Chapter 12: The Moon Shots Program and a Model of Translational Research
Dr. Bast begins with general observations about how translational research has evolved at MD Anderson under Dr. Ronald DePinho's leadership as president. He notes that Dr. DePinho's Moon Shots Program is the most direct application of the translational approach. As an example of how research can be optimally organized, Dr. Bast focuses on advances being made through the Moon Shots for treatments for breast cancer and ovarian cancer. He also explains that the patients involved in the Moon Shots trials are providing tissue for the study of nine different diseases. Dr. Bast notes that his own work on the mechanisms of autophagy in ovarian cancer (see Session One) connects to this Moon Shot.
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Tacey A. Rosolowski, PhD:
Is there a unique way? You talked earlier about how research at MD Anderson has always had this translational flavor to it. And I’m wondering if there is a unique way that MD Anderson trains people or if there’s an MD Anderson model of translational research. Is there something that’s unique to the culture here?
Robert Bast, MD:
Well, the culture here really has evolved. I think in truth there’s been much more of an emphasis on clinical research traditionally at MD Anderson. As we may have talked about in the last interview the tradition has not always had the most rigorous standards. I mentioned to you that I wrote a review article for the New England Journal on “BCG and Cancer”. A large part of that was the fact that we weren’t doing very carefully controlled trials at Anderson. And again the whole issue of controlling trials is really contextual. If you’ve got something that’s dramatically effective like penicillin for pneumonia, you may not need a randomized controlled clinical trial to prove that it is useful. Similarly, with some of our targeted therapies, if you’re looking at a very small subset of people and they respond dramatically and they live for two years rather than for two months, whether you really need a controlled randomized trial for that isn’t clear. For some of the combinations of conventional drugs that we were working on thirty or forty years ago, you needed randomized controlled trials to be sure that you were helping somebody. And so with that Irv Krakoff who had done a huge amount here not only to improve the infrastructure for clinical trials but also to improve the rigor of those trials and to make our institution respected nationally and internationally for the clinical research that was ongoing. For translation, there certainly has been translation that goes back a ways in the history of MD Anderson, but it’s really been in the last twenty years that we’ve begun to emphasize that more. And I think in fairness that’s true nationally. I talked about CA125 and trying to translate a mouse model directly to the clinic. In the 1970s I don’t think anybody had yet coined the term “translational research”, or if they had it wasn’t widely used. So that whole idea of there’s a method or methods to try to move something from the lab to the clinic and back again, and there are better and worse ways to do that, had not really been thought deeply. And so at MD Anderson we’ve seen more translational investigators recruited here and more investigators have been in working between the lab and the clinic. And that’s really the key. Not just doing clinical empirical research, but trying to understand the mechanisms that are involved in what’s going wrong in a particular person’s cancer, and then developing your therapies based on that in the lab.
Tacey A. Rosolowski, PhD:
I was wondering. You said over the last twenty years. What was it that was happening twenty years ago that shifted that emphasis into this?
Robert Bast, MD:
Well, I think in part it was the new people who came here. Certainly something I tried to contribute to the Division of Medicine at the time was the recruitment of Gordon Mills and a number of younger investigators who have changed the culture. Most importantly, John Mendelsohn’s recruitment here, a little less than twenty years ago, was very important, because John supported translational pursuits as did Margaret Kripke. They were both extremely helpful. Much of our progress depends upon whom you recruit. A number of the department chairs within medicine and surgery and others really saw the need and the importance of that. So people like Chris Logothetis recruited Wadih Arap and Renata Pasqualini, two of our exceptional translational investigators. Hagop Kantarjian recruited John Pierre Issa. The group in neuro-oncology recruited faculty who were passionate about impacting glioblastoma based on laboratory models. But you can tick off most of the departments here that began to recruit laboratory and clinically-based investigators supported by John and Margaret and the upper administration. I think that was very important.
Tacey A. Rosolowski, PhD:
I’m just looking at some of the other areas to touch on.
Robert Bast, MD:
I guess the other thing we might come back to—although I think this has been a really helpful conversation – is the physician-scientist program. One of the accomplishments of which I am most proud is the really outstanding young physician-scientists whom we have recruited. In the early days, these were faculty who had already been recruited to MD Anderson for whom we were able to free up eighty percent dedicated time to work in the laboratory. More than eighty percent of those individuals have earned their individual investigator grants and almost all of them have stayed in research. Something like twenty-seven of the twenty-eight have remained in academe. And one of them who left now heads a thirty-member team at Amgen in cardiovascular research. So they have really stayed the course and continued to contribute. Also if you look at their achievements, they’ve published more than 2,000 peer-reviewed articles. And about fourteen percent of these articles have an impact factor greater than ten. About ten percent have an impact factor greater than five. Our graduates have been awarded $25 million in grants. In the last 2-3 years with Ron DePinho’s and Ethan Dimitrovski’s interest in physician scientists—both of course are physician-scientists - we have begun recruiting physician-scientists from outside the institution. So we now have some incredible young people like Cullen Taniguchi, who’s going to be joining us. It took us a while to get CPRIT to get back in business and to help augment his recruitment package. Cullen is absolutely amazing. He graduated summa cum laude from Occidental, then was a Rhodes Scholar and completed an MD/PhD at Harvard Medical School, and trained in radiation oncology at Stanford. He has already published a number of high impact papers, and is poised and destined to make real and unique contributions to radiation oncology. He’s trying to understand radiation damage to normal organs like the intestine and has already discovered ways to keep the intestine from being damaged so that you can control the local growth of pancreatic cancers using radiation therapy. He has studied hypoxia at a very fundamental level, but is also focused on improving treatment of patients with pancreatic cancer.
Tacey A. Rosolowski, PhD:
Talk to me about what happened with Dr. DePinho’s arrival. What did that add, change to the course of translational that had already been well established here under John Mendelsohn?
Robert Bast, MD:
Well, I think John in addition to having been very supportive of recruitments of translational investigators had also begun the Center’s program as well. A number of those Centers, including the Institute for Personalized Cancer Therapy, are very translationally oriented. Some of them are more basic. But there’s a translational component of most of the Center. The Centers further helped improve the translational environment. Ron’s Moon Shots project has stimulated some of the most direct translation we’ve had. It’s been a real game changer in terms of applying what we know in the laboratory to actually helping people in a finite period of time. We’re already beginning to see some of the outcomes of that, for example in the breast and ovarian moon shot project for high grade serous ovarian cancer patients and for the triple-negative breast cancer patients. They’re doing genome sequencing but also particularly looking at BRCA1 and BRCA2 even if there’s not a strong family history. And they’re actually identifying a number of people who have mutations of those genes who you might not have predicted from families. They’ve also started to treat patients with ovarian cancer much more consistently. Anil Sood has convinced all 26 different doctors within GYN oncology to join in a common protocol for new ovarian cancer patients. Every ovarian cancer patient now gets a laparoscopy, rather than an open operation as a first step. Using a rigorous method that involves two or even three docs they score the estimated difficulty of completely removing all of the cancer up front. I don’t think we talked about this last time, but it turns out that GYN oncologists believed for decades that if you could take out most of the cancer but not all you really benefit the patient. And that belief for ovarian cancer differs from the management of almost every other solid tumor. Even in ovarian cancer, when you can get all the cancer out patients will do the best with subsequent chemotherapy. If you’re starting from trying to get rid of microscopic cells with your chemotherapy, those are the patients you cure, or at least live a lot longer. Only about a third of the patients can be completely cytoreduced if you don’t select up front. With this laparoscopic algorithm, surgeons can identify women whose cancers are most likely to be completely resectable up front. It turns out more than ninety percent of cancers can be completely removed by this technique. Those patients who are predicted not to be resectable are given three or more cycles of chemotherapy and then resected. More than eighty percent of those patients are now resectable. So instead of a 30% of patients with complete resections, you have more than 80%. Whether this will translate into the same sort of survival advantages that is seen in the one third of unselected patients who were completely resected up front still remains to be seen. With the new protocol, the investigators are getting tissue in the bank from patients before they’re treated in 120 cases over the last fourteen or fifteen months. We’re also going to have that as a group which we can use as a control to see if we do other things differently. One of the things we’re working on at the moment is not completely finalized. As part of the Moon Shot and the Ovarian SPORE we are beginning to do “second look” operations with laparoscopy for each patient as well after chemotherapy. Twenty five years ago gynecologic surgeons did that a lot, when we were developing intraperitoneal therapy or early immunotherapy. After initial surgery and chemotherapy, another operation was performed to see if there’s any cancer left. With the most sensitive imaging and with normal CA125s, still about half the patients will have tiny microscopic bits of tumor on the surface of the intestines or abdominal wall if you look for it. The problem was for many years there just wasn’t anything to do that was different and that would have made a difference in survival. So in routine practice, people have gotten away from that. But I think now with some of the work that I may have described last week with getting rid of dormant cells and the rest, we’re planning protocols for the new SPORE to try to use anti-autophagic therapy to get rid of the dormant cells. And so if we do second looks and they’re positive then patients would end up on a protocol of that, probably hydroxychloroquine as a starter, and then perhaps more sophisticated work as the preclinical studies develop. Patients with negative “second looks” would be offered immunotherapy so that there would be a treatment based on the second look operation for everyone who participated in the new trail. We can compare how well each group does to the 120 patients who’ve been pretty rigorously treated in a very uniform way. But that kind of organization just never existed at MD Anderson, or likely at any other Cancer Center. The Moon Shot has created the hope and expectation for funding for these sorts of research protocols. The Moon Shot program has catalyzed our faculty to imagine new approaches and challenged them to get things together to do research that would improve survival within the next five to ten years, rather than someday. That is the sense of direction and urgency that Ron has brought to the institution.
Bast, Robert C. Jr., MD and Rosolowski, Tacey A. PhD, "Chapter 12: The Moon Shots Program and a Model of Translational Research" (2014). Interview Chapters. 449.
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