Supplement Translational research: are we on the right track? Charles L. Sawyers

It is a great honor and privilege to stand careers. The phrase “Young Turks” comes clinical practice. before you today to deliver the 2008 Ameri- from the coincident Young Turk Revolu- There can be little doubt that over the can Society of Clinical Investigation Presi- tion against Sultan Abdul Hamid II of the past century we have met Dr. Meltzer’s dential Address. I have chosen a controver- Ottoman empire. goals. The evidence is obvious: the pro- sial topic — and one that I know intimately I should disclose that I majored in his- liferation of state-sponsored medical — that challenges the standard operating tory as an undergraduate at Princeton and schools across the US, the establish- procedures of our profession at many lev- was taught to dig deep into primary source ment of scientific standards of excellence els. While no one will object to the goal of material. In the same way that we all view through the Flexner report, the endow- applying basic biomedical research insights early scientific data from our labs with a ment of many leading private medical to clinical medicine, we can certainly debate skeptical eye, I looked into this fairy tale of institutions to enable the development the methods by which we encourage this renegade youth a bit more closely. It turns of pure medical science unfettered by process. Translational medicine has rap- out that the true instigator for the forma- the demands of clinical practice, and, of idly emerged as the rallying cry for many tion of ASCI was not so young. This was course, the establishment of combined stakeholders in biomedical research, most Dr. Samuel Meltzer (Figure 1), a New York MD-PhD programs at medical schools notably the Congress and the public, who City clinician in his mid-50s! throughout the country. rightfully want to hold us accountable for Dr. Meltzer was born in Russia and But with these successes, significant their investment of taxpayer dollars into trained in Berlin, where he was exposed to challenges remain. I list only a few here. our enterprise. Major funding sources have science-based medicine in the European These include unpredictable swings in channeled significant portions of their tradition. For unclear reasons, after this research funding that discourage young budgets into new translational research high-level training, he established a clinical investigators from following in our foot- programs, many of which prescribe specific practice in Harlem, New York, rather than steps, the misalignment of the goals of projects and even link delivery of resources pursue a medical research career in Germa- revenue-driven hospitals with the aca- to completion of defined milestones. Is ny. Then, at the age of 53, he was selected demic medical science mission, the grow- this the best way to ensure bench-to-bed- to head the first Department of Physiology ing distractions of administrative work, side science? Can translational research be and Pharmacology at the newly established and so on. These and related issues have directed from headquarters? Rockefeller Institute. This seems a remark- been eloquently covered in prior Presiden- able turn of events for a New York City cli- tial Addresses (2, 3). Before I begin that discussion, I want to nician. But in his spare time on nights and When I was a house officer at the Uni- reflect on the history of ASCI on our 100th weekends, Dr. Meltzer had been conduct- versity of California, San Francisco, my anniversary, as there are many lessons ing experiments in physiology at Columbia attending, physician-scientist Joel Ernst, in the past. As the story goes, ASCI was — riding his horse over from Harlem after founded in 1908 by 8 young physicians, seeing his last patients — and publishing all in their early 30s (1). They had been his results in the medical literature. A sam- regular attendees at the annual Associa- pling of his publications can be found on tion of American Physicians meeting, but PubMed (Figure 2). were frustrated with the conventionalism Dr. Meltzer clearly took his suboptimal of the old guard and eager to incorporate experience in blending a science-medicine more science into medicine. In response career to heart in his new position at Rock- they created the ASCI, a new society of efeller. He became a very strong, nation- young physician-scientists with a greater ally visible advocate for proper physician- focus on the interface between science and scientist training. It was he who instigated medicine. Membership was restricted, as the first 8 Young Turks to establish the today, to those in the early stages of their ASCI. In appreciation of his role as their mentor, the Young Turks selected him as This article is adapted from a presentation at the their first president. ASCI/AAP Joint Meeting, April 26, 2008, in Chicago, Dr. Meltzer delivered the first ASCI Illinois, USA. Presidential Address, entitled “The sci- Address correspondence to: Charles L. Sawyers, Howard Hughes Medical Institute, Human Oncology ence of clinical medicine: what it ought and Pathogenesis Program, Memorial Sloan-Kettering to be and the men to uphold it,” one year Cancer Center, 1275 York Avenue, New York, New York later. In it, he laid out the fundamental 10065, USA. Phone: (646) 888-2138; Fax: (646) 888- 2595; E-mail: [email protected]. principles of obtaining proper laboratory- Citation for this article: J. Clin. Invest. 118:3798–3801 based scientific training and of maintain- Figure 1 (2008). doi:10.1172/JCI37557. ing a focus on clinical science rather than Samuel Meltzer, first ASCI president.

3798 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 11 November 2008 supplement

could be quickly screened against differ- ent protein targets. Imatinib emerged as an optimized hit from the screening program at Ciba-Geigy Pharmaceuticals, directed by Alex Matter and Nick Lyden, against the platelet-derived growth factor receptor. Only later was it appreciated that imatinib inhibits ABL. Brian Druker showed that imatinib was effective in preclinical models of CML, and, together with Novartis, we moved it into the clinic, where it succeeded beyond our wildest dreams (11). What you may not recall is that less than a year after we saw these dramatic responses in CML, we began to see patients lose their response to imatinib, initially those in blast crisis. Since these relapses were occurring while patients were still taking the drug, we reasoned that either BCR-ABL–independent subclones had aris- en or that the drug was no longer inhibiting BCR-ABL. After ruling out trivial explana- tions such as enhanced drug metabolism, we ran the definitive experiment — assess- ing BCR-ABL activity in tumor cells at relapse by measuring phosphorylation of a downstream substrate CRKL. In all cases, kinase activity was restored! Furthermore, Figure 2 this biochemical resistance to kinase inhi- Selected publications by Samuel Meltzer. bition was cell autonomous because we could not inhibit BCR-ABL when the cells were exposed to imatinib ex vivo. We made handed me a copy of Joe Goldstein’s 1986 fortunate to have them converge. a short list of the possible explanations ASCI Presidential speech where he reported Many of you are familiar with the story and, in very short order, discovered a novel several cases of PAIDS (Paralyzed Academ- of imatinib (Gleevec) in chronic myeloid amino acid substitution in the BCR-ABL ic Investigator Disease Syndrome). Hav- leukemia. I want to share a brief vignette of kinase domain in the resistance subclones. ing just reviewed nominations for ASCI this story to illustrate how our laboratory Reconstitution studies proved that this membership, Joe had seen far too many and clinical lives can be linked in this era of mutation conferred drug resistance in bio- applications from investigators who were molecular medicine and offer an example chemical and cell growth assays — and we inadequately trained to move important of the kind of translational research our were done (12). clinically relevant observations forward. society should champion. In the winter of But the story gets better because John He offered this prescription: basic science 1999, Brian Druker and I witnessed dra- Kuriyan, a structural biologist interested training and technical courage (4). matic drops in the blood counts of 6 CML in very basic questions about kinase regu- In 1988 I began my postdoctoral stud- patients we treated with imatinib in the lation, had just published the cocrystal ies in Owen Witte’s laboratory at UCLA, phase I study. This single result was the cul- structure of ABL bound to imatinib (13). working on the BCR-ABL translocation mination of a series of advances dating back The threonine residue that we had iden- found in chronic myeloid leukemia. Hav- to the first description of the Philadelphia tified in patients as the site of the point ing made progress studying the signaling chromosome by Peter Nowell (5); the rec- mutation formed a hydrogen bond with properties of this fusion tyrosine kinase ognition of the reciprocal translocation of imatinib at the base of the ATP-binding oncogene and mapping the requirements chromosomes 9 and 22 by Janet Rowley (6); pocket. John and I did not know each other, for leukemic transformation, I began my the molecular identification of the BCR- and likely would never have crossed paths independent career on the 80/20 (80 per- ABL fusion tyrosine kinase by Owen Witte, had it not been for this remarkable conver- cent lab, 20 percent clinical) physician-sci- Eli Canaani, Nora Heistercamp, and John gence. Within 20 minutes of an introduc- entist track familiar to us all. We enter this Groffen (7–9); and the demonstration that tory phone call during which I outlined track with the idea that these 2 parts of BCR-ABL causes CML in mice by George our findings, John sent me a PowerPoint our lives are connected, but we know this Daley and David Baltimore (10). In parallel, slide by e-mail — which clearly delineates rarely happens. In fact, we are often warned advances in combinatorial chemistry and in a model of steric hindrance caused by the against trying to do both because clinical robotic high-throughput screening allowed T315I substitution (Figure 3). This threo- time becomes a service obligation and a the synthesis of large chemical libraries nine residue, which is conserved across distraction from our primary focus. I was containing millions of compounds that many kinases, is now called the gatekeeper

The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 11 November 2008 3799 supplement

The impact can be enormous, and fast. The focus on translational research today, whether we agree or not, is a reality. I believe this focus is justified, but only if done right, and I believe that we, as physi- cian-scientists, are uniquely qualified to address it. I do not have all the answers but will share some thoughts based on these 3 principles (Figure 4). One: Successful new medical therapies will be based on a foun- dation of precise molecular understanding of disease. Two: Translational science ques- tions can only be solved through a multi- disciplinary team approach that requires Figure 3 substantial infrastructure. Three: Human Model of imatinib binding to ABL kinase domain. The 2 panels depict wild-type Abl in complex subjects are an essential early component with STI-571 (imatinib; left) and predicted structure of STI-571 binding pocket of T315I mutant in the evaluation of new drug candidates Abl in complex with STI-571 (right). In the molecular structures representing STI-571 and Abl and should be studied at a level of scientific residue 315, nitrogen atoms are shown in blue, and oxygen atoms are shown in red. A hydro- detail comparable to that used for nonhu- gen bond between Thr315 (left) and STI-571 is shown by the dashed line. Van der Waals man preclinical model systems. interactions are depicted in gray for STI-571 (both panels), in blue for wild-type Abl residue Thr315 (left), and in red for mutant Abl residue Ile315 (right). The polypeptide backbone of the We are all aware of efforts at institutions Abl kinase domain is represented in green. Reprinted with permission from Science. across the country to build up transla- tional research — often without precisely specifying what translational research is. residue and forms a hydrogen bond with relapse, with dasatinib or a third ABL In my opinion, all of these programs are many of the ATP-competitive kinase inhib- inhibitor, nilotinib, that has also recent- controversial, and none are assured of suc- itors now in clinical development. And, as ly been approved. Some of you may be cess. Most of you are familiar with federal one might predict, analogous gatekeeper wondering whether sequential treatment initiatives such as the institutional Clinical residue mutations are associated with might select different types of mutants, and Translational Science Awards (CTSA resistance to other kinase inhibitors, such as was seen with antivirals in HIV, where grants), which have been awarded to 24 as erlotinib, in EGFR-driven lung cancer. combination therapy is required to over- institutions over the past 2 years, and the We initially wondered if drug discovery come resistance. Indeed, last year we Specialized Program of Research Excellence efforts could be refocused on compounds reported in the Journal of Clinical Investiga- (SPORE grants), awarded for organ-specific that might retain activity against this ima- tion that an increasingly complex spectrum translational cancer research through the tinib-resistant mutant. But this approach of mutations arise in CML patients who NCI. We are also witnessing growing efforts quickly became untenable as we and other relapse after sequential therapy, including by disease-focused philanthropic founda- groups began to enumerate over 50 differ- compound mutations that would have tions to steer their funding toward trans- ent amino acid substitutions associated never emerged had we used the drugs in lational research projects and even play an with imatinib resistance. Fortunately, I had combination (17). active role in directing the research. maintained contact with John Kuriyan. As I realize this vignette may seem self serv- I am very concerned about how these we mapped the growing list of mutations to ing, but I hope this example, as well as many programs are unfolding. The successes the structures solved in John’s lab, a theme of those we heard at the meeting today, that I have been a part of largely bubbled emerged. Most of these mutations share makes the point that basic science, when up from traditional investigator-initiated the common property of destabilizing the properly blended with clinical observation research programs directed by well-trained inactive, closed conformation of ABL that and molecularly based human investiga- physician-scientists, and enabled by truly is optimal for binding to imatinib (14). And tion, is what I call translational research. collaborative partnerships with the phar- it raised the enchanting notion that one might overcome these resistance mutations with an inhibitor that binds the active, open conformation. That inhibitor, dasatinib, surfaced serendipitously from a SRC kinase inhibitor project at Bristol Myers Squibb. Dasatinib is now approved by the FDA for treatment of imatinib-resistant CML. As predicted from the structural modeling studies, dasatinib was active against all but one of the imatinib-resistant mutants in preclinical models and in patients (15, 16). Today CML patients are treated sequen- Figure 4 tially, first with imatinib, and, if they Guiding principles of translational medicine.

3800 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 11 November 2008 supplement maceutical sector. These projects evolved scientists — who can work in a team science thanks to John Hawley and to Karen Guth, naturally, and quickly, when the goals of the model and conduct original, innovative who have worked tirelessly behind the various partners in the collaboration were work in addition to service work. I have no scenes to administrate our ASCI programs. aligned and, most importantly, when the illusions; this is a very difficult challenge Lastly, I congratulate you all on a remark- scientific rationale was compelling. I worry at multiple levels — requiring resources, able first 100 years of success and urge us to that successful translational research can- space, creating new academic promotion embrace our new challenges. not be prescribed through overly detailed tracks, incentives, and so on. But we are the 1. Brainard, E.R. 1959. History of the American Soci- grant mechanisms with long checklists of most qualified individuals in the biomedi- ety for Clinical Investigation, 1909–1959. J. Clin. required components. I suspect many of us cal research enterprise to address them. Invest. 38:1784–1864. have seen examples of poorly conceived sci- At Memorial Sloan-Kettering Cancer 2. Weber, B.L. 2007. In the palace of the sultan: 2007 American Society for Clinical Investigation Presi- ence forced into clinical experiments solely Center, Harold Varmus, Bob Wittes, and dential Address. J. Clin. Invest. 117:1727–1731. to qualify for translational funding. As Rick Tom Kelly decided to address some of 3. Ginsburg, D. 2002. The history and evolution of Lifton showed us today in his lecture, the these issues by creating a new program the ASCI: deja vu all over again. American Society for Clinical Investigation. J. Clin. Invest. 110:S1–S4. reviewers of these large program grants are with laboratory-based translational oncol- 4. Goldstein, J.L. 1986. On the origin and prevention often not qualified to judge the science. ogy as its mission. Our goals are to assem- of PAIDS (Paralyzed Academic Investigator’s Dis- I am also concerned about the impact of ble an outstanding group of laboratory- ease Syndrome). J. Clin. Invest. 78:848–854. 5. Nowell, P.C., and Hungerford, D.A. 1961. Chro- the unavoidable shift of funds away from trained physician-scientists across clinical mosome studies in human leukemia. II. Chron- basic science research. Imagine if John disciplines — each of whom has a passion- ic granulocytic leukemia. J. Natl. Cancer Inst. Kuriyan had not been funded to study ate commitment to human disease. These 27:1013–1035. basic structural biology of kinases. I want investigators become integral members of 6. Rowley, J.D. 1973. Letter: A new consistent chro- mosomal abnormality in chronic myelogenous leu- more translational research just as much as the clinical disease-management teams kaemia identified by quinacrine fluorescence and every disease advocate and Congressional responsible for delivery of clinical care and Giemsa staining. Nature. 243:290–293. leader, but it must be guided by and con- work together with their full-time clinical 7. Konopka, J.B., Watanabe, S.M., Singer, J.W., Collins, S.J., and Witte, O.N. 1985. Cell lines and clinical ducted with the same scientific rigor that colleagues on the development of proto- isolates derived from Ph1-positive chronic myelog- we require of basic science. Rather than cols. We are also establishing infrastruc- enous leukemia patients express c-abl proteins with prescribe specific translational projects, ture to make precise, innovative molecular a common structural alteration. Proc. Natl. Acad. Sci. U. S. A. 82:1810–1814. I favor spending resources on the infra- measurements on tissues obtained from 8. Heisterkamp, N., et al. 1983. Localization of the structure needed to conduct the kind of the patients treated on these trials — at the c-ab1 oncogene adjacent to a translocation break molecularly focused human studies that level we would expect in our own labora- point in chronic myelocytic leukaemia. Nature. 306:239–242. I described. In the context of cancer, I am tories — but centralized to enable larger 9. Shtivelman, E., Lifshitz, B., Gale, R.P., and Canaani, E. talking about the ability to annotate the throughput and quality control. This is 1985. Fused transcript of abl and bcr genes in chronic molecular status of the tumor by catalogu- but one pilot experiment currently under- myelogenous leukaemia. Nature. 315:550–554. ing relevant somatic alterations in tumor way at one institution. I hope we have a 10. Daley, G.Q., Van Etten, R.A., and Baltimore, D. 1990. Induction of chronic myelogenous leukemia DNA. We need better tools to quantify the continuing dialogue about others. in mice by the P210bcr/abl gene of the Philadelphia engagement of a drug with its target to chromosome. Science. 247:824–830. measure dose response using biochemical Acknowledgments 11. Druker, B.J., et al. 2001. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase parameters rather than toxicity parameters. A number of people have made my 3 years in chronic myeloid leukemia. N. Engl. J. Med. Finally, we need to serially track the impact on the ASCI Council truly special. First, I 344:1031–1037. of a treatment intervention on distinct thank my immediate predecessors, Eric 12. Gorre, M.E., et al. 2001. Clinical resistance to STI- 571 cancer therapy caused by BCR-ABL gene muta- molecular subsets in the tumor. Fearon and Barb Weber, for their leadership, tion or amplification. Science. 293:876–880. The goals are within our grasp with the and my successors, Nancy Andrews and Jon 13. Schindler, T., et al. 2000. Structural mechanism technologies available to us today, but we Epstein, for their wisdom and advice. Sec- for STI-571 inhibition of abelson tyrosine kinase. Science. 289:1938–1942. often compromise our clinical trial design ond, I thank my ASCI Council colleagues 14. Shah, N.P., et al. 2002. Multiple BCR-ABL kinase due to lack of infrastructure. This infra- — David Altshuler, Lynda Chin, Hal Deitz, domain mutations confer polyclonal resistance structure includes molecular pathology, Theresa Guise, Jake Liang, Jon Licht, Beth to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid molecular imaging, and bioinformatic inte- McNally, and Larry Turka — for their cama- leukemia. Cancer Cell. 2:117–125. gration of molecular and clinical datasets. raderie and support. Third, I thank Judy 15. Shah, N.P., et al. 2004. Overriding imatinib resis- It may be possible to solve some of these Swain, Elliott Kieff, and Denny Ausiello for tance with a novel ABL kinase inhibitor. Science. problems with core facilities — but these their hard work on the planning committee 305:399–401. 16. Talpaz, M., et al. 2006. Dasatinib in imatinib-resis- th core facilities, focused on human research, for this 100 anniversary meeting. Fourth, tant Philadelphia chromosome-positive leukemias. need to be different from traditional mod- I thank my wife, Susan, and my 2 children, N. Engl. J. Med. 354:2531–2541. els. These cores need to be directed by high- Sophie and Sam, for supporting my passion 17. Shah, N.P., et al. 2007. Sequential ABL kinase inhibitor therapy selects for compound drug-resis- ly trained scientists — perhaps physician- for this exciting career. Fifth, I give special tant BCR-ABL mutations with altered oncogenic potency. J. Clin. Invest. 117:2562–2569.

The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 11 November 2008 3801