Ali Akoum, PhD - Medical Conference 2014

Ali Akoum, PhD - Medical Conference 2014

Endometriosis Foundation of America 2014
Is there a need for a targeted treatment of endometriosis? The macrophage migration Inhibitory factor (MIF) as a candidate
- Ali Akoum, PhD

Than you, thank you very much Christine and thank you Dr. Seckin for having invited me. I am very pleased to be here today.

So, is there any need for a targeted treatment of endometriosis: the macrophage migration inhibitory factor (MIF) as a candidate. Well, endometriosis, the ectopic growth of endometrial tissue mainly in the peritoneal cavity is a major health problem and it affects up to 10 percent of reproductive age women and 50 to 60 percent of women and teenage girls with pelvic pain and infertility.

So what can explain the development of endometriosis? There are genetic factors indeed, hormonal factors, environmental factors and immunological factors. For the hormonal factors endometriosis is the…as an estrogen dependent disease and there is a local synthesis of estradiol in endometriotic tissues and a resistance to progesterone has been described. The immunology…pro-inflammatory cytokines have been found in the peritoneal fluid and activated peritoneal macrophages, which paradoxically seem to help endometriosis development. Indeed there is endometrial dysfunction as well and our study was the first to demonstrate abnormal responsiveness to inflammatory stimuli in eutopic endometrial cells.

The omics: genomics, proteomics and secretomics revealed major significant change locally in the peritoneal fluid but also the systemic and eutopic endometrial levels. Here is a brief summary. As you can see here many numerous genes have been found, which are involved in inflammation so growth and macrophage activation, cell adhesions, cell proliferation, cell survival, which is relevant for endometriosis pathogenesis indeed.

These findings make plausible specific biochemical diagnosis and targeted treatments but we are far from achieving this goal. What are the reasons? Maybe they have to do with the complex and multifactorial nature of the disease itself; problematic diagnosis, multiple manifestations, atypical appearance, different degrees of severity and a variety of symptoms and even absence of symptoms. There is a real problem of validation. Actually, we need to use biobank material to independently validate in large sample sizes the results and the relevance to endometriosis of the most promising genes that we found and also move forward to prospective studies.

So, do we need a targeted treatment for endometriosis? I think so. The current medical treatment of endometriosis – just a summary here: for pain associated with endometriosis; analgesics ranging from NSAIDs to opioids are used. The main current medical treatment is based on the suppression of ovarian function and estrogen production.

For infertility:  the medical management of infertility related to endometriosis in the form of hormonal suppression is ineffective actually, according to many serious organizations. Why? Because suppression of ovulation is not suitable for patients seeking pregnancy and causes side effects. So no treatment ensures relief nor is curative. And the recovery rates after treatment ends reaches about 40 percent after five years.

What is being developed for the medical treatment of endometriosis now? If you take a look at the current clinical trials actually you can find many gonadotropins…agonists and antagonists, progestins, Danazol is still there and some analgesics/anti-inflammatory factors including the JNK inhibitor, which is a kinase inhibitor. This might be promising actually but it is in phase two with depot MPA with…progesterone.

In the pipeline we mainly find steroid and steroid signaling inhibitors but some anti-inflammatory drugs did not appear to be successful unfortunately, like Pentoxifylline and anti TNFa in spite of their elevated levels in the peritoneal fluid. And anti-NGF nerve growth factors we all know they are of nerves in endometriosis associated pain; and CCR1 Antagonist which targets common receptors for MIP, Rantes and MCP-3 and other cytokines.

So, do we need a targeted treatment for endometriosis? Well, the macrophage migration inhibitor factor is not alone and endometriosis is a multifactorial disease. I am not saying that MIF is the only and sole target for endometriosis. But, you will see that it is a promising factor to target.

A brief story of MIF:  actually it started with Christine Metz who collaborated with this work for the past ten years. Our basic hypothesis is that ectopic endometrial cells produce factors that promote endothelial cell growth. As you can see here active endometriosis or active endometriotic lesions are highly vascularized so angiogenesis is a critical step for endometriosis development and progression.

This is a major step in our work. We have been able to immortalize endometriotic cells, produce a line and we have then identified by microsequencing MIF, which appears to promote endothelial cell proliferation in vitro.

As you can see here MIF is markedly expressed in endometriotic lesions particularly in active endometriotic lesions and end in the peritoneal fluid of women with endometriosis particularly in those who are infertile.

We also found elevated levels of MIF in the eutopic endometrium and you can see here that MIF levels vary according to endometriosis stage and endometriosis major symptoms such as pain and infertility.

So how may MIF be involved in the pathogenesis of endometriosis? Here are some of our findings summarized regarding infertility, angiogenesis, inflammation and local estrogen production in endometriotic lesions.

Here is a slide showing that abnormal levels of MIF, so not MIF as such, but abnormal levels of MIF inhibit sperm capacitation. Capacitation is the fertilizing capability of the sperm. It inhibits as well sperm motility as you can see here. The acrosome reaction in the presence of high levels of MIF could be harmful for sperm capacitation and motility.

We also found that MIF stimulate angiogenesis in vivo and in vitro using primary endometriotic cell… As you can see MIF in a dose dependent manner stimulates the release and secretion of VEGF, IL and MCP1, major angiogenic factors. We also found that MIF activates proteolysis. The main MMPs we looked at where MMP9 and MMP2 and you can see here that MIF stimulates MMP activation and secretion so MIF might be involved in the invasiveness of ectopic endometrial cells and the development of endometriosis.

In the other data from our group we found that MIF simulates COX2 expression and prostaglandin E2, which is…mediator of pain. You can see that MIF receptor CD74 is expressed, is highly expressed, in endometriotic lesion and silencing this receptor inhibit the MIF induced COX2 expression and prostaglandin E2 secretion.

This is an interesting thing we found, MIF appears to induce aromatase. Aromatase is an enzyme that catalyzes the biosynthesis of estrogen so MIF induces aromatase in endometriotic cells. At the same time estradiol induces MIF. So there is a kind of positive feedback loop in endometriotic lesions that may enhance the production of estrogen in eutopic endometrial lesions.

Could MIF be targeted for the treatment of endometriosis? I am going to share with you some of our in vivo findings using mice models of endometriosis. As you can see here ISO1 is a specific inhibitor of MIF, which binds actually to MIF and inhibits aromatase activity. We have tried ISO1 in vivo in mice and you can see here that mice treated with ISO1 showed significant reduction in the size and number of endometriotic lesions found. ISO1 down regulated as well numerous factors, relevant factors involved in tissue remodeling, angiogenesis, inflammation and cell survival.

This is interesting work we have done recently showing that in MIF outlook of mice, in the absence, total absence of MIF these mice actually…MIF and MIF…mice the absence of MIF led to a significant reduction of the number and size of endometriotic lesions. As you can see here 80 percent reduction and 43 percent reduction in the number and size respectively were observed. When you add back MIF to these mice here, when you add back MIF to the mice there was a significant increase in the number and size of lesions as well. So, MIF seems to be important for the development of endometriosis.

To summarize this is the feedback loop we found in endometriotic lesions between local estrogen production, which is a problem, and MIF. And maybe by breaking down this loop we may inhibit local estrogen production and inhibit inflammation and active angiogenesis in these lesions as well.

In conclusion the global endometriosis therapeutic market is forecasted to each $1.3 billion by 2017 and have an annual growth rate of six percent. But the endometriosis development pipeline is weak with only a few molecules in various phases of development. At present, the treatment options are limited to gonadotropin releasing hormone agonists and antagonists, progestins and androgen. These treatments are associated with undesirable side effects. So while endometriosis can be treated medically to relieve pain most treatments are not suitable for infertility and the recurrence rate is high.

The endometriosis treatment market needs therapeutic options with higher efficacy and better safety, in particular those with disease modifying action.

In view of our data MIF is a promising target for specific treatment of endometriosis. But other genes are likely to be promising as well. But large cohort studies and use of multicenter biobanks will first be needed to confirm relevance and then move forward to development.

I wish to thank my collaborators, Dr. Christine Metz – ten years of collaboration on MIF and on endometriosis studies; Dr. Yousef Al-Abed who has provided us with ISO1 from the Feinstein Institute for Medical Research and my team members and the funding agencies.

Thank you very much.