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Dual MOA for Eribulin in Breast Cancer

Panelists: Mark Pegram, MD, Stanford Cancer Institute; Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center
Published: Monday, May 08, 2017


Transcript:

Mark Pegram, MD:
The mechanism of action of eribulin is quite interesting. It’s an analog of a natural product, halichondrin B, which is a microtubule dynamic inhibitor. It results, basically, in stacking of the mitotic spindle during G2/M and causes a cell cycle arrest of that phase, resulting in a mitotic catastrophe. And that introduces a programmed cell death, resulting in the killing of tumor targets. So, it’s a fascinating mechanism of action, and there are other mechanisms of action of eribulin that are also coming into play and have just recently been published.

In particular, there was a paper published in 2014 on experimental model systems that looked at vascular remodeling following exposure to eribulin. And interestingly, it showed that this remodeling effect was really quite striking—and it was in vivo in actual tumors, experimentally—and it probably results in actually what might sound contradictory: an increase in profusion into the tumor, which might actually facilitate delivery of chemotherapeutics into the tumor bed. Moreover, it has been shown in those same model systems that the hypoxia is normally associated with a tumor microenvironment, which is very profound and very severe and an important cause of resistance, particularly to radioresistance, but also to chemotherapeutics.

The hypoxia constraints are relieved after exposure to eribulin in vivo. More recently, just last year, there was another paper in the British Journal of Cancer that looked at the same affect in humans. And in human subjects, a similar observation was made that there was an increase in oxygen delivery within tumors in patients after exposure to eribulin. So, I think that’s pretty interesting, and it’s parallel to the vascular normalization effects we’ve talked about over the years previously with other antiangiogenic approaches in human cancer. That’s thought to be an important mechanism to reduce hypoxia, increase drug delivery, and then you’ll get a better therapeutic response as a consequence.

Joyce O’Shaughnessy, MD: Eribulin is a novel agent, with regard to its mechanism of action. It stopped polymerization of the microtubule, similar to the vinca alkaloids, but different. It causes these nonfunctional clusters of tubule because they cannot be assembled. So, it really stops the leading edge of the microtubule and that immediately says “invasiveness” to me when cells need to move forward because they’re either a breast cancer cell and they need to metastasize and invade or they’re an endothelial cell and they’re trying to make new blood vessels for the breast cancer to get oxygen and nutrients, for example.

It is antimitotic, so it’s antiproliferative and it’ll shut down mitosis and stop cell division. But it’s also anti-invasive, anti-metastatic, and mesenchymal, these cells that are sarcomatous-like in their shape and in their biology, creeping along, assembling microtubules at that leading edge to invade through the tissue and then ultimately into vessels and to metastasize. So, eribulin is very strong on both of those parts of the metastatic process.

Mark Pegram, MD: Cancer cells are not static. Indeed, they’re very dynamic and can have a range of different properties and cellular activities and functions. And one of the problems in human cancer is the ability to metastasize. In order to do that, a cell has to make proteases that can allow digestion of the extracellular matrix so that they can move about. They have to have a motility capability, which is not easy for a cell to acquire. They have to be able to invade through a blood vessel or a loop vessel wall to gain access to the circulation.

They have to survive in that circulation environment, which is a hostile environment because of the immune system. They have to have just the right repertoire of adhesion molecules to adhere to a distant capillary bed. They have to be able to exit the vascular system, which is another type of cellular function, and then survive on a completely different microenvironment that’s foreign to them. In order to do that, cancer cells of epithelial origin have to go through a transformation called the EMT, or the epithelial mesenchymal transformation. And that is the acquisition of these capabilities to be able to have motility and survive in the circulation and then be able to set up and establish new colonies in a distant site in a foreign territory, if you will, with a different microenvironment.

And so, ideally, it would be nice to have molecules, in terms of therapeutics, that can block that EMT transition because that might reduce the metastatic burden, in theory, and result in therapeutic benefit. So, drugs that are known to have an impact on this transition I think are pretty interesting in terms of mechanism of action, and it is appealing to think that if that’s one of the mechanisms, then it should result in therapeutic benefit.

There are data on EMT transition following exposure to eribulin, and this drug actually does impact the ability of the cell to go through that transformation. That is felt to be perhaps one of the mechanisms of action of eribulin in vivo—certainly, an experimental model, if this is the case. I think there’s less information directly from the clinic to document that. But studies are forthcoming that may address that.

Transcript Edited for Clarity
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Transcript:

Mark Pegram, MD:
The mechanism of action of eribulin is quite interesting. It’s an analog of a natural product, halichondrin B, which is a microtubule dynamic inhibitor. It results, basically, in stacking of the mitotic spindle during G2/M and causes a cell cycle arrest of that phase, resulting in a mitotic catastrophe. And that introduces a programmed cell death, resulting in the killing of tumor targets. So, it’s a fascinating mechanism of action, and there are other mechanisms of action of eribulin that are also coming into play and have just recently been published.

In particular, there was a paper published in 2014 on experimental model systems that looked at vascular remodeling following exposure to eribulin. And interestingly, it showed that this remodeling effect was really quite striking—and it was in vivo in actual tumors, experimentally—and it probably results in actually what might sound contradictory: an increase in profusion into the tumor, which might actually facilitate delivery of chemotherapeutics into the tumor bed. Moreover, it has been shown in those same model systems that the hypoxia is normally associated with a tumor microenvironment, which is very profound and very severe and an important cause of resistance, particularly to radioresistance, but also to chemotherapeutics.

The hypoxia constraints are relieved after exposure to eribulin in vivo. More recently, just last year, there was another paper in the British Journal of Cancer that looked at the same affect in humans. And in human subjects, a similar observation was made that there was an increase in oxygen delivery within tumors in patients after exposure to eribulin. So, I think that’s pretty interesting, and it’s parallel to the vascular normalization effects we’ve talked about over the years previously with other antiangiogenic approaches in human cancer. That’s thought to be an important mechanism to reduce hypoxia, increase drug delivery, and then you’ll get a better therapeutic response as a consequence.

Joyce O’Shaughnessy, MD: Eribulin is a novel agent, with regard to its mechanism of action. It stopped polymerization of the microtubule, similar to the vinca alkaloids, but different. It causes these nonfunctional clusters of tubule because they cannot be assembled. So, it really stops the leading edge of the microtubule and that immediately says “invasiveness” to me when cells need to move forward because they’re either a breast cancer cell and they need to metastasize and invade or they’re an endothelial cell and they’re trying to make new blood vessels for the breast cancer to get oxygen and nutrients, for example.

It is antimitotic, so it’s antiproliferative and it’ll shut down mitosis and stop cell division. But it’s also anti-invasive, anti-metastatic, and mesenchymal, these cells that are sarcomatous-like in their shape and in their biology, creeping along, assembling microtubules at that leading edge to invade through the tissue and then ultimately into vessels and to metastasize. So, eribulin is very strong on both of those parts of the metastatic process.

Mark Pegram, MD: Cancer cells are not static. Indeed, they’re very dynamic and can have a range of different properties and cellular activities and functions. And one of the problems in human cancer is the ability to metastasize. In order to do that, a cell has to make proteases that can allow digestion of the extracellular matrix so that they can move about. They have to have a motility capability, which is not easy for a cell to acquire. They have to be able to invade through a blood vessel or a loop vessel wall to gain access to the circulation.

They have to survive in that circulation environment, which is a hostile environment because of the immune system. They have to have just the right repertoire of adhesion molecules to adhere to a distant capillary bed. They have to be able to exit the vascular system, which is another type of cellular function, and then survive on a completely different microenvironment that’s foreign to them. In order to do that, cancer cells of epithelial origin have to go through a transformation called the EMT, or the epithelial mesenchymal transformation. And that is the acquisition of these capabilities to be able to have motility and survive in the circulation and then be able to set up and establish new colonies in a distant site in a foreign territory, if you will, with a different microenvironment.

And so, ideally, it would be nice to have molecules, in terms of therapeutics, that can block that EMT transition because that might reduce the metastatic burden, in theory, and result in therapeutic benefit. So, drugs that are known to have an impact on this transition I think are pretty interesting in terms of mechanism of action, and it is appealing to think that if that’s one of the mechanisms, then it should result in therapeutic benefit.

There are data on EMT transition following exposure to eribulin, and this drug actually does impact the ability of the cell to go through that transformation. That is felt to be perhaps one of the mechanisms of action of eribulin in vivo—certainly, an experimental model, if this is the case. I think there’s less information directly from the clinic to document that. But studies are forthcoming that may address that.

Transcript Edited for Clarity
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