Tuesday, January 31, 2012

BioNews - Cancer drugs may boost breast cancer stem cell growth

31 January 2012
Appeared in BioNews 642
Two breast cancer drugs, Avastin and Sutent, may inadvertently aid cancer growth, a study in mice suggests. The drugs, designed to reduce the blood supply to tumours, were found to encourage cancer stem cell growth, potentially fuelling the spread of the cancer. The study, published in PNAS, may explain why patients treated with Avastin are at risk of relapsing and why these drugs fail to improve overall survival rate despite initially slowing the tumour's growth.
In the study, scientists at the University of Michigan treated mice that had breast cancer with Avastin and Sutent (chemical names bevacizumab and sunitinib). The drugs stop new blood vessels forming, a process called angiogenesis, so that the supply of food and oxygen to the tumour is reduced.
The cancer stem cells in the tumours of the treated mice were mostly found in pockets of low oxygen concentration, created, paradoxically, by the reduction in oxygen delivery. Cancer stem cells fuel the spread and growth of a tumour and are difficult to eliminate with radiotherapy and chemotherapy.
However, Dr Max Wicha, who led the study, suggests that such anti-angiogenic drugs may still be important in cancer therapy if used in conjunction with other drugs. 'These agents will need to be combined with cancer stem cell inhibitors, an approach now being explored in the laboratory', he said.
Avastin is currently licensed to treat breast cancer in the UK yet not available on the NHS. The UK's National Institute for Health and Clinical Excellence advised against its use in February 2011, finding insufficient evidence that it prolongs life. The drug was approved by the US Food and Drug Administration for breast cancer in 2008, but this decision was revoked in November 2011. Sutent is not prescribed for breast cancer in the UK or the USA.
Despite the negative findings on Avastin, two studies this week have suggested that it may be useful in treatment during the early stages of breast cancer. Separate studies, performed on 1,200 and 1,900 women, and both published in the New England Journal of Medicine, looked at the use of the drug prior to surgery. They both found that Avastin significantly reduced or even eliminated the tumour, making it easier to operate on. These were initial findings - the longer-term survival rate of women given Avastin pre-operatively is as yet unknown.

Thursday, January 19, 2012

Nebraskans Can Help Fight Cancer by Sharing Daffodils « Nebraska Region

People all across Nebraska can fight back against cancer and share hope for those facing the disease by supporting the American Cancer Society Daffodil Days®. This longstanding program, which involves offering daffodils to donors every spring in appreciation for their contributions, is about more than just giving beautiful flowers; it is an opportunity to share hope for a world with less cancer and more birthdays, where cancer never steals another year from anyone’s life. For a donation of $10 everyone can support the fight against cancer. As the first flower of spring, the daffodil is the American Cancer Society’s symbol of hope for a world free of cancer.
An important part of Daffodil Days is the Gift of Hope – a bouquet of 10 daffodil stems in a vase, delivered anonymously to cancer patient within the community. The Gift of Hope helps brighten a patient’s day and fosters a relationship, ensuring the patient’s and caregiver’s knowledge that the Society is helping them get well by being in their corner around the clock to guide them through every step of their cancer experience.
A special part of this year’s Daffodil Day, Shar N. Hope, is a limited-edition Boyds® by Enesco® bear designed exclusively for the American Cancer Society Daffodil Days Bear and a Bunch™. She is available for a donation of $25 and comes with a bouquet of 10 daffodil stems.
Anyone wishing to order daffodils should call their nearest American Cancer Society office no later than February 20. For a donation of $10, supporters will receive a bouquet of fresh-cut daffodils and, more importantly, the knowledge that they are helping fight cancer. The flowers will arrive and may be picked up in mid-March.
Dollars raised through Daffodil Days provide the Society with much-needed funds to save lives by helping people stay well by preventing cancer or detecting it early; helping people get well by being there for them during and after a cancer diagnosis; by finding cures through investment in groundbreaking discovery; and by fighting back by rallying lawmakers to pass laws to defeat cancer and by rallying communities worldwide to join the fight.
For more information about Daffodil Days, or to place your order, contact your nearest American Cancer Society office:
Omaha – 402-393-5803
Lincoln – 402-423-4893
Kearney – 308-237-1631

Study finds that tumor cells can prevent cancer spread

Paradoxical discovery finds that a group of cells known as pericytes help prevent metastasis

BOSTON – A new study finds that a group of little-explored cells in the tumor microenvironment likely serve as important gatekeepers against cancer progression and metastasis. Published in the January 17 issue of Cancer Cell, these findings suggest that anti-angiogenic therapies – which shrink cancer by cutting off tumors' blood supply – may inadvertently be making tumors more aggressive and likely to spread.
One approach to treating cancer targets angiogenesis, or blood vessel growth. In this new investigation, senior author Raghu Kalluri, MD, PhD, Chief of the Division of Matrix Biology at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School (HMS), wanted to find out if targeting a specific cell type, the pericyte, could inhibit tumor growth in the same way that other antiangiogenic drugs do. Pericytes are an important part of tissue vasculature, covering blood vessels and supporting their growth.
Kalluri and his colleagues began by creating mice genetically engineered to support drug-induced depletion of pericytes in growing tumors. They then deleted pericytes in implanted mouse breast cancer tumors, decreasing pericyte numbers by 60 percent. Compared with wild-type controls, they saw a 30 percent decrease in tumor volumes over 25 days. However, contrary to conventional clinical wisdom, the investigators found that the number of secondary lung tumors in the engineered mice had increased threefold compared to the control mice, indicating that the tumors had metastasized.
"If you just looked at tumor growth, the results were good," says Kalluri. "But when you looked at the whole picture, inhibiting tumor vessels was not controlling cancer progression. The cancer was, in fact, spreading."
To understand the mechanism behind this increased metastasis, Kalluri and his team examined the tumor's microenvironment to find out what changes were taking place at the molecular level. They found a fivefold percentage increase in hypoxic areas in tumors lacking pericytes. "This suggested to us that without supportive pericytes, the vasculature inside the tumor was becoming weak and leaky—even more so than it already is inside most tumors—and this was reducing the flow of oxygen to the tumor," explains Kalluri.
"Cancer cells respond to hypoxia by launching genetic survival programs," he adds. To that end, the investigators found evidence of epithelial-to-mesenchymal transition (EMT), a change that makes the cells more mobile, so they can travel through those leaky vessels to new locations, and makes them behave more like stem cells, so they are better able to survive. Experiments that demonstrated fivefold increases in protein markers of EMT showed that the cells had undergone the change. The team also found a fivefold increase in activation of Met, a receptor molecule that promotes cell migration and growth.
Importantly, the team found that these molecular changes occurred inside the smaller, pericyte-depleted tumors that had increased incidences of secondary tumors in the lungs in the mouse models. "This suggested that smaller tumors are shedding more cancer cells into the blood and causing more metastasis," says Kalluri. "We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumor of the same type with less pericyte coverage."
Because cancer therapies such as Imatinib, Sunitinib and others have been shown to decrease pericytes in tumors, the researchers' next step was to perform the same experiments in mice with primary tumors, only this time, using Imatinib and Sunitinib rather than genetic programs to decrease pericyte numbers. And while both Imatinib and Sunitinib caused a 70 percent pericyte depletion, the end results, stayed the same: metastasis increased threefold. "We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumor of the same type with less pericyte coverage," says Kalluri, who corroborated these findings in multiple types of cancer by repeating these same experiments with implanted renal cell carcinoma and melanoma tumors.
Additional experiments showed that combining pericyte-depleting drugs with the Met-inhibiting drug helped suppress EMT and metastasis.
Finally, to determine if the findings were relevant to patients, the scientists examined 130 breast cancer tumor samples of varying cancer stages and tumor sizes and compared pericyte levels with prognosis. They found that samples with low numbers of pericytes in tumor vasculature and high levels of Met expression correlated with the most deeply invasive cancers, distant metastasis and 5- and 10- year survival rates lower than 20 percent.
"These results are quite provocative and will influence clinical programs designed to target tumor angiogenesis," says Ronald A. DePinho, president of the University of Texas MD Anderson Cancer Center. "These impressive studies will inform and refine potential therapeutic approaches for many cancers."
Meanwhile, for Kalluri, the work suggests that certain assumptions about cancer must be revisited. "We must go back and audit the tumor and find out which cells play a protective role versus which cells promote growth and aggression," says Kalluri. "Not everything is black and white. There are some cells inside a tumor that are actually good in certain contexts."
Collaborators in this study include BIDMC investigators Vesselina Cooke and Valerie LeBleu (co-first authors) Doruk Keskin, Zainab Khan, Joyce O'Connell, Yingqi Teng, Michael Duncan, Liang Xie, Genta Maeda, Sylvia Vong, and Hikaru Sugimoto. Additional investigators Rafael Rocha, Aline Damascena, and Ricardo Brentani collaborated from Hospital A. C. Camargo in the National Institute of Oncogenomics of Brazil.
This study was supported by the National Institutes of Health (NIH). Kalluri is a Champalimaud investigator funded by the Champalimaud metastasis programme. Cooke is funded by a Ruth Kirschstein Post-doctoral fellowship. LeBleu is funded by an NIH training grant in gastroenterology. Duncan is funded by an NIH training grant in cancer biology, an NIH supplemental grant to support diversity, and a United Negro College Fund-Merck Postdoctoral Science Research Fellowship. Sugimoto is funded by an NIH research training grant in cardiovascular medicine. O'Connell is funded by the Department of Defense Breast Cancer Predoctoral Traineeship Award.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

The Press Association: Some cancer drugs might aid tumours

Cancer drugs that shrink tumours by cutting off their blood supply may end up helping them to spread, a study suggests.
Drugs such as Glivec and Sutent reduce the size of tumours but could also make them more aggressive and mobile, it is claimed.
A little-studied group of cells called pericytes that provide structural support to blood vessels act as "gatekeepers" to pen in cancer, scientists have discovered.
Pericytes are wiped out by some advanced cancer drugs that prevent the growth of tumour-nourishing blood vessels, the research shows. As a result tumours find it easier to "metastasise", or spread around the body.
Tests on mice showed that both Glivec and Sutent depleted pericytes by 70% while metastasis rates tripled.
Glivec, the brand name of the drug imatinib, and Sutent (sunitinib) have both been shown in trials to increase patient survival by a significant degree.
However, the research raises the possibility that ultimately they might help cancers become more deadly. Metastasis to vital organs such as the liver or brain is the chief reason why people die from cancer.
The US scientists, whose work is reported in the journal Cancer Cell, began by removing pericytes from breast cancer tumours in genetically engineered mice.
They saw a 30% decrease in tumour volumes over 25 days, but also a three-fold increase in the number of secondary tumours growing in the animals' lungs.
Dr Joanna Owens, science information manager at Cancer Research UK, said: "This research helps us understand more about how they work in different patients, and refine clinical practice. These types of drugs are only used after extensive trials that demonstrate a clear benefit for some patients."

Effect of moisturizers on prevention of hand-foot syndrome associated with capecitabine plus oxaliplatin. - ASCO

Effect of moisturizers on prevention of hand-foot syndrome associated with capecitabine plus oxaliplatin.


Multidisciplinary Treatment
Cancers of the Colon and Rectum
2012 Gastrointestinal Cancers Symposium
Session Type and Session Title:
General Poster Session C: Cancers of the Colon and Rectum
Abstract No:
J Clin Oncol 30, 2012 (suppl 4; abstr 681)
Kazuyoshi Kawakami, Mitsukuni Suenaga, Takashi Yokokawa, Kazuo Sugita, Yutaro Mae, Eri Nakamoto, Hiroshi Imada, Nobuyuki Mizunuma, Toshiharu Yamaguchi, Toshihiro Hama; Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Japan; Department of Medical Oncology, Cancer Institute Hospital, Tokyo, Japan; Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-ku, Japan; Department of Pharmacy, Cancer Institute Hospital, Tokyo, Japan; Cancer Institute Hospital, Tokyo, Japan
Abstract Disclosures

Background: Capecitabine plus oxaliplatin (XELOX) has been established as first-line treatment for patients with metastatic colorectal cancer. Hand-foot syndrome (HFS) is the most common toxicity associated with capecitabine, and the mechanism of which remains to be clarified. Appropriate management of HFS for continuing treatment is needed to ensure improved survival. In this study, we evaluated the efficacy of our candidate moisturizers for HFS, considering its compliance in each patient at a single institute. Methods: Patients who received XELOX for metastatic colorectal cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between Apr 1 2010 and Apr 30 2011 were included in this study. Pharmacists conducted the skin care for HFS using moisturizers: heparinoid ointment, a mixture of vitamin A oil and white petrolatums (1:1). All HFS events were graded according to NCI–CTC, version 4.0. The relationship between accumulated dose of capecitabine and incidence of HFS events stratified by frequency of daily moisturizers application was analyzed by using the Kaplan-Meier method. P value of <0.05 was considered significant. Results: Moisturizers were applied two or more times a day in 45 patients (Good compliance group) and once a daily in 28 patients (Poor compliance group). In terms of incidence of grade ≥1 HFS, no significant differences were observed between good compliance group and poor compliance group (p = 0.764). Incidence of grade ≥2 HFS was observed slightly higher in the poor compliance group than in the good compliance group, though the differences were not statistically significant (p = 0.286). Conclusions: The onset of capecitabine-associated HFS is independent of frequency of using moisturizers. However, more frequent application of moisturizers appeared to have a possibility to prevent severe HFS. Assessment for compliance with the moisturizers is important as well as patient-compliance-instruction by pharmacist.

Associated Presentation(s):
1. Effect of moisturizers on prevention of hand-foot syndrome associated with capecitabine plus oxaliplatin.
Meeting: 2012 Gastrointestinal Cancers Symposium
Presenter: Kazuyoshi Kawakami
Session: General Poster Session C: Cancers of the Colon and Rectum (General Poster Session)

Other Abstracts in this Sub-Category:
1. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies.
Meeting: 2012 Gastrointestinal Cancers Symposium Abstract No: LBA385 First Author: Axel Grothey
Category: Cancers of the Colon and Rectum - Multidisciplinary Treatment
2. Phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with metastatic (MET) chemotherapy refractory K-RAS wild-type (WT) colorectal carcinoma (CRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.
Meeting: 2012 Gastrointestinal Cancers Symposium Abstract No: 386 First Author: Lillian L. Siu
Category: Cancers of the Colon and Rectum - Multidisciplinary Treatment
3. Final results from study 181: Randomized phase III study of FOLFIRI with or without panitumumab (pmab) for the treatment of second-line metastatic colorectal cancer (mCRC).
Meeting: 2012 Gastrointestinal Cancers Symposium Abstract No: 387 First Author: Alberto F. Sobrero
Category: Cancers of the Colon and Rectum - Multidisciplinary Treatment

Abstracts by Kazuyoshi Kawakami:
1. Effect of moisturizers on prevention of hand-foot syndrome associated with capecitabine plus oxaliplatin.
Meeting: 2012 Gastrointestinal Cancers Symposium Abstract No: 681 First Author: Kazuyoshi Kawakami
Category: Cancers of the Colon and Rectum - Multidisciplinary Treatment
2. Prognostic role of Thymidylate Synthase (TS) gene polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy
Meeting: 2005 ASCO Annual Meeting Abstract No: 4044 First Author: K. Kawakami
Category: Gastrointestinal (Noncolorectal) Cancer - Esophageal, Gastric, or Small Bowel
3. Loss of heterozygosity at the TS locus affects tumor response and survival in individuals heterozygous for a TS promoter polymorphism
Meeting: 2003 ASCO Annual Meeting Abstract No: 492 First Author: K. Uchida
Category: Developmental Therapeutics - Experimental Therapeutics - Pharmacogenomics

Presentations by Kazuyoshi Kawakami:
1. Effect of moisturizers on prevention of hand-foot syndrome associated with capecitabine plus oxaliplatin.
Meeting: 2012 Gastrointestinal Cancers Symposium
Presenter: Kazuyoshi Kawakami
Session: General Poster Session C: Cancers of the Colon and Rectum (General Poster Session)

Educational Book Manuscripts by Kazuyoshi Kawakami:
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Tuesday, January 17, 2012

Medical researchers unsure why thyroid cancer cases on the rise - USATODAY.com

INDIANAPOLIS – Thyroid cancer, which affects about 11 people per 100,000 each year, seems to be on the rise. It's a trend that baffles medical researchers.

National Cancer Institute statistics suggest that in recent years the number of cases of this often curable cancer has increased by about 6.5%. Over a decade, that has added up to make thyroid cancer the fastest-increasing cancer, says Tod Huntley, an otolaryngologist and head and neck surgeon with the Center for Ear, Nose, Throat and Allergy in Indianapolis.
"Ten years ago, if I saw four new thyroid cancer patients a year, it would have been a lot," says G. Irene Minor, a radiation oncologist with Indiana University Health Central Indiana Cancer Center. "Now sometimes I see that many in a month, and I have seen three in a week."
Thyroid cancer is more common in women younger than 45, Minor said. Doctors don't know why that's the case, but thyroid problems in general — such as hyper- or hypo-thyroidism — are more common in women.
The thyroid helps regulate heart rate, blood pressure, body temperature and weight. Thyroid cancer is three times more common in women than men.
Why is it more prevalent?
Experts remain divided on the cause of the increase.
Some attribute it to better screening. Many smaller tumors are picked up on ultrasounds or scans done for other reasons, says Michael Moore, a head and neck surgeon with Indiana University Simon Cancer Center.
Autopsies conducted on people who died for non-thyroid-related reasons reveal that as many as 80% of people older than 60 have a thyroid lump or malignancy that went undiagnosed, Moore says.
Some think that better screening alone can't explain the increase in thyroid cancer. A recent study showed that the increase is not just in smaller tumors, which might have to do with detection, but also in larger ones, Huntley says.
"There is definitely something going on," he says. "How much is due to increased surveillance and detection and how much is due to an actual biological change in disease prevalence, we don't know, but we know it's both."
Obesity, radiation exposure and diets low in fruits and vegetables are three potential culprits, Huntley says. People who are overweight have a 20% increase in thyroid cancer; those who are obese have a 53% increase. The more dental X-rays a person has, the higher the risk, studies show.
Often, thyroid cancer has no symptoms but is diagnosed when a person or his physician notices a lump in the neck. When symptoms do occur they can include difficulty swallowing or the sensation of a lump in the throat or voice changes.
Amber Skipper, 29, who was diagnosed with thyroid cancer, had felt something in her neck but thought it was a swollen lymph node. She had been prone to bronchitis and fatigue, but she attributed that to being a working mother with two small children.
When she learned she had cancer, she vowed to fight it. Numbers were on her side. The five-year survival rate for thyroid cancer is 97%.
In October 2010, Skipper, of Westfield, Ind., had her thyroid and many lymph nodes removed and underwent treatment with radioactive iodine. She now takes a daily replacement thyroid hormone pill.
Separated from family
Because the iodine is radioactive, Skipper had to be isolated from her family for seven days. She ached to see her two young daughters, now 4 and 2, as well as her husband, Ryan, who would leave her food outside her door.
Argentina's president, Cristina Fernandez, recently had her thyroid removed for what doctors thought was a cancerous nodule. Only after the operation did they decide the mass was not cancer.
In the year since her operation, Skipper started eating more organic foods and taking vitamins. Doctors may not be able to tell her why she got cancer, but she wants to make sure she stays healthy. She also decided to become a medical assistant to help others who are sick.
Her second iodine isolation, which lasted two days, was harder than the first. Her daughters were old enough to miss her.
At the end, she got the answer she wanted: She is cancer-free.
Says Huntley: "If you had to pick a cancer, this is what you would pick."