Portal de Periódicos da CAPES

Attacking Cancer at Its Root

2009; Cell Press; Volume: 138; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2009.09.002

1097-4172

Craig B. Thompson,

Chronic Lymphocytic Leukemia Research

This year the Lasker DeBakey Clinical Research Award will be shared by Brian Druker, Nicholas Lydon, and Charles Sawyers for their development of a targeted molecular therapy for treating chronic myeloid leukemia. Their work demonstrated the ability of drugs directed against cancer-causing oncogenes to turn a rapidly fatal malignancy into a manageable chronic disease. This year the Lasker DeBakey Clinical Research Award will be shared by Brian Druker, Nicholas Lydon, and Charles Sawyers for their development of a targeted molecular therapy for treating chronic myeloid leukemia. Their work demonstrated the ability of drugs directed against cancer-causing oncogenes to turn a rapidly fatal malignancy into a manageable chronic disease. This year's Lasker DeBakey Clinical Research Award is unique. Three scientists, Brian Druker (Oregon Health and Science University), Nicholas Lydon (formerly of Novartis), and Charles Sawyers (Memorial Sloan-Kettering Cancer Center), are being recognized for a study that failed to reach its designated endpoint (Druker et al., 2001Druker B.J. Talpaz M. Resta D.J. Peng B. Buchdunger E. Ford J.M. Lydon N.B. Kantarjian H. Capdeville R. Ohno-Jones S. Sawyers C.L. N. Engl. J. Med. 2001; 344: 1031-1037Crossref PubMed Scopus (4272) Google Scholar). Cancer therapy has long been marked by toxic treatments including invasive surgery, damaging chemotherapy, and mutagenic radiation treatment. Despite numerous successes in controlling and even curing cancer using these nonspecific approaches, the side effects of these therapies have left both the public and many medical professionals emotionally conflicted concerning cancer treatment. As a result, the introduction of new cancer therapies follows a highly scripted protocol. Before a drug can be tested for its ability to treat cancer, investigators must first determine its safety. Studies are usually carried out in cancer patients who have exhausted all other existing therapeutic options. In these Phase I clinical studies, such patients volunteer to take the unproven drug. Groups of patients take the drug in increasing doses until a dose-limiting side effect is observed. Only after a maximal safe dose and the potential toxicities of a drug are defined are investigators allowed to initiate studies to determine whether a drug will have therapeutic efficacy in the treatment of cancer. The three scientists being honored with this year's Lasker Clinical Award came together to test a new therapeutic approach to cancer: the systemic administration of an inhibitor of the tyrosine kinase BCR-ABL, a mutant protein known to be involved in the pathogenesis of chronic myeloid leukemia (CML). At the time they undertook their work, most scientists believed that tyrosine kinases were required for too many essential cellular functions and were too similar in structure to be safely inhibited in vivo. In 1999, Druker, Lydon, and Sawyers designed a Phase I dose-escalation trial of what was then known as STI-571, now known as imatinib or Gleevec (Druker et al., 2001Druker B.J. Talpaz M. Resta D.J. Peng B. Buchdunger E. Ford J.M. Lydon N.B. Kantarjian H. Capdeville R. Ohno-Jones S. Sawyers C.L. N. Engl. J. Med. 2001; 344: 1031-1037Crossref PubMed Scopus (4272) Google Scholar). Despite the study's design and the prevailing concerns, they failed to identify a maximally tolerated dose. Instead, at the termination of their study, 53 of 54 of the CML patients treated with doses of 300 mg/day or more exhibited a complete hematological response. These results were quickly confirmed in Phase II and Phase III clinical trials designed to prove therapeutic efficacy (Sawyers et al., 2002Sawyers C.L. Hochhaus A. Feldman E. Goldman J.M. Miller C.B. Ottmann O.G. Schiffer C.A. Talpaz M. Guilhot F. Deininger M.W. et al.Blood. 2002; 99: 3530-3539Crossref PubMed Scopus (1034) Google Scholar, O'Brien et al., 2003O'Brien S.G. Guilhot F. Larson R.A. Gathmann I. Baccarani M. Cervantes F. Cornelissen J.J. Fischer T. Hochhaus A. Hughes T. et al.N. Engl. J. Med. 2003; 348: 994-1004Crossref PubMed Scopus (2854) Google Scholar). The drug was approved for clinical use in 2001. Today, close to 90% of the initial CML patients treated with imatinib have exhibited no disease progression and remain on treatment. The success of this study established for the first time that a somatically mutated gene that was causally involved in the pathogenesis of cancer could be safely and effectively targeted for cancer treatment. As a result, hundreds of targeted molecular therapies are now in various stages of clinical development, and the ongoing analysis of the outcomes of these studies continues to provide new insight into cancer pathogenesis and progression. When viewed in isolation, the introduction of imatinib (Gleevec) is an important addition to medical therapy. However, when viewed as the reduction to practice of over 40 years of basic cancer research, it is an astonishing story (for review, see Druker, 2008Druker B.J. Blood. 2008; 112: 4808-4817Crossref PubMed Scopus (550) Google Scholar). In the 1960s, CML was the first cancer shown to contain a recurring genetic alteration. Nowell and Hungerford demonstrated that the cells isolated from CML patients contained an abnormally small chromosome. In the 1970s, Janet Rowley and her colleagues demonstrated that this "Philadelphia chromosome" resulted from a chromosomal translocation between chromosomes 9 and 22. In the 1980s, several groups were able to demonstrate that the fusion chromosome resulted in juxtaposition of the 3′ end of the cellular homolog of the v-Abl oncogene on chromosome 9 with the 5′ end of a gene encoded on chromosome 22, given the name breakpoint cluster region (BCR). The protein product of this fusion was termed BCR-ABL. At the time of the cloning and characterization of the BCR-ABL fusion, characterization of the retroviral ABL protein had demonstrated that it belonged to a subclass of oncogenic proteins that functioned as tyrosine kinases. Like other oncogenic tyrosine kinases, the ABL protein is an enzyme that adds phosphate groups to the tyrosines of substrate proteins. The BCR-ABL fusion protein created by the Philadelphia chromosome was also shown to have tyrosine kinase activity, and tyrosine modification of its substrates was shown to play a critical role in regulating protein-protein interactions to initiate signal transduction pathways that inform cell survival, growth, and proliferation. Introduction of BCR-ABL into the hematopoietic lineage of mice resulted in leukemia, implicating this oncogene in the pathogenesis of cancer. These studies provided a dramatic demonstration that chromosomal translocations could lead to somatic alterations in enzyme regulation that contribute to cancer pathogenesis. Work to characterize the biological functions of tyrosine kinases in the 1980s implicated the normal homologs of the viral tyrosine kinases as components of cell signaling that connected surface receptors to the regulation of gene transcription and expression. As each of these genes was characterized in greater detail, the emerging importance of tyrosine phosphorylation in regulating cell signaling led many basic biologists to conclude that these genes were unlikely cancer targets. However, this did not keep clinical oncologists from hypothesizing to their trainees that these genes might be therapeutic targets if highly selective inhibitors could be developed. It is at this time that Brian Druker entered the field of medical oncology and became interested in the possibility of targeting tyrosine kinases as a cancer therapy. As an oncology fellow in Thomas Roberts' laboratory at the Dana Farber Cancer Institute, Druker was among the first to produce a monoclonal antibody against phosphotyrosine for use in studying the activity of tyrosine kinases in transformed cells. It was also during this time that Nicholas Lydon was given the task of leading a drug discovery program at Ciba-Geigy to screen their chemical libraries for compounds that could inhibit tyrosine kinases. At the time, most medicinal chemists believed that although broad kinase inhibitors might be found, they would never be specific enough to be used safely in vivo. As part of the program, Lydon and his colleagues began using the monoclonal antibody that Druker had made to study kinase activity and substrates (Buchdunger et al., 1996Buchdunger E. Zimmermann J. Mett H. Meyer T. Muller M. Druker B.J. Lydon N.B. Cancer Res. 1996; 56: 100-104PubMed Google Scholar). Although a number of inhibitors were produced as part of this program, when screened against a panel of tyrosine kinases none were found to inhibit only a single tyrosine kinase (Zimmermann et al., 1997Zimmermann J. Buchdunger E. Mett H. Meyer T. Lydon N.B. Bioorg. Med. Chem. Lett. 1997; 7: 187-192Crossref Scopus (220) Google Scholar). By 1993, Druker had set up his own laboratory at the University of Oregon and was trying to find a kinase inhibitor of BCR-ABL that might be developed for clinical use in the treatment of CML (Oda et al., 1994Oda T. Heaney C. Hagopian J.R. Okuda K. Griffin J.D. Druker B.J. J. Biol. Chem. 1994; 269: 22925-22928Abstract Full Text PDF PubMed Google Scholar, Druker, 2008Druker B.J. Blood. 2008; 112: 4808-4817Crossref PubMed Scopus (550) Google Scholar). For this effort, he contacted Lydon, who provided compounds his team had developed. Together they reported in 1996 that one of these substances had activity in killing cells transformed with BCR-ABL, but not cells transformed with the tyrosine kinase Src (Druker et al., 1996Druker B.J. Tamura S. Buchdunger E. Ohno S. Segal G.M. Fanning S. Zimmermann J. Lydon N.B. Nat. Med. 1996; 2: 561-566Crossref PubMed Scopus (3039) Google Scholar). In mice, the compound was found to be well tolerated, even though it inhibited several tyrosine kinases in addition to BCR-ABL. They were able to demonstrate in mice that the compound prevented the growth of BCR-ABL transformed cells. Based on this information, Druker began to establish a team to initiate clinical trials with the support of Novartis, which had acquired the compound as a result of the merger of Ciba-Geigy and Sandoz. Druker recruited Charles Sawyers from the University of California, Los Angeles and Moshe Talpaz from M.D. Anderson Cancer Center to join him. Together, the assembled team designed a pivotal Phase I clinical trial. In June of 1998 and May 2000, they enrolled 80 patients in their dose-escalating Phase I trial (Druker et al., 2001Druker B.J. Talpaz M. Resta D.J. Peng B. Buchdunger E. Ford J.M. Lydon N.B. Kantarjian H. Capdeville R. Ohno-Jones S. Sawyers C.L. N. Engl. J. Med. 2001; 344: 1031-1037Crossref PubMed Scopus (4272) Google Scholar). As noted above, though a dose-limiting toxicity was not defined, 98% of the patients treated with doses in excess of 300 mg/day showed a dramatic decline in their cancer cell burden. A subsequent Phase III clinical trial (O'Brien et al., 2003O'Brien S.G. Guilhot F. Larson R.A. Gathmann I. Baccarani M. Cervantes F. Cornelissen J.J. Fischer T. Hochhaus A. Hughes T. et al.N. Engl. J. Med. 2003; 348: 994-1004Crossref PubMed Scopus (2854) Google Scholar)—the international randomized study comparing interferon and imatinib that was directed by Druker—demonstrated the vast superiority of imatinib to prior therapies for chronic phase CML and determined that over 95% of patients achieved a complete hematological response at the initiation of therapy. Further follow-up of this group was published in 2006 and demonstrated that 86% of the initial patients achieved a complete cytogenetic remission. CML is a relatively asymptomatic disease. Up to half of all patients are diagnosed as the consequence of routine blood testing incidental to their disease (Figure 1). The remaining patients are diagnosed as a result of symptoms from the splenomegaly or anemia that occurs as a secondary consequence of the chronic myeloid proliferation. Untreated, most patients go on to a progressive form of the disease within 3 years, marked by the acquisition of additional cytogenetic abnormalities, a decline in mature blood cell numbers, and ultimately the appearance of undifferentiated leukemic cells that mark the disease's conversion to acute leukemia. Once a patient has converted from chronic to acute leukemia, additional chemotherapeutic treatments have little efficacy. Despite initial promise, this continues to be true for imatinib and related tyrosine kinase inhibitors (Sawyers et al., 2002Sawyers C.L. Hochhaus A. Feldman E. Goldman J.M. Miller C.B. Ottmann O.G. Schiffer C.A. Talpaz M. Guilhot F. Deininger M.W. et al.Blood. 2002; 99: 3530-3539Crossref PubMed Scopus (1034) Google Scholar, Talpaz et al., 2006Talpaz M. Shah N.P. Kantarjian H. Donato N. Nicoll J. Paquette R. Cortes J. O'Brien S. Nicaise C. Bleickardt E. et al.N. Engl. J. Med. 2006; 354: 2531-2541Crossref PubMed Scopus (1400) Google Scholar). When CML patients with progressive disease were treated, Druker and Sawyers observed that although many of these patients had an initial benefit from treatment with imatinib, the result was relatively short-lived (Sawyers et al., 2002Sawyers C.L. Hochhaus A. Feldman E. Goldman J.M. Miller C.B. Ottmann O.G. Schiffer C.A. Talpaz M. Guilhot F. Deininger M.W. et al.Blood. 2002; 99: 3530-3539Crossref PubMed Scopus (1034) Google Scholar). This prompted Sawyers to take the lead in characterizing this phenomenon. His laboratory characterized in detail an initial cohort of patients whose disease recurred despite continuous imatinib treatment (Gorre et al., 2001Gorre M.E. Mohammed M. Ellwood K. Hsu N. Paquette R. Rao P.N. Sawyers C.L. Science. 2001; 293: 876-880Crossref PubMed Scopus (2649) Google Scholar). In close to half of these patients, he found that drug resistance was associated with the outgrowth of cells that had mutations in the tyrosine kinase domain of BCR-ABL that locked the kinase in its active conformation and rendered it resistant to imatinib, which binds and locks the protein in its inactive state (Shah et al., 2002Shah N.P. Nicoll J.M. Nagar B. Gorre M.E. Paquette R.L. Kuriyan J. Sawyers C.L. Cancer Cell. 2002; 2: 117-125Abstract Full Text Full Text PDF PubMed Scopus (1389) Google Scholar). This was the final brushstroke in this bench-to-bedside masterpiece. The correlation of these mutations to the relapse of patients being treated with imatinib provided an unequivocal proof that the efficacy of imatinib is related to its ability to specifically inhibit BCR-ABL. These studies demonstrated once and for all that the inhibition of a carcinogenic lesion can safely and effectively prevent the inexorable progression that cancer exhibits in its untreated form. Together, these studies opened the molecular era of targeted therapy directed against oncogenic mutations. The combined contribution of the three awardees also provides an important example of the value of public-private cooperation. There is little doubt that the constant prodding of Druker and Sawyers led Novartis to support a Phase I trial of a drug that was felt to have limited commercial potential. At the same time, the resources commanded by Lydon to engage in chemical discovery and lead drug modifications and characterization cannot be duplicated in the current academic realm. Today, over 500 drugs based on the principles established by the discovery of imatinib are in clinical development. The oncology community has embraced the belief that targeted therapeutics hold the promise to provide more effective therapies for the treatment of cancer, disassociated from the traditional side effects of chemotherapy. Prior to the work of Druker, Lydon, and Sawyers, targeted molecular cancer therapies did exist. However, these existing therapies were not directed at the oncogenic mutations that led to cancer but instead to essential features required for both normal and neoplastic cells of certain lineages. This is best demonstrated by the role of hormonal manipulation for the treatment of breast and prostate cancer. Hormonal ablation led to regression of these tumors as well as the normal tissue from which the tumor arose. As such, these therapies were associated with significant toxicities, including the stimulation of menopausal symptoms in breast cancer patients and the complex physiological and psychological effects of castration in patients with prostate cancer. Until the work of Druker, Lydon, and Sawyers, therapy directed against the root cause of a cancer had not been undertaken. Their combined work provided a therapy that is almost universally effective for a clearly defined subset of CML patients, namely patients in the chronic phase of the disorder with a demonstrable BCR-ABL translocation. Furthermore, their demonstration that therapeutic efficacy is tied to the presence of the BCR-ABL translocation reinforced the concept that surrogate markers could be used to identify subsets of cancer patients that are likely to benefit from a targeted therapeutic. As successful as imatinib (Gleevec) has been in leading to a paradigmatic shift in the treatment of cancer, the work has also provided insights that challenge the notion of how widely or quickly its success will be replicated. Epidemiological and genetic analyses have shown that cancer occurs in a series of steps characterized by the acquisition of heritable somatic mutations. To date, targeted treatments for cancer have proven most effective when tumors can be identified at an intermediate stage of transformation. Gleevec is most effective as a single agent when it is introduced at a stage when the BCR-ABL translocation is essential for sustaining the growth and survival of the accumulating cancer cells. As the CML cells acquire additional somatic mutations that characterize blast crisis and the conversion to acute leukemia (Figure 1), inhibition of BCR-ABL has little or limited impact for many patients, suggesting that these tumors are no longer solely dependent on BCR-ABL for their maintenance. A partial demonstration of this has been provided by the finding that broader spectrum tyrosine kinase inhibitors can display efficacy even in those patients who develop progressive disease without carrying a BCR-ABL mutation that confers resistance to imatinib (Cortes et al., 2008Cortes J. Kim D.W. Raffoux E. Martinelli G. Ritchie E. Roy L. Coutre S. Corm S. Hamerschlak N. Tang J.L. et al.Leukemia. 2008; 22: 2176-2183Crossref PubMed Scopus (163) Google Scholar). These observations will lead in ensuing years to combined targeted therapies, as reproducible and treatable secondary lesions are identified in this population. These results suggest that, like the unique dependence of chronic phase CML on the BCR-ABL translocation product, we need to identify the comparable intermediate stages of disease in other malignancies. Already some examples come to mind. The role of Bcl-2 translocations in follicular lymphoma may provide such an opportunity to treat these otherwise incurable malignancies before they progress to more aggressive forms of lymphoma. The role of isocitrate dehydrogenase 1 (IDH1) as an initiating genomic lesion in intermediate grade gliomas may provide an opportunity for treatment of these tumors before they progress to malignant glioblastomas. Whether similar stages for lung cancer or other common cancers exist remains to be determined. Imatinib itself has already led to a demonstration of the importance of identifying such intermediate stages of cancer development. One of the concerns when imatinib was first introduced was that it was also known to inhibit two other tyrosine kinases, the PDGF receptor and c-Kit. Following the initial work of Druker, Lydon, and Sawyers, the safety profile of imatinib prompted investigators to explore the use of this agent in the treatment of gastrointestinal stromal tumors, which exhibit activation of the Kit receptor as one of the initiating lesions. Imatinib treatment has provided significant clinical benefit for a subpopulation of these patients (Demetri et al., 2002Demetri G.D. von Mehren M. Blanke C.D. Van den Abbeele A.D. Eisenberg B. Roberts P.J. Heinrich M.C. Tuveson D.A. Singer S. Janicek M. et al.N. Engl. J. Med. 2002; 347: 472-480Crossref PubMed Scopus (3548) Google Scholar). The myeloproliferative disorder hypereosinophilic syndrome has been demonstrated to correlate with a chromosomal translocation involving the PDGF receptor (Cools et al., 2003Cools J. DeAngelo D.J. Gotlib J. Stover E.H. Legare R.D. Cortes J. Kutok J. Clark J. Galinsky I. Griffin J.D. et al.N. Engl. J. Med. 2003; 348: 1201-1214Crossref PubMed Scopus (1433) Google Scholar). Treatment of patients with this translocation can promote hematological remission and prevent disease progression. As with CML, resistance to imatinib in this patient population has been correlated with the acquisition of mutations in the PDGF receptor kinase domain. Finally, recent studies reinforce the importance of treating patients with targeted agents at the earliest possible presentation of their disease. The rate of relapse in patients with CML declines dramatically after the first 3 years of therapy, dropping to less than 1% per year by their 5th year in therapy. Modeling experiments suggest that the higher rate of relapse seen in the first 3 years results from the outgrowth of clones bearing resistance mutations in the BCR-ABL gene already present at the start of therapy. Chronic treatment with imatinib appears to dramatically reduce the rate at which the persistent cells carrying a BCR-ABL translocation acquire additional mutations. This is in contrast to standard chemotherapeutic agents. The majority of these are mutagenic and potentially accelerate the mutation rate of the cancer cells that are not eliminated by the therapy. Unfortunately, for the patients it helps most, imatinib treatment must be maintained chronically. Even after years of therapy and complete absence of clinical disease, patients can continue to harbor BCR-ABL transformed cells. Patients who have discontinued imatinib have had their disease relapse. It appears from these clinical observations that there are sites in the bone marrow where CML progenitors can persist even when the survival benefits of BCR-ABL are suppressed. Alternatively, there may be sites of disease persistence where effective levels of imatinib are not obtained. However, as the years go by and second generation inhibitors also fail to completely eliminate the disease, this latter possibility seems less likely (Talpaz et al., 2006Talpaz M. Shah N.P. Kantarjian H. Donato N. Nicoll J. Paquette R. Cortes J. O'Brien S. Nicaise C. Bleickardt E. et al.N. Engl. J. Med. 2006; 354: 2531-2541Crossref PubMed Scopus (1400) Google Scholar). The persistence of this reservoir of cells is being studied in many laboratories. Understanding how and why such cells are retained will undoubtedly provide valuable insight into cancer pathogenesis. This year's Lasker clinical prize awardees are being honored not only for bringing basic science discoveries from the bench to the bedside, but also for how their bedside research is stimulating a deeper and more fundamental understanding of cancer. The author wishes to thank Joseph Goldstein, Timothy Ley, Tullia Lindsten, Steven Reiner, Niklas Thompson, and members of the Thompson Laboratory for their input and critical review of the manuscript.