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Andrea Miyahira: Hi, everyone, I'm Andrea Miyahira with the Prostate Cancer Foundation. With me today is Dr. Felipe Eltit from the University of British Columbia and Vancouver Prostate Center. He will discuss the paper, "Sclerotic prostate cancer bone Metastasis, woven bone lesions with a twist," published in the Journal of Bone and Mineral Research Plus. Dr. Eltit, thanks for joining us.

Felipe Eltit Guersetti: Well, thank you for inviting me. I'm really happy and glad to be here in this session and showing you the progress on our project on understanding the nature of prostate cancer bone metastasis, and specifically discussing this first article in this whole project entitled, "sclerotic prostate cancer bone metastasis, human bone lesions with the twist."

About 90% of patients with advanced prostate cancer develop bone metastasis mostly in the vertebrae and ribs. They are extremely painful. And if, as this patient that we have here, it affects vertebrae, it may generate a spinal cord compression and paralysis, dramatically affecting the quality of life of these patients. Also, because of the location, the therapeutic possibilities are really limited. And one specific feature of prostate cancer is that these metastases generate osteoblastic lesions, which means they generate more bone.

So then we had a few questions about that when we started this project: how prostate cancer bone metastasis that generates more bone associates with bone weakness and pain, if there are any specific subtypes of prostate cancer that are more prone to generate bone pain and fractures, and if we can identify those patients at risk to give them more preventive therapeutics. This paper and the first part of the project is focused on the first question, which is how the structure of the bone changes and is associated with bone weakness and pain when they have prostate cancer metastasis.

To start, I need to explain a bit about bone. Bone is a composite material. It's a tissue that's composed mostly of collagen fibers that are highly aligned, and they are embedded in or coated by minerals. So it's a composite material of ceramic minerals—calcium crystals—and collagen fibers.

These collagen fibers align in bundles that form these trabeculae that we can see here in the image. So these trabeculae that you can see in these human vertebrae align perfectly vertical to resist the compressive forces of the loading. That's the orientation. That's the whole objective of the bone.

These trabeculae have to be perfectly aligned. The collagen needs to be perfectly aligned in order to resist the forces. And all of this is maintained by a group of cells that live inside of the bone, literally buried in this mineral matrix, which are the osteocytes, which live in a hole inside of the bone in the lacuna. We call it lacunae.

And since they are buried inside of the bone, they need to communicate with other cells, and blood vessels, and nerves to get irrigation and signaling. And they do it through a network of canaliculi that you can see here in the image. So we will study how these structures change when prostate cancer bone metastasis or prostate cancer cells to bone.

The main challenge we have always is obtaining samples of bone. As I said, they are hard to obtain because nobody will take pieces of bone for any reason. So we obtain most of our samples here from the Rapid Autopsy Program of the University of Washington from Dr. Colm Morrissey and Eva Corey. And we analyze them with the equipment that we have here in the Vancouver Prostate Center.

So the first thing we did, we did a micro CT, which is a CT scan with a resolution of 5 microns. And what we found is—well, we first analyzed the control vertebrae from a cadaveric patient as well, and we see what we expected, normal trabeculae in the preferred orientation with bone marrow or medullary spaces in between those trabeculae in a normal fashion.

When we analyzed the prostate cancer patients’ bone, some patients have an osteolytic pattern with less bone, with big holes, bigger marrow space. But those patients are really few. What most patients show is an increased mineral density or mixed ratios in which most of the medullary space is filled with a mineral material, with new bone, which shows totally abnormal features, as you can see here.

Interestingly, in some patients, we see trabeculae that are maintained—that original trabeculae from the normal bone—and it seems that new bone is added in those spaces right on top of the trabeculae. But in some patients, we don't see more trabeculae—more of these trabeculae that are not existing anymore. They're totally resorbed. And we see a totally abnormal, irregular mineralized matrix. Our quantitative data supports that most of the patients develop osteosclerotic or high mineral density lesions, basically with more bone.

So how is that more bone, this new bone that's generated in these medullary spaces? So we went to high-resolution scanning electron microscopy, and we saw here how a normal bone should look and normal trabeculae in which the collagen fibers that I mentioned, the collagen bundles, align. And you can see them here as black and white lines that are aligned in the major axis of the trabeculae. You can see the lines here all over, black and white banding pattern. And the cells, the little cells, the osteocytes, are seen as little holes here, pointed out with this arrow, and they are also in an elongated shape following the long axis of the trabeculae.

We have some patients that look osteolytic, in which the bone looks like it is losing mineral density and has irregular borders. But most of our patients look like this, with new bone forming on top of this old trabeculae or definitely not trabeculae at all. What is new about this bone formed as a consequence of prostate cancer—this new bone, this irregular bone that we see here?

We see literally no banding, no band, no signs of collagen alignment here, as you can see in this image, and also a larger amount of bone cells, seen as bigger and larger numbers of holes in the bone. We can see them perfectly clear in the images here. The quantitative data, the quantification, also agrees with this observation.

So basically, our take-home message is that prostate cancer bone metastases are characterized by the deposition of abnormal bone. Basically, the patient has more bone instead of less bone, but this bone has irregular organization of the collagen, higher porosity, and abnormal protein composition that we found by immunohistochemistry. And these changes are related to decreased mechanical properties that may increase the fracture risk.

That's what we published recently in this journal. And since one of the observations that we have is a higher porosity and a higher number of cells that also have an abnormal shape, we went on to the highest resolution because most of the features in bone are observed at a nano or submicron scale. So we went to the Synchrotron Facility in France, in the European Research Synchrotron Facility. We applied for observation time, we obtained 100 hours of observation, and we went there.

What we found is, when we analyzed normal bone, we have these features in which the cells, highlighted here in yellow, connect to each other by this network of canaliculi in a regular pattern, always looking for the surface. The canaliculi align perpendicular to the major axis of the trabeculae. But when we see prostate cancer bone, it looks like this: a higher number of cells, here in purple, and the connections look totally abnormal in terms of shape and orientation.

Interestingly, when we see the boundary zone between the prostate cancer zone and a normal bone area—well, we can see and highlight the difference here between the normal bone and the prostate cancer-affected bone. Also, we see that there is no communication between them, suggesting that prostate cancer bone acts as an independent unit.

And when we analyze higher magnification of single cells, we see totally different patterns, even in normal bone compared to bone affected by prostate cancer. This amazing work cannot be possible without a huge mentoring team, collaborators, and students, and of course, our patients and their families, and our funding sources. So I will open for questions now.

Andrea Miyahira: So thank you, Dr. Eltit, for sharing this really interesting study. So what are the mechanisms that lead to these different types of bone lesions? And were there any patterns that associate with different prior treatments or clinical characteristics?

Felipe Eltit Guersetti: Well, that's an excellent question. And actually, we're working on that right now with Dr. Michael Schweizer, my colleague from the University of Washington. And the main pattern, the main relationship with the morphology of the prostate cancer bone metastasis in terms of bone generation, seems to be the type of prostate cancer cells that are in the bone.

We are describing currently—this is not published data. We're working on this. We expect to publish it shortly—different types of prostate cancer organizations. And different kinds of prostate cancer histology patterns are related to the prostate cancer bone metastasis. And we're trying to characterize if they are related to the different phenotypes of prostate cancer therapy-induced, saw neuroendocrine—we have more adenocarcinoma.

In general, the more anaplastic the cancer is, the less osteoblastic it is. It seems that the more normal prostate cancer is, the more benign it is, and it generates more bone. And the more malignant versions are more bone-resorbing. But that's something we're working on. It's not conclusive yet. That's what we have for now. But yeah, that's the key part.

Andrea Miyahira: OK. I'm looking forward to that study. So have you compared bone biology of patients with bone metastatic prostate cancer to other bone-related disorders such as osteoporosis or osteoarthritis, et cetera?

Felipe Eltit Guersetti: We have—yeah, that's another excellent question. I think the osteolytic pattern and the osteolysis we see in these patients seem to be more related to the therapy, to the androgen deprivation therapy, than to prostate cancer. And it looks really similar to osteoporotic bone in the osteolysis, the osteolytic pattern, which is a minority of the lesions we see.

But the osteosclerotic, the samples with a lot of bone—the structure looks really much like a reparative bone in fracture, but with a few differences that are, first, it never becomes normal bone. Because in reparation, when you have a fracture, the bone generates a messy structure but then it repairs quickly. Here, that reparation, that remodeling process is not happening. And there are some molecular differences that we're analyzing with proteomics.

And we're also analyzing other pathologies in my group. I'm a dentist by training; I work in bone. So we're working on other pathologies that look really similar. But the model we're using mostly is prostate cancer because it's the most frequent and one of the most severe.

Andrea Miyahira: OK, thank you. And do you think any insights from this study or your future studies will lead to any new modalities of bone-protective agents?

Felipe Eltit Guersetti: That's a really good question. And actually, what we are seeing right now in some bone pathologies is that they are using different monoclonal antibodies to block pathways of bone generation or to promote bone remodeling and generation of better quality bone. And one of them is the antibody against sclerostin called romosozumab—an antibody against a ligand, which inhibits the pathways of bone resorption and stimulates bone formation. So I think that's probably a path that we need to follow. But we need to know more about the biology of this, of course. But that's being used in other bone pathologies successfully. So I think that's probably a way to go.

Andrea Miyahira: OK, thanks. And for researchers interested in studying these aspects of bone biology, can any of these features be measured in living patients or mouse models? And are there other biomarkers that correlate with the dystopic bone patterns that you've observed?

Felipe Eltit Guersetti: The bone model is a tricky model because mice don't remodel that much, and the structure of bone is totally different. We will use it eventually, but the bone is so different that it is hard to compare. Sorry, you asked me about—oh, biomarkers. Yeah, we're doing proteomic studies, and part of the study is also finding protein markers that could hopefully predict the behavior of prostate cancer in bone.

And we're working with Dr. Wyatt too, here in prostate cancer, trying to see if there are markers in blood that can predict these lesions to happen and the severity of them associated with bone. So yeah, we're working on that.

But it's still a work in progress. We're really beginning with this, and I'm really surprised that this problem, being so old, has not been studied so thoroughly in the structure of bone, I think.

Andrea Miyahira: Yeah, thanks for doing this really important study. I look forward to the next ones. And thanks for sharing this with us today.

Felipe Eltit Guersetti: Thank you so much, Andrea. And thank you, everybody at UroToday. Thank you.