramanathan, undergraduate in biological engineering; Alan Hatton, the Ralph Landau Professor of Chemical Engineering; and Michael Sailor and Ji-Ho Park of the University of California at San Diego.

Park and Sailor are also authors of the Cancer Research paper, along with Amit Agrawal, former postdoctoral associate in HST; and Nanda Kishor Bandaru and Sarit Das of the Indian Institute of Technology Madras.

The research was funded by the National Institutes of Health, the Whitaker Foundation and the National Science Foundation. Nanopartz Inc. supplied gold nanoparticles, gold nanowires and the precursor gold nanorods used in this work.

Source:
Elizabeth Thomson

Massachusetts Institute of Technology

SEATTLE, May 5 — Italian multiple sclerosis patients treated with mitoxantrone (Novantrone) developed leukemia at up to 10 times the rate seen in previous studies, researchers reported here.