Tuesday, February 26, 2013

Saturday, February 16, 2013

What to eat? What not to eat? Keeping your perspective

The research on copper depletion has captured a lot of readers' imaginations.  But, some worry that this might mean we have to watch out for foods that might have high copper levels.  And that, of course, goes against much of what we have heard about healthy diets overall. 

High on the list are canned foods (canned mollusks top one list), veal, beef, liver, coffee, and carbonated beverages.

I am fine giving up veal, but have to admit that I used to love it BC—before cancer.  So, that did give me pause. I have largely given up beef and seldom have canned anything.  I think there is ample evidence in other research that supports these moves.

But farther down the list of high-copper foods, we come to spirulina,  mushrooms, teas, Swiss chard and—get this—water.  


But I think what we take from this is that we should go with moderation in everything.  Make sure your diet is balanced.  Your goal is to keep your immune system strong so it can fight any disease that starts to weasel its way into your body.  A healthy plant-based approach is best.

But I would work on your focus. Look at your diet as strengthening you body overall with all the right nutrients from a variety of sources.  Don't look at it as only a way to combat one disease. Recognize that your body is unique and complex and that it needs a balance of healthy goodies.  Too much kale can make you as unbalanced as too little.  And I really have to watch myself not to overdo it on the nuts.  If 5-8 are healthy, why can't I have three handfuls?   

I personally have discovered that, while I love mushrooms, I have to limit my consumption because they cause me stomach problems.  I have a green drink every morning with mushrooms (and spirulina) in the mix, but then I only have actual mushrooms 1-2 times a week.  But that is my body telling me something—I just have to work to listen.

Here's what to ask yourself:  How do you feel? Do you have energy?  Good digestion?  Good skin?  Those are all signs that your system is balanced.  If you have a problem that you can't explain right now (chemo and radiation are not great for the skin), it might make sense to sit down with a nutritionist and chart a plan for healthy overall eating.  

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about diet and TNBC in my book, Surviving Triple-Negative Breast Cancer.

Could Sunitinib Offer Treatment Options for TNBC, Especially Claudin-Low Subtype?

A News Release from M.D. Anderson

HOUSTON - Researchers have identified a pivotal protein in a cellular transformation that makes a cancer cell more resistant to treatment and more capable of growing and spreading, making it an inviting new target for drug development.

Additionally, the international team led by scientists at The University of Texas MD Anderson Cancer Center found the cancer drug sunitinib potentially has a new role in treating triple-negative, claudin-low breast cancer.

[PAT'S NOTE:  Check out the side effects of sunitinib on the link above.  Like all chemo drugs, it is far from a walk in the park.]

"We found that FOXC2 lies at the crossroads of the cellular properties of cancer stem cells and cells that have undergone epithelial to mesenchymal transition (EMT), a process of cellular change associated with generating cancer stem cells," said senior author Sendurai Mani, Ph.D., assistant professor in MD Anderson's Department of Translational Molecular Pathology and co-director of the Metastasis Research Center.
Cancer stem cells are fewer in number than other tumor cells, yet research has tied them to cancer progression and resistance to treatment. Abnormal activation of the epithelial to mesenchymal transition can create cancer stem cells, Mani noted.

Sunitinib stifles growth of cancer stem cells
"There are multiple molecular pathways that activate EMT," Mani said. "We found many of these pathways also activate FOXC2 expression to launch this transition, making FOXC2 a potentially efficient check point to block EMT from occurring," Mani said.

Research uncovering this connection, published in the journal Cancer Research, focused on cell line and mouse model experiments. The next important step will be to assess the expression and activity of FOXC2 in human tumor samples, Mani said.

In the meantime, sunitinib, known commercially as Sutent and approved by the U.S. Food and Drug Administration for three other cancers, provides interesting, more immediate, potential.

"FOXC2 is a transcription factor, a protein that binds to DNA in the promoter region of genes to activate them. For a variety of reasons, transcription factors are hard to target with drugs," Mani said.

The team found that FOXC2 also regulates the platelet derived growth factor receptor (PDGFR-Beta). In cancer cell lines, they found that the PDGFR-Beta inhibitor sunitinib inhibited growth of cells with EMT or cancer stem cell properties that have active FOXC2.

Mice with triple-negative breast cancer treated with sunitinib had smaller primary tumors, longer survival, and fewer incidences of metastasis. There also was a steep drop in the cells' ability to form mammospheres, a hallmark of cancer stem cells.

EMT: an embryonic development process reactivated by cancer
Mani is an expert on EMT and cancer stem cells and was the first author on the original EMT study in Cell when he was with Robert Weinberg, Ph.D., at the Whitehead Institute/Massachusetts Institute of Technology.

Epithelial to mesenchymal transition is important to embryonic development, turning stationary epithelial cells into mobile mesenchymal cells to move them within the embryo. For example, a cell might be converted and then gather with other cells forming, for example, the kidney. Once there, it transitions back to an epithelial cell again and stays put.

Research has shown that carcinomas, tumors that form in the epithelium (lining) of organs are able to reactivate EMT. About 85 percent of all solid tumors are carcinomas.

The researchers focused on a recently discovered subtype of triple-negative breast cancer, so called because these cells lack receptors for three common treatments for breast cancer and thus are hard to treat. The claudin-low/basal B subtype is deficient in claudin, a membrane protein that binds epithelial cells together, and is particularly aggressive.

Building on an earlier paper that showed FOXC2 is expressed more heavily in cells after EMT is induced by a variety of factors, Mani and colleagues followed up first by using short hairpin RNA to suppress FOXC2 in breast cancer cells.

Blocking FOXC2 had no effect on cell growth, but it altered both the physical appearance of the cells, increased their ability to cluster like epithelial cells, reduced protein biomarkers of mesenchymal cells and increased levels of E-cadherin, an important epithelial cell marker.

Additional experiments showed that FOXC2 did not regulate three proteins known to separately launch EMT. They also found that breast cancer cells primed to undergo EMT became less invasive when FOXC2 was knocked down.

Impact on cancer stem cells
Knocking down FOXC2 in mammary epithelial cell lines with stem cell properties caused:

  • A reversal of expression of two cell surface cancer stem cell markers, CD44 and CD24.
  • A reduction in their ability to form mammospheres.
  • Heightened sensitivity to the chemotherapy drug paclitaxel. Chemo resistance is a hallmark of cancer stem cells.
They also found FOXC2 elevated in cancer cells with stem cell properties.
Examining cell lines in malignant human mammary epithelial cells showed:

  • Forced expression of FOXC2 alone is sufficient to induce EMT resulting in cancer stem cells.
  • Overexpression of the FOXC2 protein led to more efficient tumor formation.
  • Aggressive growth and metastasis in mice, with FOXC2-enhanced cells spreading to the lungs, liver, hind leg bone and to the brain, while unenhanced cancer cells did not spread at all.
FOXC2 boosts claudin-low breast cancer cells
FOXC2 was found overexpressed in metastatic tumors compared to primary tumors in two claudin-low human breast cancer xenografts. A second experiment showed all six claudin-low cell lines overexpressed FOXC2 compared to none of the other 7 cell lines. FOXC2 is required both for mesenchymal and invasive capacity of three claudin-low breast cancer cell lines. Blocking FOXC2 increased the cells' epithelial properties and decreased mesenchymal characteristics.

Mani and colleagues had earlier found increased expression of PDGFR-B in cells forced to undergo EMT. "We thought PDGFR-B might be a druggable target in these FOXC2-expressing cells," Mani said. They found suppressing FOXC2 reduced the ability of three cancer cell lines to migrate towards PDGF-B.
Mani said the team believes that targeting FOXC2 pathway using either PDGFR-beta inhibitors or other yet-to-be-known small-molecule inhibitors will be an effective therapeutic strategy for inhibiting EMT and consequently reducing EMT/cancer stem cell-associated metastasis, relapse and therapy resistance.
MD Anderson has filed a patent application connected to this study.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Most, but not all, TNBC tumors are basal-like

[PAT"S NOTE:  This isn't really all that new, but it does shows that researchers are fine-tuning their definitions of TNBC, which will lead to new treatment.]

CHAPEL HILL, N.C. – Triple-negative breast cancers are more biologically diverse than previously believed and classification should be expanded to reflect this heterogeneity, according to University of North Carolina researchers.

In a study published in the February issue of The Oncologist conducted by UNC and the Vall d'Hebron Institute of Oncology in Barcelona, Spain, a team lead by Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center, examined more than 1,700 breast tumors, including 412 triple negative (TN) breast cancers, and concluded that triple-negative cancers, and basal-like breast cancers should not be considered as a single type, since more than 30 percent of triple-negative cancers lack biological markers associated with basal-like tumors.

Breast cancers are sometimes classified into four main subtypes – basal-like (often called TN), luminal A, luminal B and HER2-enriched. While targeted therapies have been developed to exploit the weaknesses of some types of breast cancers, the lack of these drug markers on TN cancers means patients with these tumors must undergo broader, more aggressive therapies.

The researchers found at least four disease subtypes within TN tumors, with more than 75 percent of the tumors falling into the basal-like subtype. [PAT'S NOTE:  This contradicts the previous statement earlier in the release that says more than 30 percent are NOT basal-like.] Further research is needed to identify the distinct biomarkers shared by the expanded subtypes of TN cancers. The ultimate goal will be to target the individual biomarkers of these subtypes and create therapies that target their individual biology, according to Dr. Perou.

"Today, given that the basal-like subtype is the majority of TN patients, I believe that if we are to make therapeutic progress against TN disease, we are going to need to target the unique biology of the Basal-like subtype" said Dr. Perou.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Wednesday, February 13, 2013

Could Copper Depletion Be a Cure for Metastatic TNBC?

A News Release from Weill Cornell Medical College

NEW YORK (February 13, 2013) -- An anti-copper drug compound that disables the ability of bone marrow cells from setting up a "home" in organs to receive and nurture migrating cancer tumor cells has shown surprising benefit for metastatic triple-negative breast cancer.
Results of a new phase II clinical trial conducted by researchers at Weill Cornell Medical College and reported in the Annals of Oncology shows that patients who are copper depleted show a signficantly reduced risk of relapse.  In fact, only two of 11 study participants with a history of advanced triple-negative breast cancer relapsed within 10 months after using the anti-copper drug, tetrathiomolybdate (TM).

"These study findings are very promising and potentially a very exciting advance in our efforts to help women who are at the highest risk of recurrence," says the study's senior investigator, Dr. Linda Vahdat, director of the Breast Cancer Research Program, chief of the Solid Tumor Service and professor of medicine at Weill Cornell Medical College.

Dr. Vahdat says four of the study participants with a history of metastatic triple-negative breast cancer have remained disease free for between three and five and a half years.  
"The anti-copper compound appears to be keeping tumors that want to spread in a dormant state," reports Dr. Vahdat, who is also medical oncologist at the Iris Cantor Women's Health Center at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "We believe one of the important ways it works is by affecting the tumor microenvironment, specifically the bone marrow-derived cells that are critical for metastasis progression."

In addition, study participants with either stage 3 or stage 4 breast cancer without evidence of disease after treatment have also fared well. The progression-free survival rate among these 29 patients in the study has been 85 percent, to date.

"As good as these interim findings look to us, we cannot talk about significant benefit until we compare TM treatment to other therapies," she says. Dr. Vahdat expects to launch a phase III randomized clinical trial in the near future.

This research is a report of the first 40 patients. The clinical trial, which began in 2007, has been expanded many times and now includes 60 patients, more than half of who have triple-negative breast cancer.

Deplete Copper to Prevent Cancer Spread

New discoveries in the science of metastasis and examination of the body's utilization of copper to promote cancer spread led to this clinical trial.

Investigators at Weill Cornell, including some of this study's co-authors, have contributed to the recent understanding of the role bone marrow cells play in promoting metastasis. They previously found that a collection of bone marrow-derived cells, which include VEGFR1+ hematopoietic progenitor cells (HPCs), prepare a site in distant organs to accept cancer cells. HPCs also recruit endothelial progenitor cells (EPCs), among others, to activate an "angiogenic switch" that establish blood vessels at the site to feed newly migrated cancer cells.

Breast cancer research studies conducted at Weill Cornell have also found that immediately prior to cancer relapse, levels of EPCs and HPCs rise significantly further, suggesting that the EPC target of the copper depletion approach is one that makes sense.

"Breast tumors want to move to specific organs, and these EPCs and HPCs cells leave a 'popcorn trail' for cancer cells to follow, as well as provide the building blocks for blood vessels to greet them as they arrive," Dr. Vahdat says.

Copper is critical to mobilizing these cells. Copper is essential to the metastatic process. It is a key component of enzymes that help turn on angiogenesis in the tumor microenvironment, and it also appears to play a role in directing cancer cell migration and invasion, according to researchers.

TM is a copper chelation compound used to treat Wilson's disease, a hereditary copper metabolism disorder, and has been studied in phase I and phase II clinical trials for a number of disorders. Animal studies have demonstrated that depleting copper decreases proliferation of EPCs, as well as blood vessel formation and tumor growth.

Dr. Vahdat's study is the first human clinical trial to utilize a copper depletion strategy to modulate EPCs in breast cancer patients with an extraordinarily high risk of relapse from hidden residual disease. Most of the studies in other solid tumors with visible advanced disease have been disappointing, say researchers.

Despite improvements in breast cancer therapy, there is significant risk of relapse in a high-risk subset of patients. The risk of relapse in stage 3 patients is 50-75 percent over five years, and patients with stage 4 breast cancer always recur. Triple-negative breast cancer patients have a poorer prognosis even when diagnosed in early disease stages.

"These triple-negative patients represent a substantial proportion of metastatic breast cancer patients," says Dr. Vahdat. "These are the patients that need the most attention, which is why we have focused most of the resources of our Metastases Research Program on this problem."

In the study, researchers found that 75 percent of patients achieved the copper depletion target using TM after one month of therapy, and that copper depletion was most efficient (91 percent) in patients with triple-negative tumors, compared to other tumor types (41 percent). In copper-depleted patients only, there was a significant reduction in EPCs, and the 10-month relapse-free survival was 85 percent. In addition, TM was found to be safe and well-tolerated in patients.

The study shows copper depletion appears to inhibit the production, release, and mobilization of EPCs from the bone marrow, leading to a suppressed angiogenic switch and tumor dormancy.

"There are a lot of cancer experts at Weill Cornell working very hard to understand this precise mechanism, define the clinical benefit in this ongoing copper depletion drug clinical trial, and determine its future study," says Dr. Vahdat. "Keeping cancer dormant is what we all want for our patients -- especially triple-negative breast cancer patients at highest risk of recurrence."

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.


Saturday, February 9, 2013

Two Linked Antibodies Show Progress Against TNBC

News Release from the  Weizmann Institute of Science 

In a study in mice,  two EGFR-blocking antibodies prevented the growth and spread of triple-negative tumors. 

Cancer drugs of the new, molecular generation destroy malignant breast tumors in a targeted manner: They block characteristic molecules on tumor cells - receptors for the hormones estrogen or progesterone, or a co-receptor, called HER2, that binds to many growth factors. But about one in every six breast tumors has none of these receptors. Such cancers are called triple-negative.

Some of these therapy-resistant cancers have a potential molecular target for cancer drugs, a growth-factor receptor called EGFR, but an EGFR-blocking drug has proved ineffective in treating them. In a study published recently in the Proceedings of the National Academy of Sciences, Weizmann Institute researchers propose a potential solution: to simultaneously treat triple-negative breast cancer with two EGFR-blocking antibodies instead of one. In a study in mice, the scientists showed that a certain combination of two antibodies indeed prevented the growth and spread of triple-negative tumors. 

Of the different combinations they tried, the scientists found that the approach worked when the two antibodies bound to different parts of the EGFR molecule. The combined action of the antibodies was stronger than would have been expected by simply adding up the separate effects of each. Apparently, the use of the two antibodies created an entirely new anti-cancer mechanism: In addition to blocking the EGFR and recruiting the help of immune cells, the antibodies probably overwhelmed the EGFR by their sheer weight, causing it to collapse inward from the membrane into the tumor cell.

Deprived of EGFR on its surface, the cells were no longer receiving the growth signals, preventing the growth of the tumor. This approach resembles the natural functioning of the immune system, which tends to block essential antigens at several sites by targeting them with multiple antibodies. If supported by further studies, the two-antibody approach, in combination with chemotherapy, might in the future be developed into an effective treatment for triple-negative breast cancer.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Wednesday, February 6, 2013

Protein GATA3 lacking in TNBC tumors

From a news release from the University of California at San Francisco

In the January 27, 2013 online edition of Nature Cell Biology, UC San Francisco researchers describe how the protein  GATA3 — which is abnormal or absent in many cases of human breast cancer — normally works to prevent metastasis.

The absence or loss of GATA3 can free cancerous cells to break free from their defined roles and tethers within a tumor, to move away from the tumor mass, to induce cancer-promoting inflammation, and to stimulate the development of new blood vessels that can help spreading cancerous cells regrow as tumors in new locations.

Along with many other proteins, GATA3 also is absent in  triple negative  breast cancers.

"People knew that some of these genes were turned on in some cancers, but they did not know they were turned on because GATA3 and microRNA29b were turned off," said Zena Werb, PhD, a UCSF professor of anatomy who led the research. "If you have 20 genes that are becoming less active all at once due to microRNA29b, it could have a profound effect."

Working with mice, the researchers found that restoring microRNA29b to one of the most deadly types of breast cancer stopped metastasis. But the researchers also found that if they knocked out the microRNA29b, tumors spread even in the presence of GATA3, suggesting that microRNA29b can be the driver of metastasis.
In the mouse models of breast cancer studied by Werb's team, GATA3 normally restrains cancerous cells from breaking away from the main tumor and migrating to other organs.

It might be possible, Werb said, to develop drugs that inhibit breast cancer metastasis by re-activating these controls in cancerous cells that have lost the normal protein.

Many researchers who study early stages of cancer focus on abnormal genes and proteins that cause cells to expand their numbers rapidly, a hallmark of cancer.

However, the ability to spread to distant places and to eventually cause lethal complications requires not only cell division and tumor growth, but also changes in how the cancerous cell negotiates with its surroundings. This relationship must be altered to permit cancer to spread, according to earlier research findings by Werb and others.

"Many of the key processes in cancer that GATA3 suppresses take place outside the cell, in the surrounding environment," she said.

GATA3 is a master control for luminal cells, which line the milk-carrying ducts of the breast. In essence, GATA3 dictates the defining characteristics of a normal breast cell, Werb said.

"The targeting we would like to do is to give back microRNA29b specifically to breast tumor cells to prevent metastasis," Werb said.

New pathways to brain metastases uncovered

NOTE: Triple-negative breast cancer, if it is going to spread, often spreads to the brain.  Currently, drugs to treat metastatic breast cancer have had mixed effect.  This research, by defining the way breast cancer might move to the brain, could be a first step in finding therapies to combat that spread.  Hurry, hurry, docs!

PHILADELPHIA — Researchers have identified two molecules that could potentially serve as biomarkers in predicting brain metastases in patients with breast cancer, according to data published in Cancer Research, a publication of the American Association for Cancer Research.

Currently, most deaths from breast cancer are a result of metastatic disease. New research shows that cancer stem-like cells — commonly defined as cells within a tumor with the capacity to initiate a new tumor, proliferate rapidly, differentiate and cause chemotherapy resistance — may play a role in breast cancer metastasis.

“Recent research has shown that microRNAs are involved in tumor initiation and progression, and we hypothesized that they also may play a role in metastasis, particularly in relation to cancer stem-like cells,” said Kounosuke Watabe, Ph.D., associate director for basic science at the University of Mississippi Medical Center in Jackson, Miss.

Watabe and colleagues performed microRNA profile analysis on RNA extracted from cancer stem-like cells isolated from a human breast cancer cell line and two highly metastatic variants of this cell line.

“We found that miR-7 is a metastasis suppressor in cancer stem-like cells,” Watabe said. “When we increased expression of miR-7 in cancer stem-like cells from metastatic human breast cancer cell lines, it suppressed their metastatic properties.”

Next, the researchers examined the molecular pathway downstream of miR-7 to find its targets and discovered that miR-7 suppressed expression of KLF4.

“High expression of KLF4 was inversely associated with brain metastasis-free survival but was not associated with bone metastasis,” Watabe said. “This was confirmed in an animal model when we found that expression of miR-7 significantly suppressed the ability of cancer stem-like cells to metastasize to the brain but not the bone.”
Finally, the researchers tested tumor samples from patients with breast cancer whose disease metastasized to the brain. Results showed that miR-7 was downregulated and KLF4 was upregulated. The miR-7/KLF4 axis played a critical role in cancer stem-like cell brain metastasis, according to Watabe.

Few treatments currently exist for brain metastasis because few drugs can penetrate the blood–brain barrier, which prevents chemotherapy from reaching the brain.

“Cancer cells find the brain to be a kind of sanctuary where they can survive longer,” Watabe said. “It is possible that miR-7 and KLF4 may serve as diagnostic or prognostic markers, or therapeutic targets for the prediction of, or treatment of, brain metastasis.”