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Conversations With Prostate Cancer Experts


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Prostate Cancer Dormancy + Disseminated Tumor Cells

Dr. Julio Aguirre Ghiso is a Professor of Medicine, Hematology and Medical Oncology and Oncological Sciences at Ichan School of Medicine at Mount Sinai in New York City. His research explores why and how in some patients disseminated tumor cells can remain dormant for years after initial treatment before reactivating to form incurable metastases.

Prostatepedia spoke with him about his research and about a clinical trial testing his findings that is currently looking for prostate cancer patients.

To  learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us or download the issue.

Why did you become involved in cancer research? What is it about cancer research that has kept you interested?

Dr. Julio Aguirre-Ghiso: When I was an undergraduate student, I was looking for challenging problems to solve in biology. Serendipitously, I started working and volunteering for a cancer biology team in Argentina, where I trained. I became very interested. I was working on tumor immunology. Then I became very interested in the cell biology of cancer cells. At some point, I realized that it didn’t really matter if it was cancer or Alzheimer’s or some other basic biological questions on other organisms; what I really was curious about was solving tough problems and answering questions. This was a good mix where, if I were able to do it, I would also be helping people with cancer in the future.

Focusing on cancer would give me an opportunity to apply my curiosity to something that is relevant for people. That was the original intention. Since I was not an MD, my curiosity was about mostly biological questions. This was a fitting problem to go after.

Let’s talk about the concept of disseminated tumor cells. Can you explain to us how that works and how it is related to the development of metastasis?

Dr. Aguirre-Ghiso: Patients usually present with what’s called a primary tumor. That’s the first cancer lesion ever found in that patient. At that time, doctors will do certain tests on that primary tumor to understand if it had gone through certain changes that would make it able to spread. When cancer cells grow, they may acquire certain abilities that allow them to spread from that primary site—from, let’s say, the prostrate or the breast—to other parts of the body.

The disseminated tumor cells are these cells that have spread throughout the body. They have disseminated from the primary tumor to other organs in the body. Those could be the bones; the liver; the brain; or the lung. When they arrive to those organs, they’re not immediately able to grow. Since they’re usually solitary cells–that’s how we find them in the patient samples and in the mouse models that we’ve used—we call them disseminated tumor cells. They’re not yet metastases, but they’re not in the primary tumor. They’ve left and arrived to other organs. That’s the definition of these disseminated tumor cells.

Why are they important? We and others have provided compelling evidence that these cells are the source of the metastases. Those are the cells, not all of them, but some of them, that are able to eventually grow into metastases that affect the functioning of the organ, and sometimes systemically, the functioning of the patient. That’s what leads to death. That’s why these cells are important.

Do all disseminated tumor cells eventually grow into metastases?

Dr. Aguirre-Ghiso: No.

How do you know which disseminated tumor cells are going to grow into metastases and which are not?

Dr. Aguirre-Ghiso: Well, that’s been a major challenge and a major push from my program: to try to get in early and identify those disseminated tumor cells so that we have some idea if a patient carries disseminated tumor cells that are not going to do anything and the patient doesn’t have to worry, or if the patient carries some cells that look like they’re switching and they’re going to form metastases.

That has been our goal. It’s not yet a clinical test, but that’s why we have pushed the boundaries of our research to get to that point as fast as possible because we think that instead of waiting and not doing anything or treating blindly and then waiting until those metastases grow, we can intervene earlier. We would like to be able to say that this patient has only dormant cells and they don’t look like they’re going to reactivate based on certain markers or gene signatures.

That patient would then only need to be monitored, but new treatments may allow eliminating even those cells. If another patient has a mixture of cells some of which are fully dormant and some of which look like proliferative cells, we would treat him in a different way.

We have provided data for this from our mouse models and from clinical patient samples in prostate cancer. We published two papers in 2014 and in 2015 on this.

Not all cells are going to grow.

In fact, if you look at early lesions in breast cancer, for example, disseminated tumor cells are found in the bone marrow of 13-15% of women with ductal carcinoma in situ but only a small fraction of that 13-15% will develop metastases. It’s not a given that if these cells are there they’re going to grow, but if they are there, there is a higher risk of metastases. That has been proven by large population studies that have been published in The New England Journal of Medicine. This is true for not only breast cancer but for other cancers as well. The goal and the challenge is to have enough information to be able to predict accurately what those cells are going to do when you detect them.

Where we are in the timeline of being able to predict which patient is carrying potentially dangerous disseminated cancer cells and which is carrying dormant disseminated cancer cells?

Dr. Aguirre-Ghiso: We have different areas of research into these disseminated tumor cells. Why they are dormant? Why do they sleep in the body for a long time and then awaken? We discovered a marker in 2015 that could distinguish these deep-sleeping cells in both prostate cancer and breast cancer models. If the cells had this marker, they would behave in this dormant way, and if they didn’t have this marker, they would look more like a proliferative or an about-to-reactivate cancer cell.

At that time, it was correlative between just two groups of patients. Last year, we published a paper on breast cancer where we used the same marker detected in tumor cells disseminated to the bone marrow of breast cancer patients. We were able to show that if patients had this marker they were much less likely to relapse with bone metastases than if they didn’t have this marker. In 2015, we’ve published the original finding where we just said this is probably a good marker; we understand how it works in mouse models. In 2018, we showed that the presence of the markers can distinguish retrospectively how patients behaved. Now the challenge is for people to start using the markers prospectively to see if it helps them make decisions on how to treat or monitor patients. We are very much at the early stages of applying the information that we have generated and bringing it into the clinic.

On the other hand, in that same 2015 paper, we were able to show that if we use two drugs that are FDA-approved and combine them in sequence, we can turn on these dormancy mechanisms in different types of cancer cells—i.e. breast, prostate, and head and neck cancer cells. Because these drugs were available—and there are independent studies showing that when prostate cancer patients are treated with hormonal therapy and anti-androgens, they turn on this marker of dormancy that tells you the cancer is deciding to go into sleeping mode— we wondered if we could repurpose those drugs and treat prostate cancer patients at risk of developing metastases to see if we could delay the onset of metastasis and keep the disseminated tumor cells in a dormant state.

To read the rest of our conversation and to learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us. Or download the issue.


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Biochemical Recurrence

In March, we’re talking about biochemical recurrence.

Dr. Snuffy Myers frames the issue for us below.

Not a member? Join us to read conversations with Drs. Daniel George, Pedro Barata, Julio Aguirre-Ghiso, and Rahul Aggarwal.

Pp_March_2018_V4_N7

This issue focuses on treatment issues for men with an increasing PSA after prostatectomy or prostate radiation. In this introduction, I will review some basic concepts that should help you follow the discussion more easily.

If surgery has successfully removed the prostate gland, the only source of PSA will be surviving cancer cells. After radiation, there can be normal prostate cells in addition to cancer cells. However, prostate cancer cells differ from normal prostate cells because the cancer cells are able to grow in a particular manner. Cancer cells grow by doubling: 1 cell becomes 2; 2 become 4; 4 become 8. Cancer cells do this at a constant rate.

For example, if the cancer cells double every year, then on subsequent years, the number of cancer cells would be 1, 2, 4, 8, 16, 32, 64, 128, 256, and so on. As a general rule, it takes 15 doublings to go from 1 cancer cell to a mass 1 centimeter across. At 1 centimeter, cancer masses generally become detectable by CT scan. As a rough rule of thumb, it takes another 15 doublings to reach a lethal cancer burden.

The implication is that half of the cancer growth occurs below the level of detectability.

Unlike most cancers, our ability to follow prostate cancer is not limited to imaging tools like the

CT or bone scans. We have PSA as a biochemical marker that can be used to follow the cancer. The PSA is a much more sensitive indicator of cancer presence than both CT or bone scan and can indicate the presence of recurrent cancer months to years earlier.

In most patients, the PSA level is roughly proportional to the size of the cancer mass: if the cancer doubles in size, the PSA will double. Thus, the PSA doubling time is thought to provide an estimate of the cancer doubling time. PSA doubling times faster than 3 months usually indicate rapidly growing disease associated with short survival unless treated aggressively. PSA doubling times slower than 9 months usually indicate much less aggressive cancers. PSA doubling times greater than two years are associated with prostate cancers that can take a decade or more to cause metastases detected by the scans.

As a result, it is common to see men after surgery or radiation who have an increasing PSA, but no other evidence of disease. In those patients, PSA doubling time represents the only well established tool to determine the aggressiveness of the cancer and how soon metastatic cancer might manifest itself.

PSA, however, provides no information about the location of the cancer. Is it present in bone, lymph node, liver, or lung? The recent advances in PET scans mean that the cancer can now be detected while it is much smaller than would be the case with CT or bone scan. However, clinical trials have yet to prove this early detection improves the outcome of treatment.

Finally, there is the problem of late relapses. After surgery, patients can have an undetectable PSA for years—even more than a decade— and then recur. What was going on during that silent interval and what changed to trigger recurrent cancer? This phenomenon is called cancer dormancy and is also reviewed in this issue.

Charles E. Myers, Jr., MD