Innovations Ahead: Decreasing Thrombosis in Patients with Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program. Today I'm happy to be joined by Dr. Tatiana Byzova, a staff member in the neurosciences program in the Lerner Research Institute at Cleveland Clinic. She's here today to talk to us about decreasing thrombosis in patients with cancer. Welcome.

Tatiana Byzova, PhD: Thank you. Pleasure to be here.

Dale Shepard, MD, PhD: Maybe to start, give us a little idea of what your role is here at Cleveland Clinic.

Tatiana Byzova, PhD: I became a staff member at CCF in 2000, and I used to be in Department of Molecular Cardiology, now I moved to Department of Neuroscience, and for a number of years, my main focus is on biology and various pathologists of blood vessels.

Dale Shepard, MD, PhD: Excellent. And we're going to tap into that and we're going to talk about tumors and platelets and thrombosis, very good. Maybe to start with, maybe you can give us a little bit of an idea of how important thrombosis is when we think about cancer?

Tatiana Byzova, PhD: For cancer patients, the risk of thrombosis is exceptionally high. In fact, it's estimated that cancer patients are up to five times more likely to experience thrombosis, and this percentage increases dramatically in elderly patients and patients with existing cardiovascular complications. Moreover, a lot of recent clinical research shows that occurrence of thrombosis is associated with much poorer prognosis and shortage of survival in a number of cancers. The complications of cancer thrombosis might be very severe, such as pulmonary embolism, deep vein thrombosis, stroke, and venous thromboembolism. Moreover, thrombotic complications in cancer might impact on the treatment. Blood clots known to interfere with delivery of chemo therapeutic drugs to the tumor site and reduce the effectiveness. And they might also hinder surgical procedures or radiation therapy by changing, affecting blood flow and increasing the risk of complications. It's always known to be associated with poor high risk of disease progression and poor outcomes, as I've already mentioned. And last but not least, thrombosis might present a lot of diagnostic challenges. Symptoms of blood clots such as pain, swelling, redness, may be attributed to the cancer and it also might lead to delayed diagnosis.

Dale Shepard, MD, PhD: And when you talk about the impact of thrombosis on prognosis, that could be people that have PE for instance, very early on, and it's the thrombosis itself, but also about delivery of care.

Tatiana Byzova, PhD: Right. In fact, historically multiple incidents of thrombosis were shown to be diagnostic. Very often thrombosis presents itself faster than the tumor itself. That's known to be a fact for a number of cancers.

Dale Shepard, MD, PhD: Excellent. Somebody gets cancer associated thrombosis. We have a lot of different people; different backgrounds might be listening. What are the current therapies? How do we treat that currently?

Tatiana Byzova, PhD: Currently, one of the most popular is anticoagulant therapy that considers it to be mainstream treatment for cancer thrombosis. They pretty much prevent formation of new blood clots, reduce the risk of existing clots, and most commonly used are low molecular weight heparin such as enoxaparin, Vitamin K, antagonists such as warfarin, also direct oral anticoagulants been in use such as rivaroxaban and others. They alternative to low molecular weight heparin, they shouldn't be relatively effective in some cancer patients.

Dale Shepard, MD, PhD: It has a huge impact on patients. What are some of the downfalls of current therapies?

Tatiana Byzova, PhD: Since all of these drugs, all known antithrombotic drugs, they target pathways that are involved in thrombosis, but also in normal hemostasis. And what we might anticipate is an increased incidence of bleeding episodes in these patients, which also has a lot of complications.

Dale Shepard, MD, PhD: Tell us a little bit about that balance between we want to not form clots and we want to not have bleeding, tell us a little bit about that.

Tatiana Byzova, PhD: A number of cancer treatments increase the risk of bleeding. It's not limited to surgery or any invasive procedures, but a lot of tyrosinase kinase inhibitors can shift this balance between ability to form clots and excessive bleeding. And in many situations, it is really crucial to make sure that the patient's hemostatic function is intact to prevent excessive bleeding and complications. And one of the probably best examples is normal hemostasis, particularly important for stroke prevention and management.

Dale Shepard, MD, PhD: Tell us a little bit about what you've been working on in terms of cancer and thrombosis.

Tatiana Byzova, PhD: For years, my lab has been interested in cancer and thrombosis in general and interested in the mechanism of tumor communication with various organs, which would include pre-metastatic and metastatic communications. And several years ago, we published a manuscript that's showing that metastatic cancer is able to affect their future metastatic niche such as bone. We also demonstrated that this particular communication was depleted by platelets. If you deplete platelets, there are no changes in the bone and also decreases incidences of metastasis. We applied to NH, we got a substantial funding for these projects from NH and American Heart. And we wanted to answer a simple question, "How exactly do platelets become tumor educated messengers?" And this was completely unknown. In a recent study that we just published in circulation research, which showed that aggressive tumors that release small extracellular vesical, which in turn can be engulfed by platelets. This uptake leads to accumulation of cancer-specific markers, first of all, which actually creates a window of opportunity of using platelets as a cancer for prognostic purposes. And also, this small cell vehicle from cancer, they change reprogram platelets. Platelets become hyperreactive.

Dale Shepard, MD, PhD: Essentially tumors release these vesicles, platelets interact with the vesicles, and then they're more likely to cause thrombus.

Tatiana Byzova, PhD: They take then engulf them by a mechanism. And we delineated the complete mechanism for this process, how these vesicles are getting into the platelets.

Dale Shepard, MD, PhD: And what exactly are these vehicles? Is there something in the vehicles? Tell us a little bit about the vehicles.

Tatiana Byzova, PhD: It's like solar cell fragments. They have membranes and inside of them they have proteins, and they have RNAs and a number of modulators that can change machinery of other cells. That's how pretty many tumors are able to reprogram other cells just by sending these particular vesicles. First of all, there are a lot of fragments of RNA specific for cancer, which we are able to detect in these vesicles and also in platelets. And we actually have done this for this particular study using blood from patients with prostate cancer prior and after radical prostatectomy. We can see the markers of prostate cancer and platelets and in vesicles in patients before, but not after.

Dale Shepard, MD, PhD: Interesting. And when we think about having a tumor, and you mentioned about metastases, if you think about having a tumor, and sometimes we think about metastases forming by cells going through the lymphatics, but also through blood. And these platelets and vesicles, is that part of the mechanism by which the cells become metastatic?

Tatiana Byzova, PhD: Yes. Platelets are known actually to surround tumor cells and protect them from other immune cells, and they're also known to assist cells infiltrating through the vascular wall. The platelets themselves can assist metastasis. But probably the biggest problem is that platelets became hyperreactive, which results in high incidents and higher risk of thrombosis.

Dale Shepard, MD, PhD: Is there any feedback? You'd mentioned previously like anticoagulants, they stopped the activation and growth of clots. Is there any feedback on the release of the vehicles or, no?

Tatiana Byzova, PhD: Not that I know of, but there is feedback on the original growth of tumor.

Dale Shepard, MD, PhD: Got you.

Tatiana Byzova, PhD: The blockade of platelets has overall antitumor genetic effect, and actually, it helps the number of therapies become more efficient, for instance, like tyrosinase kinase inhibitors are more efficient if we are taking care of platelet component.

Dale Shepard, MD, PhD: Interesting. Are there mechanisms that we can use to treat thrombosis, or is the risk of thrombosis based on these vesicles?

Tatiana Byzova, PhD: What is really important is just to understand platelets, they become activated and there are not a number of pathways of platelet activation and then been explored as a target for cardiovascular disease, we know quite a few of them. And they have also been explored for a number of other diseases, however, all of them that target known pathways, and if the target known pathways, those the same pathway that would mediate normal hemostasis. It's important to find a new cancer specific pathway. And that's exactly what we did. We showed that this small vesicle released by tumors, they bind two platelets, where small vesicle protein CD63 and receptor on the platelets. As a result, the vesicles get in and are able to reprogram platelets, making them hyperactive, susceptible for clotting. And this is a completely new pathway. In fact, we eliminated the entire pathway leading to platelet aggregation and its new pathway.

If you target any member or any stage of this pathway, we'll target something new that is not involved in hemostasis. And the most efficient way that we thought of is just to prevent the interaction with the small vehicles. We developed a panel of follow antibodies. We also used existing antibodies against CD63 that would block this small vehicle. We prevent the entrance to platelets, platelet hyperactivity and prevent thrombosis. And probably the most important component of our work is that we show that normal hemostasis remains absolutely intact. Its only tumor induced hyperactivity goes away.

Dale Shepard, MD, PhD: Because you targeted that.

Tatiana Byzova, PhD: Targeting only cancer components.

Dale Shepard, MD, PhD: That CD63, doesn't impact normal thrombosis?

Tatiana Byzova, PhD: CD63, yes. Does not. In fact, it's a very safe target. There are known knockouts of this molecule and they don't have very dramatic phenotypes. It's only specific to cancer.

Dale Shepard, MD, PhD: And do we have antibodies against CD63, that can be brought into the clinic?

Tatiana Byzova, PhD: Yes. We are actually patenting, we submitted disclosure patent together with our innovations on the use of anti CD63 antibodies to prevent exosome intake by platelets. And also, we are actually developing an entire new line of antibodies against exosomes that will be blocking for a number of implications, first of all, cancer.

Dale Shepard, MD, PhD: Are there any ways to inhibit the release of the vehicles or mostly at this point the work is focused on how to manage them once released?

Tatiana Byzova, PhD: It's very difficult to manage release. The release of vesicles correlates with aggressiveness of tumor. And very often even small tumors that are highly metastatic would release tons of these vesicles before we even know there is a tumor in particular patients. Up to this point, it's very hard to do. And those small vehicles, they're not a hundred percent like typical for tumors. They're also released by other cells in case of distress or dysfunction in pathological situations. For instance, they like signs of distress, but also propagated of distress. For instance, one of the thrombotic complications, COVID, is most likely mediated by the small vesicles. And we believe that antibodies, if we can trap these vehicles, also can prevent complications from COVID and sepsis.

Dale Shepard, MD, PhD: Very good. When we think about it, you've mentioned a couple of times about aggressiveness of tumors, and I guess just to clarify that, we know that thrombosis is much more common in some kinds of cancer, like kidney cancer or glioblastomas and things like that. Is it more histology based or is it when you say aggressiveness, is that any tumor that's actively growing or are there some subtypes that are more likely?

Tatiana Byzova, PhD: Yeah, actively growing tumor and a tumor that is prone to metastasis. Those tumors, highly metastatic tumors, release substantially more of the particles and the content of the spar particles, small vesicles might be different. We intend on catching them all before they get into other cells, to platelets. But another good side effect is if we catch the small vesicles, they also can affect bone marrow cells also, they can also work on pre metastatic niche. We are hoping that by blocking them, these messengers, we can stop a number of events.

Dale Shepard, MD, PhD: And one might imagine that if these vesicles have an impact, not only on ability to develop metastatic disease, but also thrombosis, do you see there might be a role where somebody's diagnosed with cancer and as part of their anti-cancer therapy, they're preventatively given these?

Tatiana Byzova, PhD: A number of cancers, I think it's going to be a must. Moreover, it's known that giving thrombotic drugs actually increases efficiency of any treatments like chemotherapy, radiation treatment. It's actually become very common for prostate cancers, for instance, to give antithrombotic drugs. This particular drug is safe, which is really, it makes a lot of difference for glioblastoma for a number of cancers. We don't want to have bleeding in patients with glioblastoma. And this also should be extremely efficient in patients on tyrosinase kinase inhibitors because they actually have a lot of thrombotic complications due to the drug.

Dale Shepard, MD, PhD: Got a lot of VEGF interactions, things like that.

Tatiana Byzova, PhD: We believe that this should be used. Those are antibodies that will be humanized, the small fragments, they're very safe, very specific. And the field and the number of fields of using small fragments of antibodies seem to be growing despite the presence of other small compounds, some small molecules.

Dale Shepard, MD, PhD: How far away are we in terms of clinical trial development, clinical use of these?

Tatiana Byzova, PhD: We just got the sequence of these antibodies, which is really interesting. We know antigen, we made sure that the small fragments operational work very nicely. We don't need to use the entire antibody. We use only FAB fragments, and we need to humanize it, go through safety, we are ready.

Dale Shepard, MD, PhD: Excellent. Is this all being developed here at the clinic or are we working with others?

Tatiana Byzova, PhD: Not yet, but it's in progress with our innovations department. And they're helping quite a bit in terms of patenting and spreading this technology. But eventually we probably will need strong pharmaceutical companies that would share this load of work.

Dale Shepard, MD, PhD: Fantastic. What do you think are going to be the largest barriers to bringing this to clinical use?

Tatiana Byzova, PhD: The partnership with pharmaceutical companies, most likely how this will develop. And I believe that these drugs are very efficient and most likely will take off relatively fast for different types of pathologies. But I think safety, FDA approvals, that's probably the biggest problems.

Dale Shepard, MD, PhD: That's great. Because oftentimes clinically we think about thrombosis ends up being something that's more of a reactionary treatment. We're treating patients, they develop a clot, we do something about it. This is a totally different way to think about how to manage it's fantastic.

Tatiana Byzova, PhD: And it will also change the efficacy of existing therapies.

Dale Shepard, MD, PhD: And as you stated, the mortality and morbidity of clots is not insignificant. That's great.

Tatiana Byzova, PhD: In fact, there are several cancers, some of them you mentioned that the main cause of death is not metastasis, not the growth of cancer, but thrombosis.

Dale Shepard, MD, PhD: You're doing great work and you've given us some good insight and we'll look forward to keeping track of this technology and this way to manage. And we're hoping for good things here. Thanks for being with us.

Tatiana Byzova, PhD: Pleasure.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled. This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. Don't forget, you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.