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A new way to help breast cancer patients?

A new study out of Huntsman Cancer Institute brings hope for better treatment to many cancer patients, especially those facing breast cancer. In 2013, 230,815 women and 2,109 men in the United States were diagnosed with breast cancer.
40,860 of those women and 464 of those men died as a result of their breast cancer.

 The Human Skeleton

Adults have 206 bones. This is a photograph of a femur, the bone inside the thigh.

 
Human femur

Here's what the inside looks like:

 

Cross section of human femur

 

Bone is mostly a non-living composite of proteins and minerals. But there are some living cells in there.

If we look at it under a microscope, we see this:

 

Bone under a microscope

 

If we stain it and then look more closely at it under a microscope, we can see the two most important kinds of cells inside bone. They’re called osteoclasts and osteoblasts.

 

Bone osteoblasts and osteoclasts under a microscope

 

We think of bones as very solid and unchanging. In fact, this isn’t the case. That composite of proteins and minerals is made by the osteoblasts, while it’s broken down by the osteoclasts. The two kinds of cells are involved in a delicate balancing act that’s very important for the structure of bones. Together, they allow for bone repair and bone remodeling.

Bone repair happens after injuries like fractures or after micro-damage, which is sustained during normal movement. Damaged parts of the bone are broken down and removed by osteoclasts, and the osteoblasts come afterward to form new bone.

Bone remodeling is the process of old bone being removed from the skeleton and replaced with new bone tissue. This helps the skeleton both to grow and to respond to functional demands—things like making load-bearing bones thicker and stronger in people who regularly carry something heavy like a backpack. In adults, about 10% of the skeleton is replaced in a year.

If the balancing act between the work done by osteoblasts and osteoclasts is disrupted, bone disease results. One kind of bone disease is osteoporosis.

 

Bone Damage

Osteoporosis is common among the elderly, and especially common among women who have gone through menopause. One way it happens is through osteoclasts becoming more active than osteoblasts. Bones lose density and thus, a considerable amount of strength. As a result, they're more easily broken. Osteoporosis often causes debilitating pain and can lead to disability or early death.

 

2l.jpg.2000x2000_q85_autocrop.jpg 1l.jpg.2000x2000_q85_autocrop.jpg
Healthy bone tissue Bone tissue damaged from osteoporosis

 

As it turns out, some kinds of cancer lead to this same thing when they metastasize to bone: osteoclasts become more active than osteoblasts and bones are destroyed. Some of the types of cancer where this is seen are multiple myeloma and lung cancer. Another type is breast cancer, which is especially of concern because 70% of patients whose breast cancer has metastasized have bone metastases.

For many of these patients, the damage to their bones is resistant to treatment. Once cancer has reached a patient’s bones it is generally not curable.

This is where breast cancer researcher Dr. Alana Welm’s work comes in. She’s a breast cancer researcher at Huntsman Cancer Institute, and she recently published a study which begins to find a solution to this problem.

But before she could do that, she had another problem.

In labs like hers, lab-grown cancer cells are injected into mice and the mice are observed or treated. Mice are used as models for disease and treatment effects in humans due to similarities in genetics and the way our bodies work. They also reproduce quickly, so diseases that are induced by changing their genes can be studied across multiple generations. So she and her team of researchers would inject mice with lab-grown cancer cells and wait for the cancer to metastasize to the mice’s bones, but nothing ever happened. Mice aren’t resistant to cancer in any way, so they knew the problem was with the lab-grown cancer cells. She tells the story of how they solved the problem in this video: 

 

It’s a solution that could uniquely be reached at Huntsman Cancer Institute, and it opened the doors not only for her recent study but for even more personalized treatment of cancer patients next door in the cancer hospital.

Once Dr. Welm had mice with bone metastases, her lab could perform basic research to try to understand exactly how the bone damage was triggered.

 

Welm's Basic Research

One biological pathway was already known. It’s a cycle, actually. Cancer metastasizes to bone and the osteoclasts there become more active. As they break down the bone’s mineral composite, a chemical called transformation growth factor beta (also called TGFβ, but we’ll nickname it Tom for less confusion) is released into the bloodstream and causes two things in tumors: first, that the tumor grows and second, that the tumor releases more chemicals called parathyroid hormone-related peptide (nicknamed Phil) and interleukin-11 (we’ll call it Ira).

Phil and Ira (or parathyroid hormone-related peptide and interleukin-11 if you’re feeling more scientific) travel from the tumor back to the bone, where they meet up with an osteoclast.

On their surfaces, osteoclasts have receptors called RANK. Receptors are a little like the coin slots on vending machines. They have an area where something can be inserted and, once it has been, changes happen on the other side. Scientifically speaking, this is called stimulation. In the case of a vending machine, your snack is grabbed and dropped to where you can get it out. Receptors and vending maching coin slots also similar in that they’re specific. Usually, vending machines will only accept nickels, dimes, or quarters. If you tried to use currency from other countries, arcade tokens, or even pennies, usually nothing will happen on the other side. In the case of RANK, Phil and Ira must come along and as a result the osteoclast becomes more active again—dissolving more bone. This leads to the release of more Tom (TGFβ) from the bone and the cycle continues. 

RANK pathway--the old model for bone destruction

 

Not only was this cycle already known, but there were also already drugs being used to treat bone damage in cancer patients. One, called denosumab, prevents RANK from working very well, so it doesn’t increase the activity of osteoclasts very much. Treatment with it results in about an 18% improvement in this process of bone damage. Additionally, a whole class of drugs exists that keeps osteoclasts from dissolving more bone than they regularly should in the first place. Their use results in about a 33% improvement.

Despite these treatments, 30 to 50% of patients with bone metastasis continue to develop bone damage, so Dr. Welm considered the possibility that there was another biological pathway that led to this same process.

What she found is that there is another way to increase the activity of osteoclasts. It was already known that about 40% of breast cancer tumor cells release a protein called macrophage-stimulating protein (it’s shortened to MSP, but we’ll continue the nicknames for simplicity’s sake: Mary). It was also already known that osteoclasts have another type of receptor on their surfaces besides RANK. It’s called RON, and the only thing that makes it work is Mary (MSP). What wasn’t known is exactly what RON does.

Dr. Welm’s lab performed multiple experiments, which led them to propose the following model. Once RON is working, it activates a protein called SRC kinase (we’ll call it Sally). Sally then leads to increased osteoclast activity and the resultant imbalance between osteoclast and osteoblast activity causes bone damage. They also theorize that the two pathways--RANK, the previously known path, and RON, the new one--converge on Sally (SRC kinase).

So the cycle actually looks a little more like this:

 

RANK and RON pathways--the new model for bone degradation

 

Once they had proposed the model, they recognized that the RON receptor could be an important target. If they could stop the RON receptor from activating Sally (SRC kinase), it would be an alternate means of disrupting the cycle than had previously been tried.

They needed to test their theory. In some of their mice, they removed the gene that tells osteoclast cells to build the RON receptors. The osteoclasts in the bones of those mice would have no RON receptors at all. Then they injected the mice with cancer cells and waited to see what would happen. Dr. Welm says,

We found it completely protected the bones from destruction. We saw probably 10 times less bone destruction, almost down to nothing. Even when the mice got cancer in their bones, the bones stayed in much better shape.”

They knew that disrupting the RON receptors works. However, It's not possible to remove genes from people because there are two copies in every cell in the body, and the number of cells in the human body is somewhere near 37.2 trillion. The genes are removed from the mice when they are only embryos, and have very few cells.

But medication can sometimes keep receptors like the RON receptor from doing their jobs. They tried two drugs that would interfere with the receptor’s activities in mice. They got good results again.

Next, they tried the two drugs in a phase I clinical trial of patients without cancer (phase I trials are usually performed in healthy people), almost all over the age of 50. Their study says, “We reasoned that, regardless of cancer diagnosis and even in the absence of bone metastasis”, interfering with the RON receptor’s activities would affect the balance of osteoblast and osteoclast activities, “especially in postmenopausal women because of their high rate of bone loss”.

After treatment for a month, a little under 66% saw less bone destruction and about the same percent of subjects experienced an increase in bone repair. And, just as they predicted, larger effects were seen in the women, who were post-menopausal and had higher rates of bone loss to begin with. 72% of them experienced a drop of at least 25% in bone destruction.

There were very few side effects.

The results prompt future clinical trials of the two drugs in women with breast cancer. Since the biological pathway targeted begins with tumor cells that release Mary (MSP), those are the patients for whom the drugs may be effective—40% of breast cancer patients. Dr. Welm says, “If we can help 40% of metastatic breast cancer patients, that’s a great step. If we could actually see our work benefit even one person, I would be thrilled.” She thinks, in the future, the drugs may be used in conjunction with one or both of the previously existing drug therapies and that it may also be useful for patients experiencing bone destruction as a result of other cancers like multiple myeloma and lung cancer.

The drugs will need more testing.

 

If you want to help make more research like this possible, please check out our United Against Cancer golf tournament.


Sources:

Andrade, Kelsi, Jaime Fornetti, Ling Zhao, Scott C. Miller, R. Lor Randall, Neysi Anderson, Susan E. Waltz, Mark Mchale, and Alana L. Welm. "RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis." Science Translational Medicine 9.374 (2017): n. pag. Web. 01 Mar. 2017.

"Bone Research Society 1950-2015." Gallery - Bone Research Society. N.p., n.d. Web. 12 May 2017.

Eveleth, Rose. "There are 37.2 Trillion Cells in Your Body." Smithsonian.com. Smithsonian Institution, 24 Oct. 2013. Web. 12 May 2017.

Spencer, Geoff. "Background on Mouse as a Model Organism." National Human Genome Research Institute (NHGRI). National Institutes of Health, 23 Mar. 2012. Web. 12 May 2017.

U of U Health Sciences. "Huntsman scientists identify bone degradation process within metastatic breast cancer." EurekAlert! American Association for the Advancement of Science, 25 Jan. 2017. Web. 12 May 2017. 

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