Sunday, June 29, 2014

Virus Kills 100 Percent of TNBC Cells in Mice

From a news release from Pennsylvania State University
A virus not known to cause disease kills triple-negative breast cancer cells and killed tumors grown from these cells in mice, according to Penn State College of Medicine researchers. Understanding how the virus kills cancer may lead to new treatments for TNBC.
Adeno-associated virus type 2 (AAV2) infects humans but is not known to cause sickness. In prior studies, the researchers tested the virus on a variety of breast cancers that represent degrees of aggressiveness and on human papillomavirus-positive cervical cancer cells. The virus initiated natural cell death in cancer cells without affecting healthy cells.
"Treatment of breast cancer remains difficult because there are multiple signaling pathways that promote tumor growth and develop resistance to treatment," said Craig Meyers, Ph.D., Distinguished Professor of Microbiology and Immunology.
Signaling pathways involve molecules in a cell that control cell functions—such as cell division. For example, the first molecule in the process receives a signal to begin. It then tells another molecule to work, and so on.
"There is an urgent and ongoing need for the development of novel therapies which efficiently target triple-negative breast cancers," Meyers said.
In the current study, the researchers tested AAV2 on a cell-line representative of triple-negative breast cancer. The researchers report their results in Cancer Biology & Therapy.
The AAV2 killed 100 percent of the cells in the laboratory by activating proteins called caspases, which are essential for the cell's natural death. In addition, consistent with past studies, AAV2-infected cancer cells produced more Ki-67, an immunity system activating protein and c-Myc, a protein that helps both to increase cell growth and induce apoptosis. The cancer cell growth slowed by day 17 and all cells were dead by day 21. AAV2 mediated cell killing of multiple breast cancer cell lines representing both low and high grades of cancer and targeted the cancer cells independent of hormone or growth factor classification.
The researchers then injected AAV2 into human breast cancer cell line-derived tumors in mice without functioning immune systems. Mice that received AAV2 outlived the untreated mice and did not show signs of being sick, unlike the untreated mice. Tumor sizes decreased in the treated mice, areas of cell death were visible and all AAV2 treated mice survived through the study, a direct contrast to the untreated mice.
"These results are significant, since tumor necrosis, or death, in response to therapy is also used as the measure of an effective chemotherapeutic," Meyers said.

Future studies should look at the use of AAV2 body-wide in mice, which would better model what happens in humans, according to Meyers.

Friday, June 13, 2014

Breast Cancer Patients Don't Meet Exercise Guidelines

A news release from the Cancer News Room:

Physical activity after breast cancer diagnosis has been linked with prolonged survival and improved quality of life, but most participants in a large breast cancer study did not meet national physical activity guidelines after they were diagnosed. African-American women were less likely to meet the guidelines than white women. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the findings indicate that efforts to promote physical activity in breast cancer patients may need to be significantly enhanced.

The US Department of Health and Human Services, as well as the American Cancer Society, recommends adults engage in at least 150 minutes of moderate-intensity physical activity or 75 minutes of vigorous-intensity physical activity (or an equivalent combination) each week for general health benefits and for chronic disease prevention and management.

To test whether there is capacity for improvement in the physical activity levels of women with breast cancer, Brionna Hair, a doctoral candidate in epidemiology at the University of North Carolina at Chapel Hill, and her colleagues examined levels of and changes in physical activity following breast cancer diagnosis, overall and by race, in a population-based study of breast cancer patients. The study assessed pre- and post-diagnosis physical activity levels in 1,735 women aged 20 to 74 years who were diagnosed with invasive breast cancer between 2008 and 2011 in 44 counties of North Carolina.

The researchers found that only 35 percent of breast cancer survivors met current physical activity guidelines post-diagnosis. A decrease in activity approximately six months after diagnosis was reported by 59 percent of patients, with the average participant reducing activity by 15 metabolic equivalent hours—equivalent to about five hours per week of brisk walking. When compared with white women, African-American women were about 40 percent less likely to meet national physical activity guidelines post-diagnosis, although their reported weekly post-diagnosis physical activity was not significantly different from that of White women (12 vs 14 metabolic equivalent hours). Hair noted that African-American women experience higher mortality from breast cancer than other groups in the United States.

“Medical care providers should discuss the role physical activity plays in improving breast cancer outcomes with their patients, and strategies that may be successful in increasing physical activity among breast cancer patients need to be comprehensively evaluated and implemented,” Hair said.

[Pat's note:]  I could't find info in the research that tested specifically for TNBC, but much previous research has shown a reduction in risk of recurrence for women with TNBC who exercised regularly.  Likewise, African-American women who get breast cancer are more likely to get TNBC than are white women.  I cover all of this in my book, Surviving Triple-Negative Breast Cancer.

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Sunday, June 1, 2014

Cutting calories may cut risk of metastasis in TNBC

Restricting calories may improve outcomes for women with triple-negative breast cancer, according to a study published May 26th in Breast Cancer Research and Treatment.  Research showed that TNBC was less likely to metastasize in mice that were fed a restricted diet.

When mouse models of triple negative cancer were fed 30 percent less than what they ate when given free access to food, the cancer cells decreased their production of microRNAs 17 and 20 (miR 17/20). Researchers have found that this group of miRs is often increased in triple negative cancers that metastasize.

Breast cancer patients are often treated with hormonal therapy to block tumor growth, and steroids to counteract the side effects of chemotherapy. However, both treatments can cause a patient to have altered metabolism, which can lead to weight gain. In fact, women gain an average of 10 pounds in their first year of treatment. Recent studies have shown that too much weight makes standard treatments for breast cancer less effective, and those who gain weight during treatment have worse cancer outcomes. 

"That's why it's important to look at metabolism when treating women with cancer," says says senior author Nicole Simone, M.D., an associate professor in the department of Radiation Oncology at Thomas Jefferson University.

In earlier studies, Simone and colleagues had shown that calorie restriction boosted the tumor-killing effects of radiation therapy. This study examined which molecular pathways were involved in this cooperative effect.

The investigators noticed that microRNAs – a type of RNA that regulates other genes in the cell – specifically miR 17 and 20, decreased the most when mice were treated with both radiation and calorie restriction. This decrease in turn increased the production of proteins involved in maintaining the extracellular matrix. 

"A strong matrix creates a sort of cage around the tumor, making it more difficult for cancer cells to escape and spread to new sites in the body," Simone says.

Understanding the link to miR 17 also gives researchers a molecular target for diagnosing cancers that are more likely to metastasize and, potentially, for developing a new drug to treat the cancers. In theory, a drug that decreased miR 17 could have the same effect on the extracellular matrix as calorie restriction. However, targeting a single molecular pathway, such as the miR17, is unlikely to be as effective as calorie restriction, Simone says. Triple negative breast cancers tend to be quite different genetically from patient to patient. If calorie restriction is as effective in women as it is in animal models, then it would likely change the expression patterns of a large set of genes, hitting multiple targets at once without toxicity.

In order to test that this hypothesis is true in humans, Simone is enrolling patients in the CaReFOR (Calorie Restriction for Oncology Research) trial. As the first trial like it in the country, women undergoing radiation therapy for breast cancer receive nutritional counseling and are guided through their weight loss plan as they undergo their treatment for breast cancer.

From a news release from Thomas Jefferson University.

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Two genes may block TNBC; drugs already exist

Blocking two genes that contribute to breast cancer tumor formation may reduce the risk of triple negative breast cancer, according to a study now online at the Proceedings of the National Academy of Sciences.

The genes are MLF2 and RPL39, which work together to block nitric oxide signaling and affect blood vessel recruitment in tumors. 

Drugs already exist that can block nitric oxide signaling, which means targeted drug for some forms of TNBC may already exist.  Houston Methodist Cancer Center plans clinical trials “in the near future,” according to researchers and center director Jenny Chang, M.D. For FDA approval, drugs need to successfully perform through three stages of clinical trials, although tests on existing drugs could streamline the process.

Mutations in  MLF2 and RPL39 in human patients were associated with worse survival in triple negative breast cancer patients.

The researchers also looked at which configurations of small inhibitory RNA (siRNA) were most efficient at shutting down MLF2 and RPL39 in breast cancer stem cell lines. siRNA molecules interfere with the cell's ability to express genes and have proven to be effective drug tools for a wide variety of diseases, including some cancers.

In preliminary studies, the combination of siRNA and the chemotherapy drug docetaxel significantly reduced tumor volume relative to chemotherapy alone and also appeared to prolong survival. Separate analyses showed suppression with siRNA appeared to yield fewer metastases to lung tissue. 

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Saturday, May 24, 2014

Enzyme Kills TNBC And Spares Non-Cancerous Cells

Targeting a specific enzyme—O-GlcNAc transferase (OGT)— can kill triple-negative breast cancer cells but spare non-tumor cells, according to a study in the online edition of Molecular Cell.

Researchers discovered that reducing levels of OGT or blocking OGT activity selectively killed cancer cells but spared non-cancer breast cells. This reduces critical metabolites involved in energy production that feeds cancer growth and survival. 

The team showed that TNBC tumors contain higher expression of OGT and HIF-1a compared to other breast cancer subtypes. These results provide evidence that targeting OGT may provide targeted therapy for TNBC.

• Edited from a news release from Drexel University College of Medicine.

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• For more details on TNBC, check out the well-reviewed Surviving Triple-Negative Breast Cancer, which many TNBC survivors call their "bible."

Study Finds Clues to How TNBC Spreads

Researchers have identified chemical signals that triple-negative breast cancer cells use to recruit two types of normal cells needed for the cancer’s spread. The study, which was done on mice, appears in the online early May edition of the Proceedings of the National Academy of Sciences.

The research focused on a chemical signal called hypoxia-inducible factor 1 (HIF-1), which cells release to help them cope with low-oxygen conditions. Earlier, the group determined that HIF-1 helps breast tumor cells survive the low-oxygen conditions in which they often live, and spread to other parts of the body such as the lungs. "In breast cancer, it's not the original tumor that kills patients, but the metastases," says Gregg Semenza, M.D., Ph.D., a professor and director of the Vascular Biology Program in the Johns Hopkins University School of Medicine's Institute for Cell Engineering.

All of the breast cancer cells used in the study were triple-negative, which have been shown in previous research to contain more HIF-1 than other types of breast cancers.

"This study adds to the evidence that a HIF-1 inhibitor drug could be an effective addition to chemotherapy regimens, especially for triple-negative breast cancers," Semenza says. Several potential drugs of this kind are now in the early stages of development, he notes.

"Blocking one of these cell-recruiting signals in a mouse's tumor made it much less likely to metastasize or spread," Semenza says. "If a drug can be found that safely blocks the same signal in humans, it could be a very useful addition to current treatment—particularly for patients with chemotherapy-resistant tumors."

Also in a previous study, Semenza's group found that HIF-1 induced adult mesenchymal stem cells to release a signal to nearby breast cancer cells, which made them more likely to spread. The researchers suspected this communication might run both ways and that the stem cells' presence might also help the cancer to recruit the host animal's white blood cells. Breast cancers need the support of several types of host cells in order to metastasize, including mesenchymal stem cells and one type of white blood cell, Semenza notes.

Studying tumor cells grown in a dish, Semenza's team used chemicals that blocked the functions of various proteins to map a web of signals between breast cancer cells, menenchymal stem cells and white blood cells. One positive feedback loop brought mesenchymal stem cells close in to the breast cancer cells. A separate loop of signals between the stem cells and cancer cells caused the cancer cells to release a chemical "beacon" that drew in white blood cells.

The concentrations of all the signals in the web were increased by the presence of HIF-1—and ultimately, by low-oxygen conditions.
The team then used genetic engineering to reduce the levels of the cell-recruiting signals in breast cancer cells and implanted those cells into female mice. Compared with unaltered breast cancer cells, those with reduced recruiting power grew into similar-sized tumors, Semenza says, but were much less likely to spread.

From a news release from the Johns Hopkins University School of Medicine.

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Newly Diagnosed with Breast Cancer? Some Questions to Ask the Doc

Understanding your diagnosis is key to understanding your treatment.   To decide the right path for you, use the questions below as the start of your discussion.  Always ask how a treatment affects you specifically—if your doctor sounds like he is offering a cookie-cutter approach, it is time for a second opinion.  No two women are the same; no two diseases are identical. 

What clinical stage is my tumor? And what are the implications of that stage? Early stage breast cancer is typically stage 1 and 2.  Stage 3 means either a larger tumor or affected lymph nodes.  Stage 4 is metastatic breast cancer, meaning the disease has spread beyond the breast and nodes, usually to the bones, lungs, brain, or liver.

What kind of surgery do you recommend and why?  Why is that choice specifically better for me?  If your surgeon recommends a mastectomy, ask for data that show that this approach is better for you than a lumpectomy.  If, in contrast, you worry that a lumpectomy is enough, ask for data on its effects on your specific diagnosis.

Do I need chemotherapy? If so, should I have it before or after surgery?  If I have it before, and the tumor responds to the chemo, what surgery would you plan afterward?

What is my prognosis with chemo?  What is my prognosis without chemo?  How will my individual risk be reduced?  What is my individual risk of recurrence without chemo, what is my risk of recurrence with chemo?

What chemo drugs do you use and why?
Do you have literature on those drugs, their effects, and their side effects?  If he says, “We have taken care of the side effects,” as one doctor told me, challenge that statement.  They have not taken care of the side effects.

What type of radiation do you suggest? Is accelerated partial breast irradiation an option?  What is its success potential in my specific case?  Is whole breast radiation better?  If so, why?

What about reconstruction? Will I need it?   Do you recommend it?  If so should I have it done immediately or should I delay it until after treatment?

Can I talk to other women who have gone through this treatment?  Hearing from actual women is good.  This does not necessarily mean a support group—it means being able to call a smart woman who has already walked this road and talk with her about how that feels.

• This is an excerpt from Surviving Triple-Negative Breast Cancer, which includes additional details on staging and treatment, including chemotherapy, radiation, and surgery.

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Saturday, May 10, 2014

Leukemia Drug Could Be Targeted Therapy for TNBC

A drug used to treat leukemia patients shows promise in fighting triple-negative breast cancer, according to a study published in PLOS ONE.

The drug imatinib mesylate targets a protein  found in roughly half of the TNBC tumor samples tested and stops the growth process.

“The next step is to organize a phase one clinical trial, where we would test this drug in a small number of women with this cancer subtype in addition to their regular treatment. We hope to be able to start that process shortly,” said Dr. Wael M. ElShamy, associate professor of biochemistry and researcher at the University of Mississippi Medical Center.

If the drug imatinib passes clinical trials, it would be a new targeted therapy for TNBC.  It already has Food and Drug Administration approval for use in humans so that could speed its use for TNBC.  Oncologists currently prescribe imatinib for children and adults with certain types of leukemia.

Read the full news release from the University of Mississippi Medical Center.

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