Chapter 20: The "Unholy Triad Moon Shot" and the Women's Cancer Moon Shots
Dr. Mills begins this chapter by explaining the intellectual foundation for the "Unholy Triad Moon Shot" he currently heads. This discussion also provides a snapshot of the organic process by which a new research area takes shape. First he lists the three "untarget-able mutations" included in the "unholy triad" --p53, Ras oncogene, and amplification of Myc. He explains that the executive leadership suggested combining the examination of all three of these mutations in a single Moon Shot. (He notes that the investigation of them will have relevance for all the Moon Shots.) Next, Dr. Mills talks about the organization and aims of the Ovarian Cancer and Breast Moon Shots, originally included in one single, Women's Cancer Moon Shot. He tells the story of the evolution of these Moon Shots that address cancers in which inherited abnormalities of BRCA 1 and 2 play significant roles. He explains the process by which the diseases were separated into distinct initiatives. Dr. Mills next talks about how the approach taken in these Moon Shots has intrigued many observers. He gives the example of Astra Zeneca, a company which has agreed to supply drugs and funds for clinical trials in order to study how the drugs work. He sketches the importance of this kind of partnership and mentions that another company stepped forward to supply technology.
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Gordon B. Mills, MD, PhD :I have been asked to make a presentation on what is called the unholy triad Moon Shot. There are three molecular events in cancer that we really do not or cannot target efficiently today, and they are the most common genetic changes across tumors. That is mutations in P-53, mutations in RAS, in amplification of MIC, and it's called the unholy triad because they are so common. They represent ugly, nasty tumors, and we can't do much about them. We have a few ideas and a few hints but barely. And indeed, we generally call these untargetable. You know, our personalized cancer medicine program, we do not have good ways to target these, and so I've been asked to put together a proposal. This encompasses the vast majority of difficult cancers we deal with, and my plan for the first year is to do nothing, is simply to step back and pull every single paper out of the literature that has given a hint of what you might do about these, and now ask, is that information robust, generalizable, real, and are there hints already in existence, that if we just pay attention, we can pull this across what's called the valley of death, the research idea into how you would implement. You would do building during that time. You would build the technologies necessary to say if I had something, would I know? If I had a drug that would have activity in a RAS mutant tumor, would I even know I had it? Do I have models that make sense and do they really reflect what's happening in patients? These are things that again, going back to the concept that I put forward, of getting together a team of leaders, getting together people who are thinking, and then actually doing almost nothing. It's not really nothing, but we're not going to say here are the thirty things we're going to do, but rather, saying we don't know what we're going to do, now let's figure it out. Again, that's the antithesis of science. If I went to NCI with that idea, I'd be laughed out of the room, at least a grant application to NCI, saying all I'm going to do is figure out whether what other people have done is real, they would say you're nuts, but that's what we do need to do.
Tacey Ann Rosolowski, PhD:Yeah.
Gordon B. Mills, MD, PhD :Not real, but real in application, this implementation question.
Tacey Ann Rosolowski, PhD:That seems like an essential building block, to know the intellectual terrain in which you're going to be moving.
Gordon B. Mills, MD, PhD :But actually going in and taking the stuff from that intellectual terrain, and now asking, in a rigorous manner --much of what's done in industry, by the way-- of saying, Is this a valid target? Is this something that is worth now, investing $100 million, which is what industry is talking about, of building a drug to take through to the clinic. Actually, that's an underestimate of what it costs. So you have a very different set of criteria that one would move for validation of concept, and I think that that rigor, that cynicism, that saying I'm talking about building a five or ten-year project, not something I'm doing this year to get a paper out so I can get a grant, but rather, five or ten years from now, how do we make this process happen, is one that we'll see if there's any traction.
Tacey Ann Rosolowski, PhD:We'll stay tuned on that one. When do you present that?
Gordon B. Mills, MD, PhD :Sometime in the next few weeks. We don't have a set date. I had actually proposed to do this for P-53 only, and the reason behind that is that in high grade serous ovation cancer, the worst ovarian cancer, I headed the Women's Cancer Moon Shot, which is now the Breast Cancer Moon Shot and the Ovarian Cancer Moon Shot, I was a co-head. In high grade serous ovarian cancer, every patient has a mutation in P-53, or an abnormality in P-53. Indeed, if they don't, the pathologist was wrong, and that's the way I would state it. Over five hundred cases have been looked at extremely carefully, and there's maybe one where there isn't a mutation in P-53, where the pathologists agree it really is high grade serous ovarian cancer. And I would say that one out of five hundred says there's a mistake somewhere there. Was it mis-sequenced, was it missed, or is it simply not a high grade serous ovarian cancer? But that then makes this such an absolute requirement, that we have something to do about it. Now, we have some drugs that we are evaluating here at the MD Anderson Cancer Center, that may have activity, that is a little better in P-53 mutant tumors. We, my own laboratory, is attempting to identify and validate drugs that correct certain types of P-53. I have interacted with a significant number of leaders in the field outside of MD Anderson, to say Would you be interested, would you play, would you even consider moving to MD Anderson, to lead this program, and there's been a lot of enthusiasm. I must admit, that when I bring up the concept of just simply stepping back and saying what could be moved forward, I do get sort of two answers: ‘Well, I already have something that needs to go forward, my own idea is great,’ and the other half is Oh yes, this is what we do need to do. And so I think it's an intriguing opportunity. My argument was –is-- that okay, MD Anderson could simply stand up and say, We are taking on the hardest of the hard problems. The National Cancer Institute has built a program around RAS, the whole National Cancer Institute and all of the United States is doing RAS. MD Anderson will do the tougher one, P-53, by itself. That would be something that we could use to drive a program, to drive fundraising. The senior people said, Well, why don't we just do this big and call it the unholy triad, and put together the concepts that cross the processes, and if we can't convince the community that this is an effort that should be supported and funded, we're not doing our work right. The important thing is, is it crosses pretty well every Moon Shot, and so this would be something that would, I think begin to bring together concepts across all of them and teams, now teams of teams, across Moon Shots. I think there's a few where these are not major players, but the vast majority of the cancers that are encompassed in the Moon Shot, are the tough, ugly cancers, and they are defined by these three aberrations.
Tacey Ann Rosolowski, PhD:Interesting. Did you want to speak in more detail, about the Breast and Ovarian Moon Shots?
Gordon B. Mills, MD, PhD :I'll talk about the Ovarian Cancer Moon Shot for a moment, or even I'll talk about both. We were asked originally, myself, Mien-Chie Hung [oral history interview], and Anil Sood, to put together a program that would integrate the breast and ovarian cancer difficult diseases. And that being the high grade serous ovarian cancer that encompasses 70 percent of ovarian cancers, and the triple negative breast cancers, including particularly, a subset of those called basal breast cancers, which encompass about 15 percent of breast cancers, but are the worst and the most aggressive, and those that we have the least opportunity outside of chemotherapy, to help today. The reason behind this is that remarkably, these two diseases have more in common in terms of their underlying processes, their pathophysiology, than does triple negative breast cancer and luminal or ER-positive breast cancer. They are different diseases, they are unrelated to each other, they do not interconvert. They can't interconvert. By learning both at a clinical level and at a basic science level, across ovary and breast, you could potentially do more with the group of scientists involved and clinicians involved, than you would do looking at each one separately.
Tacey Ann Rosolowski, PhD:I recall that you were, when you were working with the interleukin-2, you said you were working at the interface between ovarian and breast cancer. So this is really an extension of that early interest.
Gordon B. Mills, MD, PhD :I think many people have worked on both sides. These really are very related diseases and although I told you it's universal in ovarian cancer, to have P-53 mutations, it's about 80 percent of triple negative breast cancers. I'm suspicious that if one were to ask about the function of P53 in its pathway, it would be much higher than that. The other major commonality between the two is the role of the BRCA-1 and the BRCA-2 genes. Now, they're called breast cancer 1, breast cancer 2. They are actually ovarian cancer 1, ovarian cancer 2. They have much more impact on ovarian cancer than they do on breast cancer, but breast cancer is more common, and so it came out of that direction, but those, the genetic abnormalities that lead to BRCA-1 and 2, both inherited and acquired, and the therapeutic liabilities that are engendered by those are the same across the two different tumor types. So, one of our major opportunities and one of our major drivers across the combined Moon Shot and continuing in each one of them somewhat independently, we still work together. This is not a matter of saying you're going over here and you'll never talk together. We still work together and I'll come back to that in a moment. Is to capitalize on that abnormality and drugs that are currently available to target that abnormality, called PARP inhibitors. Both programs have major efforts around how best to use those drugs, how to combine PARP inhibitors, how to identify patients that will benefit from PARP inhibitors and indeed, we've run trials within the Women's Cancer Moon Shot, with both breast and ovary being entered on exactly the same trial. The other part is that the term I like to use is that many of these cancers are due to an inherited abnormality and the genetics of this does not respect the organization at MD Anderson, where breast cancer is here and ovarian cancer is here. These patients are at risk for both diseases almost equally, as well as many others, and that we need a program to help, not only the patient who is in front of us who may have abnormalities in BRCA-1 or BRCA-2, or related genes, where we know that even with no family history, 15 percent, give or take, of patients, with high grade serous ovarian cancer or triple negative breast cancer, will have an inherited gene, and that means their family members are at risk, and so one of the opportunities again, was to build an outreach program wherein we would offer testing to every single patient in the program, and find a way to help their family members. One of the opportunities that is exciting is if one could do that and determine how to identify and prevent cancers in these high risk individuals, i.e. family members of people with cancer, you could potentially, with appropriate prevention technologies that are currently available, not ones that we like but that are available, have a 5 to 10 percent change in outcomes in five years, by preventing people from developing these two ugly diseases that we can't treat well once they occur. So having these together made great sense. What has happened is that there are not only commonalities, but there are differences in the diseases. And further, the initial efforts were focused around just one type of ovarian cancer and one type of breast cancer, where there are many types of each of those, and it came to the point where each of the groups said, We've done this neat stuff together, it's time for us to be able to spread that effort and process much more broadly and have a breast cancer group, an ovarian cancer group. And yes, we will continue to work together, but the breast cancer group will be able to focus on the ones that are like ovarian cancers and be able to work freely on other types of breast cancer that are important. And the same question on the ovarian cancer side, of Yes we have been focused on this high-grade serous ovarian cancer group, but patients who have other types of ovarian cancer need major efforts. There is quite limited commonality between those and breast cancer, and so we've moved a little more into two programs, adequately supported, more support for the two programs than the two together. So the institution has said that this really is a promotion, not a concern, to really give these programs the chance to move forward on a broader basis.
Tacey Ann Rosolowski, PhD:What are some of the findings? Are there findings that are being converted into care opportunities right now?
Gordon B. Mills, MD, PhD :I'm actually going to do one or two things first. So, simply having made this commitment to making a difference, through the Moon Shot effort as I described it, has engaged parts of the community. For example, Astra Zeneca came forward and said, We want to participate in the Women's Cancer Moon Shot, albeit the funding that we have available is for ovarian cancer, but we will develop an alliance with you wherein we bring our drugs, ideas, and $10 million to the table, no questions asked, and we will work together to do information driven clinical trials, not to try and register our drug, which is their normal role in life, but rather, to understand how our drug works, who it works for, and more importantly, what is the next combination we need to do. That would not have happened if there had not been a Moon Shot, and in part, we leveraged the Moon Shot against the Astra Zeneca funds, and vice versa. We will cover, from Moon Shot efforts, some of the translational and basic biology studies that will make their effort go further, and vice versa.
Tacey Ann Rosolowski, PhD:So obviously, I'm assuming that Astra Zeneca felt that there was, basically MD Anderson was taking over some of the research work, so they could afford to invest in this way? What made them say we don't need to use you to help register the drug?
Gordon B. Mills, MD, PhD :They have programs to register drugs elsewhere. They came to us because of the unique concept of the Moon Shot, which is to make progress over time and to have some of that flexibility and the resources to do so. So, I think it is the point of -- and I'm not saying we don't participate in registration trials. It's that this alliance was separate, with the idea of this very clear and important goal that most of the time is not the major driving effort of industry. And you understand why. Industry wants to get their drug registered so that they can get money coming in. They have investors. That's all critically important. But this was a group of people that -because the Moon Shot was in play, and because we had said this is what we are going to do-- were quite willing to say, We'll work with you to make this happen. The Moon Shot existing helped make that occur. I can't say it wouldn't have occurred without it, but I am quite comfortable that it was a major part of why this happened and happened easily. And indeed, I have another company that came to us about the same time and said we want to develop a new technology with you, and we will put funds on the table to make that happen, again, because the resources of the Moon Shot will make what we can do go further, and further the ability to say we're participating in the Moon Shot. That's a nontrivial process by which they can leverage their own efforts and funds. So those consequences are really a major positive and we've used this with philanthropy, we've used it with grants, we've used it with industry, as I was just talking about. So just having this concept of saying we will answer this question one way or another, has been something that we can leverage.
Tacey Ann Rosolowski, PhD:I'm really glad you told those stories, because they really bring together, the information that you've provided earlier, about what happens or what can happen when you reorganize the way science is being done. So it's really put a nice cap on all of that, yeah. Anything else that you would like to tell about the Moon Shots at this point, or final thoughts?
Mills, Gordon B. M.D., Ph.D. and Rosolowski, Tacey A. Ph.D., "Chapter 20: The "Unholy Triad Moon Shot" and the Women's Cancer Moon Shots" (2016). Interview Chapters. 79.