As breast cancer awareness month draws to a close, I wanted to highlight a few breast cancer posts from other medical bloggers:
Suture For a Living asks: "Is Breast Cancer Over-Diagnosed?"
Bayblab writes about research on a diabetes medication killing breast cancer stem cells.
Science Update Blog discusses claims that we are "Two years from breast cancer cure".
Highlight Health's Allison Bland says "The Review is in: Lifestyle Changes Prevent Breast Cancer
and Healthcare Hacks discuss the benefits of weightlifting in breast cancer survivors.
If you've found any interesting breast cancer blogs or posts, link to them in the comments!
Related posts:
Does Vitamin D Help Prevent Breast Cancer?
Breast Cancer Risk & Alcohol
Cancer Stem Cells and Familial Cancer Risk for Breast Cancer
Wednesday, October 28, 2009
As Breast Cancer Awareness Month Draws to a Close
Thursday, August 27, 2009
Therapeutic Cloning Takes A Big Step Forward
Leigh Syndrome
Myoneurogenic Gastrointestinal Encephalopathy
What do these disorders have in common? They are all mitochondrial diseases.
What is a mitochondrial disease? Mitochondria are the parts of a cell that are responsible for generating energy. Mitochondria contain DNA, just like the nucleus does. Mutations in mitochondrial DNA can cause them not to function correctly, and some of these mutations cause the diseases listed above (and others).
Since all mitochondrial DNA is inherited from the mother, replacing mitochondrial DNA that carries a disease-causing mutation with mitochondrial DNA from another source would prevent a woman from passing on such a disease to her children.
That is the basis for the work by Shoukhrat Mitalipov’s group at the Oregon Health and Science University published online in Nature on August 26. This group took an egg from a female monkey and removed the nucleus, replacing it with the nucleus from a different female. This hybrid egg, with nuclear DNA from one female and mitochondrial DNA from another female, was fertilized, and the resulting embryo was allowed to develop. Not every embryo developed normally, but some developed into seemingly normal monkeys like the ones shown above.
This approach would allow a couple with a family history of mitochondrial disease on the mother’s side to have children with mitochondria donated by an unrelated woman, and they could have children with no risk of developing the disease.
The monkeys described in the paper have genetic contributions from 3 adults. Does that mean there are three parents? I guess that depends on how you define “parent.” If you are a parent simply by virtue of having contributed DNA to a child, then yes, these monkeys have 3 parents. Of course, if a parent is defined as the adults who raise you, then a child conceived in this way would have 2 parents. The ones who raise the child.
Experiments like these raise huge ethical issues. Therapeutic cloning like this introduces changes directly into the germline (the DNA that is passed from parent to offspring), something that has long been taboo in the mainstream scientific community. It also raises interesting custody issues (does the donor of the mitochondrial DNA have any parental rights?). I’d be interested to hear what people think about this.
Like it or not, we are on the verge of a new era of genetic medicine. Some aspects of genetic medicine will not be controversial (tailoring medical treatments based on the presence of specific mutations), but other aspects are sure to raise questions (like the experiments described in this paper). It is critical that we begin to have serious, society-wide discussions about these issues, before it is too late and the discussions become arguments.
Wednesday, August 19, 2009
When Translational Research Really Translates
Our laboratory studies cancer stem cells. I have blogged about these cells before. Cancer stem cells are thought to be a small population of cells within a tumor that are resistant to chemotherapy and are capable of regenerating a new tumor. Thus, these cells are thought to be responsible for local relapses and for metastatic disease. Because they are resistant to chemotherapy, our usual treatments don’t get rid of them, so finding ways to kill these cells is critical to the further advancement of cancer treatment.
There are many theories to explain the resistance of cancer stem cells to chemotherapy. One of these is that there are important metabolic differences between cancer stem cells and most other cancer cells. One such difference might involve a signaling pathway called mTOR. mTOR stands for “mammalian target of rapamycin.” Rapamycin is a drug that is used primarily to prevent the rejection of transplanted organs. It turns out that rapamycin works by interfering with the function of a specific enzyme that was given the name mTOR.
For a variety of reasons, inhibiting mTOR activity has been predicted to make cells more sensitive to chemotherapy. In collaboration with another researcher at Johns Hopkins, Jonathan Powell, our laboratory has done some experiments that seem to show that inhibiting mTOR increases the sensitivity of cancer stem cells to chemotherapy.
Last winter, we responded to a call from the National Comprehensive Cancer Network for research proposals utilizing an mTOR inhibitor for the treatment of cancer. Based on our laboratory data, we proposed a clinical trial that would treat patients with a combination of a chemotherapy drug (liposomal doxorubicin, or Doxil) and an mTOR inhibitor (in this case temsirolimus, or Torisel).
In March we learned that our proposal would be funded.
On Monday, I signed the contract that will allow our clinical trial, now approved by the Institutional Review Board, the Food and Drug Administration, and the Johns Hopkins Clinical Research Committee, to begin to enroll patients. We hope to treat our first patients in late August.
I can’t wait to see whether we are able to help the patients willing to enroll in this trial! How gratifying it would be to know that work in our lab led to a new way to treat cancer patients. That, after all, is why we do this.
Saturday, March 7, 2009
A Bright New Day for Stem Cell Research – Undoing Bad Policy
The “Breaking News” alert came to my phone last night: on Monday, President Obama is planning to sign an executive order reversing the restrictions on embryonic stem cell research put in place by President Bush in 2001. This comes as a surprise to no one, as Obama made it clear that he was opposed to these restrictions throughout the 2008 presidential campaign.
The occasion of this reversal of federal policy seems to be a good time to talk a bit about stem cells. The President’s decision is sure to provoke intense debate, and this debate can only be healthy if it is based on fact, not emotion.
Let’s start with the basics. What is a stem cell? 
As I discussed in a prior post, a stem cell is a primitive cell that is capable of generating more “daughter” cells with more specific function as well as making more copies of themselves. Every organ and tissue in your body contains stem cells. As the most mature cells die, they are replaced by cells derived from these “organ stem cells,” which also continuously replenish themselves. Stem cells such as these are often referred to as “adult stem cells” because they are found in adult humans. There are also “umbilical cord stem cells” which are found in the blood in the umbilical cords of newborn babies and many oncologists believe that there are “cancer stem cells” that drive the growth and spread (“metastasis”) of tumors.
The controversial cells are called “embryonic stem cells” because they are derived not from adults but from human embryos. In the process of obtaining embryonic stem cells, the embryo is destroyed.
Why all the excitement about stem cells? Because stem cells are so primitive, and their job in the body is to produce cells with a more specific function, it is believed that stem cells can be coaxed into producing virtually any other tissue type. This means that the therapeutic implications of stem cell biology are limitless.
Doctors could grow new organs to replace defective ones, and if they used the patient’s own stem cells, there would be no need to take medicines to prevent rejection. Diabetics could get a new pancreas that works instead of injecting themselves with insulin. Patients with spinal cord injuries could walk again.
So why the controversy?
Arguments about the ethics of stem cell research arise from questions about the source of the stem cells. Although “adult” stem cells can be obtained from an adult person, who can give informed consent for the procedure and who will (most likely) not be harmed by the procedure, embryonic stem cells require the destruction of an embryo. Those who believe an embryo is a human life entitled to the same protections as a child or adult argue that this amounts to murder and believe that it is unethical to murder an embryo to help treat disease in an adult.
Opponents of embryonic stem cell research believe that adult stem cells provide appropriate material for study and should be the sole focus of stem cell research.
Do they have a valid point? Maybe, but maybe not. So-called “adult stem cells” are not as primitive as embryonic stem cells. They already have some characteristics of the organ from which they are derived (liver, kidney, bone marrow…). So to make them turn into a different tissue is more complicated and more difficult. These “adult stem cells” have to first lose the characteristics of the tissue they came from and then gain the characteristics of the tissue they are being turned into. So far, doctors have been unable to accomplish this task on a large scale. Embryonic stem cells, because they are the most primitive stem cells available, should be easier to turn into the tissue of choice.
Since 2001, federally funded scientists have been forbidden to work with embryonic stem cells that were not already in existence. This has significantly limited progress in developing stem cell-based therapies. Despite this, the ban has not been all bad. As with all clouds, there was a silver lining. The limitations imposed by President Bush forced scientists to be creative. One novel source of stem cells that may not have been developed otherwise, is called “induced pluripotent stem cells,” abbreviated iPS. These are cells that do not start as stem cells but are manipulated in the lab to act like stem cells. Many scientists are as excited about the potential of iPS as they are about other stem cell types.
Clearly this is a very complex topic, and I have oversimplified a lot. The bottom line is that I am excited that the order President Obama is signing will not only open the door to new stem cell research, but may also signal a new era in science policy – an era where scientific decisions are made based on science, rather than on ideology.
Related Posts:
The Stem Cell Thing
Stem Cells, or “A Rose By Any Other Name…”
Cancer Stem Cells and Familial Cancer Risk for Breast Cancer
Monday, March 3, 2008
Cancer Stem Cells and Familial Cancer Risk for Breast Cancer
One of the most important current trends in cancer biology is the study of cancer stem cells. The cancer stem cell model holds that cancer originates in tissue stem cells, and that dysregulation of these cells underlies the development of the tumor. Also, the cancer stem cell model suggests that tumors contain a small population of cells with stem cell properties (self-renewal and limitless proliferation), that these cells are resistant to chemotherapy, and that these are the cells that cause the majority of relapses.
Another important concept in oncology is hereditary cancer. Although 1 in 8 women will develop breast cancer, it has long been known that women with a family history of breast cancer are more likely to develop breast cancer themselves than are women with no such history. This observation led to the discovery of breast cancer predisposition genes such as BRCA1. Women who inherit a mutated form of this gene from a parent have a lifetime risk of breast cancer that is greater than 90% and are also at increased risk of ovarian cancer.
An interesting paper published recently in Proceedings of the National Academy of Sciences shows how these two concepts are linked. This group, led by Max Wicha from University of Michigan, wanted to investigate whether BRCA1 plays a role in the biology of mammary stem cells. Their first step was to treat normal mammary cells in a way that dramatically reduces how much BRCA1 they make (by using small interfering RNA, siRNA, a tool to inhibit the activity of a specific gene). They found that decreasing the amount of BRCA1 substantially increases the number of cells with stem-cell-like properties. This shows that one role of BRCA1 is to limit the proliferation of mammary stem cells. Because mammary stem cells are the cells that give rise to breast cancer, limiting their proliferation is protective against developing breast cancer, and loss of this protection increases the risk of developing a tumor.
The scientists were able to examine breast tissue from 13 women who were known to have a mutation in BRCA1 and from 22 women with no family history of breast cancer. 5 of the 13 samples from the women with BRCA1 mutations contained “lobules” (clusters) of cells composed almost entirely of mammary stem cells, and none of the samples from the 22 control women had such lobules. 4 of the 5 women (80%) with these “stem cell lobules” went on to develop cancer in the 9 years after the samples were obtained, compared with only 2 of the 8 women (25%) with a BRCA1 mutation but no “stem cell lobules.” Although the number of women studied was small, this difference (80% vs. 25%) was statistically significant. This result supports the idea that the increased number of mammary stem cells seen in women with a BRCA1 mutation is an early step in breast cancer development.
Normal mammary stem cells can give rise to one of two cell types, called myoepithelial cells and luminal epithelial cells. The breast ducts are lined with luminal epithelial cells, and these are surrounded by a layer of myoepithelial cells. Both can give rise to breast cancer, and women with a mutation in BRCA1 are much more likely to develop a cancer of the myoepithelial cells. Interestingly, Wicha and his colleagues showed that loss of BRCA1 function (as would happen in a woman with a BRCA1 mutation) interferes with the ability of the mammary stem cells to develop into luminal epithelial cells, but still allows the generation of normal myoepithelial cells.
One of the other functions of BRCA1 is to help maintain the integrity of cellular DNA. Loss of BRCA1 function impairs the ability of cells to correct DNA damage and leads to the accumulation of mutations. These two functions of BRCA1 together go a long way toward explaining why women with a mutation in this gene are at such high risk of developing breast cancer in particular. Loss of BRCA1 function leads to an accumulation of mammary stem cells and of myoepithelial cells that are both impaired in their ability to correct DNA damage, resulting in an extraordinarily high risk of developing breast cancer.
These findings support the cancer stem cell hypothesis by suggesting that dysregulation of stem cell self-renewal and differentiation is important for both sporadic and inherited breast cancer. What remains is to determine the role of BRCA1 in normal ovarian function, because women with mutations in this gene are prone to ovarian cancer as well.
Wednesday, November 7, 2007
Stem Cells, or “A Rose, By Any Other Name…”
Over the past several years the media has been full of stories about stem cells.
The topic of stem cells is one that everyone, from President Bush on down, has a strong opinion about.
But what are stem cells? Are there different types of stem cells? And what kinds of things are researchers hoping to learn about by doing “stem cell research”?
I’ll try to answer some of those questions here.
First of all, what is a stem cell?
To answer that, I’ll start with one of the main principles of modern biology: in every organ in your body, there are cells that are fully developed (differentiated is the term scientists use), and cells that sit in reserve to replace the differentiated cells as they age. Those cells that sit in reserve are unique in their ability to both create copies of themselves (called self-renewal) and to create “daughter cells” that are more differentiated. These “daughter cells” are stem cells.
Stem cells come in two varieties: the ones that are found in mature organs (like bone marrow) and the ones that are found in a developing embryo and give rise to the entire body.
So what are the controversies that surround stem cells? Well, the major controversy is over the source of stem cells that scientists use for their experiments. For example, most people are not concerned about stem cells that are harvested from bone marrow, but they do object to embryonic stem cells that require the destruction of an embryo. I guess it’s obvious why some people find that objectionable but others do not.
What good are stem cells, anyway? What kinds of things do scientists think they can do with stem cells? I study stem cells. I know many other people who study stem cells. No one I know wants to do what the loudest anti-stem-cell-research voices are shouting about – clone a human. What we do want to do is exploit the potential of these cells to replace broken cells and cure human disease.
How might this happen? Well, let’s use spinal cord injury as an example. At the moment, there’s no way to reverse a serious spinal cord injury because the nerve cells that make up the spinal cord don’t regrow once they are damaged. But imagine if we could take stem cells and grow new nerve cells and we could put those cells into an injured spinal cord and fix it. We could reverse paralysis. That would be amazing.
Or… what if we could replace the cells in the pancreas that are destroyed in patients who have diabetes? If we could reliably turn stem cells into insulin-producing cells, diabetes would change from a disease that can be “managed” with multiple daily injections of insulin to a curable disorder. What a difference that would make!
What about cancer research? Why do I study stem cells? Well, many oncologists believe that tumors, like normal organs, are composed of differentiated cells and stem cells. It is the stem cells that are resistant to chemotherapy and radiation therapy. It is the stem cells that are responsible for relapse. It is the chemotherapy-resistant stem cells that spread throughout the body and ultimately kill patients. So, unlike my colleagues who want to harness stem cells for good, I want to learn what makes them tick, learn their vulnerabilities, and exploit those vulnerabilities to develop treatments that will cure patients without making them as sick as our current chemotherapies do.
Several states, including California and my own home state of Maryland, have recognized the enormous importance of stem cell research and have designated significant sums to support stem cell research. In contrast, the federal government placed significant restrictions on stem cell research back in 2001. Hopefully soon they will realize the mistake they made, listen to Nancy Reagan, and give this vital area of research the support it deserves.
Tuesday, August 21, 2007
The Stem Cell Thing
One of the best parts of my job is that not only do I have the pleasure of taking care of children and young adults with sarcomas, but I also run a laboratory where we conduct research that we all hope will eventually lead to new treatments for my patients. I am going to talk a little about my laboratory research today.
One of the hottest new ideas in the world of cancer research is the concept of the “cancer stem cell.” As many of you who have been involved with Ewing’s sarcoma patients know, the correlation between response to therapy and cure is not very strong. In other words, although patients with widely metastatic disease can respond well to chemotherapy and to radiation therapy, relapse is frequent and cure rates remain less than 25%.
Why is this?
One possible explanation is the existence of a cancer stem cell. Cancer researchers used to believe that all cells within a tumor were the same, and that any one of them is capable of unlimited growth and of spreading to distant sites. We now know that this is not the case. Only a small fraction of the cells in a tumor are capable of unlimited growth. The rest will only divide a few times before dying. This recognition led to the development of the Cancer Stem Cell Model.
The Cancer Stem Cell Model predicts that the small number of cells capable of unlimited self-renewal would have properties similar to other stem cells, such as bone marrow stem cells and the embryonic stem cells that we read about in the papers all the time. These cells would be responsible for maintaining the primary tumor population and should be relatively resistant to chemotherapy. This would make them the primary cells causing relapse because of their ability to survive the treatments that kill the majority of the other cancer cells. Cancer stem cells have been identified in several types of cancer, including leukemia, breast cancer, brain tumors, and others.
So…. Are there sarcoma stem cells? That remains an open question, but one that we are in the process of studying in my lab.
We have some very exciting preliminary data that makes me think that we may have identified Ewing’s sarcoma stem cells. This, of course, is just the first step. After we are able to prove that these cells exist, the real fun will begin! We have a plan in place to learn as much as we can as quickly as we can about the basic biology of these cells.
Hopefully our research will have a big impact on many aspects of the care of sarcoma patients:1. We can isolate sarcoma stem cells and try to find drugs that can kill them.
2. We can devise a rapid test for sarcoma stem cells that might allow us to better predict who will relapse and who will not.
3. We can devise strategies to identify these cells in biopsy specimens to be able to determine if treatments have killed stem cells in the patient.
4. We can devise new treatment strategies specifically targeting stem cells that hopefully will result in higher cure rates than currently used chemotherapy with fewer side effects.
It is an exciting time in cancer research…. This new theory goes a long way toward explaining why chemotherapy can make a tumor go away but might not cure the patient. Identifying the cells responsible for relapse will allow us to make big strides in treatment and hopefully dramatically improve our treatments.
I’m lucky to be able to work in both worlds (the lab and the hospital) and be in a position to guide research findings from the laboratory into the hospital and witness first hand this revolution in cancer treatment – away from toxic chemotherapy and toward targeted therapy* more precisely aimed at the cancer.
*An article I wrote for ESUN, the newsletter for the Liddy Shriver Sarcoma Initiative, on targeted therapies for sarcomas
