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Ubenimex (bestatin) treats lymphedema in mice. Will the drug help you?

Could the drug Ubenimex (also known as bestatin) be used to treat lymphedema in humans? A nice study was recently published, and a clinical trial is underway. But how excited should we be?

There is some buzz happening about the Ubenimex lymphedema clinical trial (see the ‘ULTRA’ clinical trial details here). Patients have inquired about the drug in our clinics, there are numerous press releases about it including one on the Stanford University website (see here), and a lymphedema blog I enjoy recently interviewed the Chief Medical Officer of the pharmaceutical company involved (see here).

I haven’t had a chance to dig into the science of this study until now. My own doctoral thesis was vaguely related (I studied natural biochemicals that direct our bodies ‘stem cells’ to do things: make new cells, turn into different types of cells, or to die), so I was looking forward to giving this study a good read.

Let me start by saying that the research supporting a possible therapeutic role for Ubenimex in lymphedema is well-done and very impressive in both its scale and depth (you can read the abstract of the study of interest here). I also sincerely hope that the clinical trial will demonstrate improvement in the lymphedema symptoms of study participants. But the skeptical scientist in me isn’t feeling overly optimistic about the likelihood that this clinical trial will show a large benefit to patients. Let me explain:

Here’s where the excitement about treating lymphedema with Ubenimex (bestatin) comes from

The Stanford University press release about this new study states:

  1. “The researchers found that the buildup of lymph fluid is actually an inflammatory response within the tissue of the skin, not merely a “plumbing” problem within the lymphatic system, as previously thought.”
  2. “…scientists discovered that a naturally occurring inflammatory substance known as leukotriene B4, or LTB4, is elevated in both animal models of lymphedema and in humans with the disease, and that at elevated levels it causes tissue inflammation and impaired lymphatic function.”
  3. “Further research in mice showed that by using pharmacological agents to target LTB4, scientists were able to induce lymphatic repair and reversal of the disease processes.”

Combined with the fact that Ubenimex (bestatin) has been used for 35 years in Japan as a chemotherapy adjuvant for leukemia (and so has a history of safety in humans), these statements make for a very enticing story and a lot of optimism.

Optimism is great, and I’m glad the pharmaceutical company is funding the clinical trial and that further research on the effects of Ubenimex on lymphedema is ongoing. But the above statements issued in the press release are not an accurate representation of the results of this key study.

What does the Ubenimex (bestatin) lymphedema study actually tell us?

The authors of this study (ref 1) used an experimental mouse model of lymphedema to investigate the effects of Ubenimex on lymphedema. Here’s what they did: they made a very small circular cut around the base of each mouse tail. This cut severs lymph vessels. As expected, the mice subsequently developed lymphedema in their tails because lymph drainage (ie, the lymphatic ‘plumbing’) was disrupted. If the mice are left untreated from this injury they will naturally recover some lymphatic function, but they will not heal completely, and will instead suffer from chronic swelling in their tails.

Here’s the exciting part: the researchers found that if you treat these injured mice with bestatin, the mice are better able to heal the damage caused to their lymphatic vessels. This in turn improves their lymphatic drainage, and permanently reduces their swelling. In other words, in mice who’ve had their tails cut, bestatin worked as a treatment for lymphedema!

(You can skip this next section if you don’t feel like reading more details about the science of the study)

The science

Through a nice collection of experiments the researchers discovered how bestatin works to reverse swelling and prevent chronic lymphedema the mice. They observed a naturally occurring substance called leukotriene B4 (LTB4) (which is a member of a group of biochemical signals known as ‘cytokines’) at the site of the injury, and noticed further that it plays a big part in the healing process. In the first three days following the tail-cutting surgery, a small amount of LTB4 can be found at the injury site. This small amount of LTB4 works to HELP the mouse heal from the injury, and when they experimentally blocked LTB4 at this stage, healing was reduced. Low levels of LTB4 appears to promote healing by encouraging beneficial immune cells to come to the site of injury, AND (importantly) by directing the damaged cells of the lymph vessels to grow and repair the damage. (If you are a cell biology fan and are curious about how exactly LTB4 is doing this, it appears to be related to activating the Notch1 and VEGFR3 signaling pathways in these cells).

Unfortunately, after the third day following the surgery, things got out of control. Levels of LTB4 got too high, which in turn caused too much inflammation.  Importantly, it also changed what cells of the lymph vessels were doing. The researchers discovered that high levels of LTB4 had the OPPOSITE effect as low levels. High levels of LTB4 told the cells to STOP trying to heal the vessels (by deactivating Notch1 and VEGFR3 activity in the cells). In other words, the mouse tails try to heal themselves for the first three days with the help of LTB4, but after day three LTB4 levels become too high, and this tells the healing process to stop prematurely. In a nutshell: low levels of the LTB4 cytokine helps lymphatic healing, but high levels prevent lymphatic healing.

So how does the experimental drug bestatin fit into this picture?  What happens if you give these mice the bestatin drug, which blocks the activity of LTB4? As you would guess, the study showed that if you give bestatin to the mice too early (before day 3), it will prevent healing and make lymphedema worse. BUT if you give it to the mice after day 3 (when inflammatory processes get out of control), it can shut down the excessively high levels of LTB4, remove the negative effects caused by high levels of LTB4, and allow the mouse to heal and recover lymphatic function!

The paper had a lot of interesting data and figures in it, but one that is particularly impactful is reproduced in Figure 1 below. In this figure you can see two mouse tails that underwent surgery. One was treated with bestatin (the bottom one), while the other was treated with a harmless solution of saline (the top one). Although it can be a little hard to see in this photo (the authors captured the photo from a video they made), in the bestatin treated mouse you can see a dye called NIR that was injected into the tail lymphatics travelling past the wound site on it’s way back into the body of the mouse (‘proximal’ means towards the center of the mouse). In the mice treated with saline no dye is visible proximal to the wound. This shows visually that meaningful lymphatic function is restored by bestatin treatment.

Ubenimex (bestatin) can treat lymphedema in mice

Figure 1: Ubenimex (bestatin) can improve lymphatic function in an experimental mouse model of lymphedema (figure adapted from ref 1). NIR dye injected into tail lymphatics is seen travelling through the wound site in mice treated with bestatin, but not in control mice treated with saline solution.

 

(If you’ve skipped the above, you can rejoin here:)

The study conclusions

Contrary to the press release, the scientists did not find that the buildup of lymph fluid is due to an ‘inflammatory response’ rather than ‘merely a plumbing problem’. Instead, they found that insufficient healing after an injury to the lymphatic system (which is a plumbing problem) is caused by an excess buildup of LTB4 (a pro-inflammatory factor) which at high doses limits normal lymphatic healing processes.

This might feel like I’m splitting hairs a bit, but I’m not. This distinction is very important, because it suggests that Ubenimex (bestatin) may help NEW lymphatic injuries heal, but ONLY if natural healing is biologically possible, and ONLY if it is given at the right time and right dose. In contrast, the press release implicitly suggests that bestatin may reduce the symptoms of lymphedema regardless of the underlying plumbing problem and divorced from the normal healing process – which is not supported by the available data. To say it more plainly: this data does not say that elevated levels of LTB4 “causes impaired lymphatic function”, it instead says that it causes impaired lymphatic healing.

But LTB4 was shown in the study to also reduce general inflammation in the area, so perhaps a reduction in inflammation could also be playing a beneficial role in curing lymphedema in mice?

Not so, or at least the data doesn’t support this hypothesis. The data suggests that the benefit of bestatin for treating lymphedema is ONLY due to its ability to stop LTB4 from telling the cells of the damaged lymphatic vessels (the plumbing) to stop trying to heal themselves, and has little or nothing to do with reducing general inflammation. This is why other anti-inflammatory drugs studied by the researchers were unable to treat lymphedema in the mice, and why the researchers concluded:

“it is unlikely that blocking inflammation alone is sufficient to reverse disease”

If Ubenimex (bestatin) has only been shown to repair lymphedema by allowing natural healing mechanisms to proceed unhindered by the inflammatory factor LTB4, should we expect it to work in human cases of secondary lymphedema?

The researchers show that LTB4 is elevated in humans with lymphedema, and that human lymphatic endothelial cells studied in a lab grow when LTB4 levels are low, but stop growing when they are high. These observations suggest that bestatin plays a similar role in humans as it does in mice.

This means that there is a good chance that if you cut a lymphatic vessel in a human and treat the human with bestatin at the right time and dose to encourage healing, that the results would be better than if bestatin were not used. That’s pretty exciting.

But how does this relate to real-world patients with lymphedema? This is where we need to start extrapolating from the data. If, as the study suggests, bestatin is ONLY beneficial because it removes a natural barrier to normal healing (which is different than “inducing repair” as stated in the press release), then we should ONLY expect it to work when healing processes are active, and when healing is possible. This is where it is important to note a distinction between the mouse experimental model and a human with the disease. The mouse model of lymphedema destroys a very small length (a few millimeters) of a handful of lymph vessels, vessels that can normally undergo some healing on their own, even without bestatin to help. The human experience of lymphedema is very different from the experimental mouse model.

The most common form of lymphedema in humans, is lymphedema secondary to cancer. This results from much greater lymphatic damage than is incurred in the mouse model. Rather than damaging a few millimeters of a few lymph vessels, in humans whole lymph nodes are removed and/or irradiated. Lymph nodes act in part as collecting chambers for lymph fluid flowing from smaller vessels toward larger ones, en route to rejoin the circulatory system at the heart. Normal injury healing processes in humans appear unable to regrow such substantial tissue structures. Worse still, as days pass after lymph node surgery and/or radiation, scar tissue can onset which further challenges lymphatic drainage and can lead to disuse of the limb (which is also detrimental). Eventually the onset of lymphedema can cause additional damage to the neighbouring lymphatic vessels in the area, through overburdening and gradual tissue changes.

Therefore, if bestatin’s only function in curing lymphedema is to remove the barrier that LTB4 creates to normal healing, then we should expect it to have little or no effect on established cases of lymphedema in humans. We can’t expect the drug to regrow missing lymph nodes, or to repair significant vessel damage. But LTB4 is present and elevated in human patients with lymphedema (as it is with inflammation caused by other injuries or conditions), so blocking it with bestatin could still have some positive effects. I’m speculating here without data, but perhaps smaller ongoing lymphatic damage caused by disease progression could be reduced or reversed by the drug. This could potentially reduce symptoms or fend off disease progression.

Could Ubenimex (bestatin) help cases of primary lymphedema where patients are born with the condition or with a predisposition to developing it?

Individuals with primary lymphedema may be less likely to respond positively to bestatin for two reasons:

  1. Primary lymphedema is caused by a lymphatic defect that patients are born with and which manifests as lymphedema either right away, or later in life, typically after a lymphatic challenge. So unlike for cases of secondary lymphedema, with primary lymphedema there is no primary injury that the body is trying to repair.
  2. Some cases of primary lymphedema are known to be caused by abnormal lymphatic cell behaviour. One underlying cause of primary lymphedema appears to be mutations that interfere with the function of a cell protein called VEGFR3 that helps lymphatic cells communicate with their environment and thus decide what to do (ref 2). Unfortunately, the current study suggests that LTB4’s action on lymphatic cells is via VEGFR3. If this is true, then blocking LTB4 with bestatin in these patients could have no impact whatsoever on their lymphatic cells – because the cells simply can’t respond to it. The same would be true for cases of primary lymphedema caused by some other defect in a piece of the cell machinery that works in concert with VEGFR3.

However, cases of primary lymphedema not caused by disrupted VEGFR3 might benefit from bestatin in the same way that secondary lymphedema might: by helping reduce and reverse smaller ongoing lymphatic damage associated with disease progression. But once again, we are hypothesizing without data.

Summary

Ubenimex (bestatin) can reverse the development of experimental lymphedema in mice by blocking an inflammatory protein called LTB4 that prematurely stops the normal healing process. Blocking LTB4 at the right time allows the mice to heal their lymphatic injury and avoid getting chronic lymphedema.

This discovery is an exciting and significant contribution to our understanding of lymphedema, and offers a novel and potentially beneficial treatment avenue for the disease. But the available data suggests that Ubenimex will unfortunately not represent a cure for lymphedema in humans.

A cure for lymphedema in humans will require repair or regeneration of the significant underlying lymphatic ‘plumbing problem’ found in humans, a problem that natural healing processes are seemingly unable to repair. Even though Ubenimex isn’t expected to solve this underlying problem, it could potentially help with the symptoms of the disease by encouraging normal lymphatic repair processes to heal the smaller ongoing lymphatic damage that occurs with disease progression. There is currently no data for us to look at, so we don’t know if Ubenimex will offer a significant benefit to patients, a minimal benefit, or no benefit at all. But since Ubenimex has previously been shown to be relatively safe and well tolerated, it’s both exciting and heartening that a pharmaceutical company is funding a clinical trial to find out.

References

  1. Tian W., Rockson S.G., Jiang X., Kim J., et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med. 2017 May 10;9(389).
  2. Karkkainen M.J., Ferrell R.E., Lawrence E.C., Kimak M.A., et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphedema. Nat Genet. 2000 Jun;25(2):153-9.

2 Comments

  1. deb deb says:

     One of the problems lymphedema biomedical researchers have to deal with is establishing an animal model of “chronic lymphedema”. There is no “chronic disease” animal model for lymphedema, to the best of my knowledge. I have not read the entire research article yet, but I generally concur with the opinions expressed in this article from what I have heard, and I know that this finding of changing levels of the targeted molecule was discussed at a recent forum of scientists in Chicago. However, it is surmised that chronic lymphedema does create some degree of a chronic inflammatory state. There is still so much to be discovered in lymphedema research, and we do all need to get behind the biomedical research to support its movement forward towards better understanding of the disease! It is drastically behind compared to other chronic diseases because of poor funding, and it is only biomedical research that will lead to enough of an understanding of the disease to create new treatments for it.

  2. Ryan Davey Ryan Davey says:

    I think you hit the nail on the head Deb. Part of the misunderstanding that this article has generated in the online discussion comes from the fact that physiological processes at play during induced acute lymphatic injury (such as in the mouse model) are different from those active during chronic lymphatic insufficiency – so drugs that are found to be beneficial in the mouse model may have relevance to lymphatic HEALING processes that occur BEFORE the onset of lymphedema, but be less relevant (or irrelevant) to the chronic disease state. So the mouse model is certainly not an ideal model for human lymphedema, but given that lymphedema is a progressively worsening condition (if not managed) typified by ONGOING lymphatic damage, chronic inflammation, and tissues changes (such as hardening), there is a chance that factors involved in early lymphatic healing of the primary injury may also be beneficial for addressing ongoing damage and repair processes during chronic disease. So we should remain hopeful that pharmaceutical options will become available to help manage symptoms and/or hopefully delay/prevent disease progression. And it is very nice to see a pharmaceutical company getting behind a clinical trail for secondary lymphedema – getting commercial interests involved is a necessary step :)

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