Dr. Shaomeng Wang Video (Text Version)
Title of Talk: Design of New Cancer Therapies by Targeting Key Apoptosis Regulators and Protein-Protein Interactions
Speaker
This is Dr. Shaomeng Wang and it’s a real pleasure and honor to introduce him. He is our Professor of Medicinal Chemistry, Internal Medicine and Pharmacology at the University of Michigan where he also serves as Co-Director of the Molecular Therapeutics Program in the Comprehensive Cancer Center there and is also Director of Cancer Drug Discovery at the University of Michigan Comprehensive Cancer Center, so a number of hats, all very much focused around drug discovery, target therapeutics in cancer.
His research interests focus on the design synthesis, characterization, and development of molecularly targeted novel small molecules and he has worked on a number of new computational and informatics methods and tools for drug discovery, so really kind of reformatting our whole paradigm of how we go about identifying and selecting targets for treatment and again sort of that idea of kind of creative approaches that maybe are—don’t fit that sort of traditional canonical approach for drug discovery, really thinking outside the box if you will.
He’s a Senior Editor for the Journal of Medicinal Chemistry and he’s also co-founder of Ascenta Therapeutics founded in 2003 and focused on novel drug development and cancer agents. He before being at the University of Michigan, he—he received his—his Ph.D. at Case Western and did his post-doctoral training at the National Cancer Institute and was on staff at Georgetown before coming to Michigan. Please welcome Dr. Wang to the podium.
Shaomeng Wang, Ph.D.; University of Michigan Comprehensive Cancer Center, Departments of Internal Medicine and Pharmacology and Medicinal Chemistry, University of Michigan
Thank you for that very nice introduction. So I’d like to talk about some research we have been doing, concentrating on the problem cell death pathway. We know actually one of the hallmark of human cancer including prostate cancer is the resistant to cell death when you treat them with the drugs. So we like to actually look at this approach to then target the most critical key cell death blockade in this pathway to develop new therapeutics.
And so this we use actually the common theme in our research in the last decade either to try to remove the key roadblock for cell death induction. So if we’re looking at a key cell blockade, we know that the numbers of key molecules are blocking cell death with including the BCR2 pathways, a number of members in this pathway and also another pathway called the IAP protein called IP proteins also blocking cell death in multiple ways. Another way that we know that a molecule called MDM2 protein that blocks a tumor suppressor p53, and if you’re looking at how this molecule works, all involves protein-protein interaction which is one of the areas that is almost impossible to target in pharmaceutical industry.
So we like to really develop the removal of this blockade to promote tumor cells to—to kill themselves using the natural program cell mechanism. And of course at a number of critical questions we say you know do we need to remove all of them? How do we develop effective therapy that will target this regulator and can this kind of new treatment approach have activity as a single agent or do we have to use it in combination?
So if you’re looking at the—this—this molecules—that I’ve mentioned, they all involve protein-protein dimerization to regulate the cell death using interaction between the protein and the proteins. And this compared to targeting enzymes and receptors is essentially an impossible task to do in regular paradigms. And this is another example showing p53 and MDM2 interaction also using the protein-protein interruption using p53, and the binding property in MDM2.
Likewise the [IPOs] are [inaudible] and you can [inaudible], so in this kind of a paradigm if you’re looking at a traditional protein drug industry, if you take the target and do a screening and basically most of the time you end up with nothing to go forward, so that’s why drug companies traditionally stay away from this area because they’re too difficult or even impossible to target.
So we saw the way in academia so we actually have the—I think the time and patience and innovation to really go after these impossible targets.
And I already mentioned that it is a largely unexplored area in drug development. It is extremely difficult to target. There are very, very few successes in this. And I want to share with you just two examples of what I’ve been doing that in this area actually we now have in each category compounded either in clinical development or already in [IND].
And so one of the areas that we have been targeting—and targeting the key blockade called a BCR-2 proteins and in this—in this case actually we have a [inaudible]. We take early compounds we call AT101, which have a model affinity of BCR-2 protein. We take them to about a total of 13 trials including four trials in prostate. We have—very early indications of drawing [inaudible] in treating castration-resistant tumors and however when we take them to Phase 2 with 220 patients; the drug therapy improved their survival although it reduced the PSA quite significantly in more than 60 to 70% of patients. And the lesson we learned here is that this drug maybe only has modest affinity so we need to improve, so we’ve been spending the last 17 years to make a compound that is essentially 1,000-times more potent specific against the protein and we’re taking them right now into clinical development.
Another area that I want to share with you is the development of all these small molecules IAP proteins, another compound that is in clinical development. So if you’re looking at how this molecule works, you find the [inaudible] the cell there is multiple different places, here what we call downstream by inhibiting the capases 3, 7, and 9, here up-stream by inhibiting the [inaudible] blocking cell deaths and this is a common pathway used by prostate cancer cells as well as other cells. And one of the molecules identified in 2000—this molecule called Smac. Smac actually really is from mitochondria at a cross-road in the cyto-cell and then it’s able to target a multiple IAP proteins through [inaudible] binding, so all that will be to really develop small molecules that can mimic the natural function of Smac proteins so thereby used as a potential treatment.
So there’s studies done by [inaudible] group from Princeton, showed the Smac protein from [inaudible] interacting with the Bir in XIAP so we use this as our platform for the development of drugs. And so the idea will be that if we’re able to actually remove the [inaudible-IP] to [inaudible] come from all the cell deaths in prostate cancer cells. So this is how the interaction between Smac with XIAP showing here; actually we’re showing how they were 19 [inaudible]—potentially the druggable site. So we spent about 5 years taking this [inaudible] which is another drug [inaudible]. It’s not cell permeable; it’s not stable and cannot get into cells and it’s not stable in cell culture media or in models. We made over 300 compounds essentially and converted this—the peptide into only active small molecular inhibitor against these proteins. So this compound in fact is 500—five to 50 to 100 times more potent than the natural Smac with very low binding—with very high binding affinity to multiple IAP proteins and the—[inaudible] functional assay showing in this slide. It’s actually reversed in [inaudible] to activity. And also one of the [inaudible]—this is a small—rapid degrading cIAP1 protein in PBC3 cell and every other cell we looked within 15 minutes, and there were low concentrations so they really have mobility problems multiple IAP members.
And by doing so actually this compound we removed the inhibition XIAP and also cIAP in multiple places and another thing actually we—we found out that—our people found out in order to cure tumor cells you really need to have [inaudible]. In this case, the [inaudible] for cell death either the [inaudible] ligand; so where [TFR are present] in tumor cells; actually this probably happened to a lot of tumors [inaudible] because this is the cytokine molecule and—and tumor actually is [in the form of the disease] and produces a lot of cytokines. So in the present [TFR] when the Smac and [inaudible] binds to CRP1 they remove by degradation, also remove XIAP but they were competing with XIAP bonding [inaudible] thereby removing multiple places of the cell death blockade, and by doing so we actually [inaudible] tumor cells in this paradigm.
And indeed in about 15% of tumor cell lines we see this very nice tumor grows [inaudible] and this is cells that do have a certain level [TFR] produced and secreting [inaudible]. So only in cells with the [TFR] secretion; in culture you see this kind of inhibition.
If you’re looking at—in prostate cancer cells these are a person’s cells—actually in vitro do not produce the [TFR] thereby they’re not very effective when you treat them with a drug in this setting; however, we thought that we can still use a drug in combination with Taxotere because one of the ways Taxotere kills tumor cells is through—is through copase activation and [inaudible]. So we did indeed [inaudible] in [PD3] and [DO5]; two are castration resistant or androgen sensitive with tumor cell lines. We can shift the response with Taxotere by at least one log.
The interesting thing if you’re looking at activity of the drug in vivo in animal models we actually see that Taxotere has some activity and interestingly the AT406 actually has quite a stronger activity as a single agent. It does work very well in combination with Taxotere to completely suppress the tumor. If you use a higher dose of AT406 we can kill 100% tumor growth in patients in these models as well as another model has [inaudible].
So this combo also has [RIDU] drug properties; it is water soluble, in all the activity in rodents or in—in dogs and monkeys. We did—and the animal studies show very—show that they were well tolerated in—in animals, so we take one while into clinical development in January 2010 in Duke, in North Michigan, and the Mayo Clinic. So one of the things actually that we—we’re very passionate about is really translating our discovery in the science into the clinic. So the—the drug actually we designed [inaudible] in the laboratory a number of years ago, right now is treating patients right in our hospital—right actual downstairs in the same building we work at the University of Michigan. So the patient population solid tumor with day one to five cycle every 21 days—PO dosing and we look at a biomarker in tumor tissue—start with the tissue in trying to see better serum markers. And the preliminary data shows that it’s very well tolerated in patients and rarely the toxicity—we only see grade one to two fatigue right now. We are right now achieving the exposure, what we have seen frequent models for achieving very strong on the tumor activity.
We see [inaudible] activity including [inaudible] degradation in tumor tissues as well as again on the other tissues. So additional trials right now planned including five or ten different trials that will be supported by the National Cancer Institute and one trial we’re actually right now working on is the—the combination with Taxotere in castration-resistant prostate cancer trial at Michigan.
I want to give you another area also that is considered to be impossible target. It was developed in specifically small molecules—activator of tumor cell [inaudible] actually without causing DNA damage. Traditionally we actually have radiation therapy and the chemo-drugs which can actually [inaudible] and do so by targeting DNA damage and thereby creating both the tumor cells and the—as well as the normal cells. So this is one way we think we can actually kill tumor cells specifically without harming normal cells. And we actually know p53 the one—the target that people really have been fascinated with for the last 25 years, plays a major role in tumor development and as well as [inaudible] response. And if you’re looking at the p53 studies so p53 [inaudible] wild-type studies in about 80% of prostate cancer patients, especially in early disease when the disease progresses, actually we see p53 got mutated, suggesting a key role of p53 in suppressing tumor growth. So one way to actually—the dominant inhibitor of p53 activity in—in vivo is this MDM2 protein when p53 is functional and use MDM2 to really bond to p53 in [inaudible] activity. So we thought that if we are able to build a small molecule we could actually targeted it in [inaudible], we can activate p53 specifically in cells with [inaudible]. Again, this is a protein-protein and however, looking at the structure it appears to be druggable because it has a well-defined binding pocket. So we—we started this effort in 2004 to develop specific small molecules targeting this protein-protein dimerization.
So to put it at a 5 year into one slide for the design, actually we developed a [inaudible] compound called 219 represented here and mimicking all the p53 key binding element by 1,000-times more potent than p53 [by itself]. It’s already bioavailable. It’s bioavailable in mice, rats, and dogs and also in monkeys. And if you’re looking at—so this is compound specific—actually with p53 in tumor cells with a lot of p53 like in lung cancer cells or in cells in prostate—those [inaudible] and increase the p53 very strongly at the submicromolar concentration is also actually—actually the p53 in normal cells—normal [PIC] cells so the question that will just come up—specifically in treating tumor cells versus normal cells. The answer is yes.
If you look at 209 in treating cancer cells with the p53, we see 60% of cell death reduction when we treat lung cancer cells. We see essentially nothing happens in normal cells, so getting very specific [inaudible] when you treat tumor cells versus normal cells with MDM2 inhibitor.
And the in vivo, actually we see this drug given orally, very effective in inhibiting tumor growth actually a part of the tumor [body] induction, so this is with an [inaudible] compound. Right now with more [inaudible] compound we found actually even a single dose can complete tumor regression in a model compared to for example Taxotere and this drug caused very minimal weight loss. Also in terms of toxicity, we see very little toxicity even when you treat the mice for 14 days twice a day with very high doses with this drug in other tissues we look at it including bone marrow tissue and many other tissues which normally could be [inaudible] activation.
So we—in fact have been able to design a compound that’s much better than what nature can do or 1,000 nonpotent than natural p53 peptide. We show that the active tumor passed away in both normal tumor cells or with wild-type p53 of specifically treating killing tumor cells and not normal cells and the very strong tumor activity in prostate cancer models with lots of p53 and this activated mouse, p53 does not cause damage to normal tissues so it’s really specific to tumor cells and we’ve licensed the compound through numerous vendors for development. We anticipate that the drug will be in clinic by the end of this year.
So I think that often this kind of idea to does not get supported from NIH because of high risk. And you really have to finish a project before you can get the funding. So we’re fortunate to actually get funding for our research program from the DoD and also from the Prostate Cancer Foundation well before we can get other funding from the government agencies. So we really got the project started; otherwise, I think it’s a little [inaudible] and we would never get it tested. And so I think for judging that—really that to maintain this kind of research with a high-risk, high-potential of high-pay-off is critical and when we actually applaud the effort DoD has been doing to support prostate cancer research and other cancer research. And those are the people working in the laboratories and I actually cover a lot of—data—I would not mention specific people’s names up here.
Thank you very much for your attention. I’m happy to take any questions.
Question
My name is Richard Liebert and I’m with the Prostate Cancer Coalition of North Carolina. Before asking my question, I’d just like to publicly thank Dr. George. He was one of the physicians we consulted after our prostatectomy and determined that we had advanced prostate cancer and he spent close to an hour and a half with my wife and I in the clinic. So thank you, Dr. George, for the time that you spend with folks in the clinic.
My question has to do with AT406 and often times we see in committees where there’s some combination of a new drug with Taxotere. If this drug goes through with the NCI funding, will you vary the level of Taxotere in patients to see if the lower dose of Taxotere can be tolerated by patients?
Dr. Wang
So I think that’s a very good clinical question that people often ask—can you lower the standard chemo-specific dose thereby you can lower toxicity potentially in the clinic without actually reducing the benefit. You can add another drug. I think in our laboratory model, the answer is yes; you can use a lower dose of Taxotere. You still achieve a stronger activity when you combine AT406 with the drug and in the clinic I think it will be a tricky question—whether or not the physicians will allow to lower the standard chemotherapy dose in patients with typically by what people can do in the clinic, but I think scientifically that’s a very, very good approach to go in my personal view.
Question
Glenn Spielman from Albany, New York, Man to Man; I got a couple of questions like with a prior presentation. There was a requirement of having had chemotherapy, for example, Taxotere. Do you have such a requirement that someone is already into a chemo or on the other end, someone who has not been into chemo?
Dr. Wang
No; I think in both cases there are two different combinations. It doesn’t—do not require the combination with chemo. Actually we show that in vivo, AT406 either were effective as a single agent in inhibiting tumor growth essentially 100% when we treat them orally without seeing any toxicity in animals. Likewise, for the MDM2 inhibitor actually we do not require the use with chemo in order to achieve very strong activity, so it does not. But I think that it does actually [inaudible] the activity of another drug.
Question
Excuse me; you also mentioned soft tissue. Will it work in bone mets?
Dr. Wang
Right now we do not know. I think that one thing—we’re looking at it in the clinic to see if we actually will have an effect in bone metastases.
Question
Okay; and last question—relative to preexisting conditions and/or co-morbidities do you have any exclusions?
Dr. Wang
So right now I think that in our Phase 1 that for inclusion we require a patient to have good liver function and just for the concern of potential of maybe the cytokine but so far we haven't seen any actually really major toxicity. We see grade one and two fatigue. But those actually are quite transient that go away quite rapidly, so—so far we actually have no major worry in the clinic about it but I think as a precaution we do have a screening criteria to make sure a patient has normal liver function.
Thank you.
Question
I have a quick question for you and it’s a little bit of a philosophical question I guess and that has to do with the mechanisms of resistance and sensitivity to chemotherapy, so do you view apoptosis as something that can add to the sensitivity of chemotherapy or is it something that can overcome resistance to chemotherapy? Are these the same mechanisms or are these related but slightly different to process?
Dr. Wang
I think that they are probably related. For example, I would take one example that in the case of the BCR2 proteins, we know that Taxotere works and this is in part by degradation of MCO1. We know in prostate cancer and actually in addition to MCO1, BCR2 and BCR1 protein have very high levels compared to normal tissues thereby will be beneficial. On the other hand, people who have lesions like what we are doing now—remove all the [inaudible] blockade, [inaudible] I think that will be actually working more effective.
Question
I have one more question. Dennis O’Hara from the Poughkeepsie, New York, Man to Man. I was wondering if there’s such a thing as too much apoptosis. You know you read Vitamin C is apoptosis, Vitamin D is apoptosis, now you’re giving apoptosis—can we have too much?
Dr. Wang
Right; yes. That’s actually a very interesting question. I will say this. If you’re looking at a tumor and tumors apoptosis signals actually are much stronger than normal tissue, so tumors are pretty [inaudible] and at the same time they also die. The reason tumors die not fast enough is that they actually have this key we call a blockade, preventing them to die not fast enough. So if you look at the [inaudible]—growth versus the dying, so tumors doesn’t grow more than dying so thereby I don’t think for a tumor that there’s such thing as too much apoptosis. I think that we can specifically promote proapoptosis in tumor cells without doing that in normal tissues—we’re going to see major pharmaceutical advancement.
Thank you.