Joel Hornby: | Hi everyone. Welcome to this Cambridge Healthtech Institute podcast for the upcoming Immunomodulatory Small Molecules, taking place this September, the 27th to the 28th, at Discovery On Target in Boston. My name is Joel Hornby, and I am a Conference Director for Cambridge Healthtech Institute. Today I have the pleasure of interviewing Dr. Tauseef Butt, President and CEO of Progenra Incorporated. Tauseef will be presenting on both Immunomodulatory Small Molecules and Targeting the Ubiquitin Proteasome System at Discovery On Target this year. Tauseef, thank you for joining us. |
Tauseef Butt: | You're welcome. It's a pleasure to be here. |
Joel Hornby: | Immunomodulatory therapies are a huge focus for healthcare industries, particularly in oncology, where much of the excitement of late seems to be around antibody or gene and cell-based therapies. Can you speak to us about working with
immunomodulatory small molecules, and what the benefits and challenges may be? |
Tauseef Butt: | Well, it's well-established that macromolecules or biologicals, like Keytruda and CTLA-4, are demonstrating remarkable potency and activity in a number of cancers, and of course it's very exciting. And perhaps, a number of other biologicals
that are in clinical trials. I think at one point somebody suggested that it may be 500 clinical trials going on with biologicals, but there are a couple of problems with biologicals. One is that thus far, we have seen only about 25 to 30 percent efficacy, so it appears that biologicals are not really working in all cancers, and of course, the data is still coming out. So, we are in need of molecules that would really
improve the efficacy and we believe that small molecules will do that. I would outline a few advantages of small molecules, because that has been the traditional pharmaceuticals. For number one: you can rationally design and dial in and dial out the dosages for small molecules. Number two: there is a historical precedent for development of small molecules. Of course, we know that the technology for biologicals has advanced as well. Number three: small molecules give you an opportunity for auto-bioavailability that is not possible with biologicals and antibodies. The other issue, and I believe the reason why small molecules are superior and perhaps the main reason why biologicals are not demonstrating efficacy in many of the cancers, is the exposure to tumor microenvironment is not available to
biologicals, so we believe that small molecules can easily access the tumor microenvironment. And the other reason I would like to add is that intracellular targets are not made available, in most cases, to biologicals, because they cannot get into the cell. And of course, last but not the least, making small molecules is cheaper and making biologicals is expensive, so the cost of goods would suggest that small molecules would be the way for future to tap the immuno-oncology markets, and that's
what we are doing. |
Joel Hornby: | Your work especially focuses on ubiquitin protease USP7 inhibitors, which you hope to initiate Phase I cancer immunomodulatory clinical trials for in early 2018. How did they perform so far when tested in animal models? |
Tauseef Butt: | Well, the USP7 is a very important target for cancer. It turns out that there are a variety of cancers that are dependent on USP7, and on the other hand, it is also established that USP7 is a major player that is responsible for the type
of T regulatory cells that embed tumor and they repel the T effector cells, or natural killer cells, from attacking the tumor, so USP7 plays a role in tumor evasion as well. So what you have is that two different models of USP7. Number one, you can inhibit USP7 and directly kill tumor and number two, the USP7 is playing a role in allowing T regulatory cells to embed tumor, therefore what we know what's called
tumor evasion. So we have tested USP7 inhibitors in two different models. One is what is called the newt/ mice model, where we have examined the direct effect of USP7 inhibitor in killing cells, so in this respect, some of this data has been published.
USP7 inhibitors have demonstrated remarkable efficacy in multiple myeloma models, in T-cell leukemia models, in neuroblastoma models, and colorectal cancer models. So those of you who may be interested in learning more about the data with these models where USP7 inhibitors have demonstrated direct anticancer activity, they can go to our website and some of the references are given in this most recent
paper published by Tavana et al 2016 in Nature Medicine. And again, it's in our website, www.progenra.com Now, the most exciting aspect of USP7 and its role in human oncology is that USP7 is responsible for removing ubiquitin on transcription factor FOXP3, which is the major regulator of T regulatory cell function, so inhibitors of USP7 essentially
block T regulatory cells and thereby they unleash T effector cells, or natural killer cells, to attack tumors. Here you have a mechanism where immune system is being stimulated to attack tumors, so there we have tested USP7 inhibitors in lung cancer model, mesothelioma, medulloblastoma, melanoma, and we are testing them in colorectal cancer models. So the bottom line is that USP7 inhibitors have demonstrated anticancer activity both in direct antitumor activity but also in immune competence mice models and to my knowledge, I don't know a compound that has a dual activity. In other
words, it's hitting the cancer cell but at the same time, it's stimulating the immune system to kill the cancer, and that is really the exciting aspect of USP7 inhibitors. |
Joel Hornby: | Could you please tell us a little bit more about Progenra's discovery platform, and what other plans you have in store for developing immunomodulatory strategies? |
Tauseef Butt: | Progenra is very focused on ubiquitin pathway, so we have developed a number of technologies. As many of the scientists know, that ubiquitin pathway is very complex, and there are a number of genes that control the pathway and they are
primarily ubiquitin ligases and the ubiquitilases. There are about 1,000 genes that play a role, so Progenra has developed a technology platform whereby you could readily develop assays for a variety of ubiquitin ligases as well as
the ubiquitilases, and we have potentially expressed about 50 D-ubiquitilases, optimized their assays, and adapted many of them for high input screening, and by the same token, we have also expressed, purified, and developed assays
for about 30 ubiquitin ligases. Some of these enzymes play a very important role in cells, especially in T regulatory cells, so we are targeting ubiquitin ligases for immuno-oncology. We are also targeting a couple of other D-ubiquitilases that belong to the same family
as USP7 for immune-oncology targets. So again, there is a lot of information available about our technology platform on our website, www.progenra.com |
Joel Hornby: | Thanks Tauseef. So Discovery On Target this September, the 27th to the 28th, is just around the corner. What are you looking forward to achieving there? |
Tauseef Butt: | Well, it appears that there are a number of parallel sessions, so I have three goals. Number one, that I wish to inform myself with developments that are taking place in other areas, especially in epigenetics, and, for example methylases
and deacetylases, but more importantly, the ubiquitin proteasome meeting. I have one goal and that is that I wish to share our latest data on the role of USP7 inhibitors in immuno-oncology, and the case that I will be making will be that the small molecules have a big role to play in immuno-oncology, and I believe
that some of the problems or lack of efficacy that we see in biologicals can be overcome by small molecules. That is going to be the bottom line of my presentation to CHI. |
Joel Hornby: | Thank you Tauseef. And really, thank you very much for your time today and expert insights. |
Tauseef Butt: | Well thank you for giving me this opportunity to speak to you and your audience. |
Joel Hornby: | Dr. Tauseef Butt, President and CEO of Progenra Incorported, will be speaking on Immunomodulatory Small Molecules and Targeting the Ubiquitin Proteasome System at Discovery On Target, this September, the 27th to the 28th, at the Westin
Copley Place, Boston. If you'd like to hear Tauseef speak in person, go to www.discoveryontarget.com where you can register, entering the key code "podcast" and where you'll also be able to see many other exciting tracks, talks, and features planned for this
year's Discovery On Target. Once again, I'm Joel Hornby from Cambridge Healthtech Institute. Thank you again for listening. |