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David M. Thomas and Andrew J. Wagner

Connective tissue tumors comprise a rich array of subtypes, many of which possess strong pathognomonic phenotypes and genotypes of therapeutic significance. This article describes recent applications of targeted and nontargeted therapeutic agents in connective tissue tumors that illustrate important themes in drug development. Targeted therapy has exploited the paradigms of oncogene and lineage addiction. In other cases, potential targets are more difficult to classify, such as the role of the insulin-like growth factor 1 pathway in Ewing's sarcoma. Understanding why these pathways seem critical in some cancers, and in some individuals but not others, is important in identifying novel therapeutic opportunities in an age of personalized medicine.

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Josh Lauring, Ben Ho Park and Antonio C. Wolff

levels of growth factor receptors (trastuzumab, IGF1R inhibitors, EGFR inhibitors, lapatinib), PIK3CA (nonselective and selective PI3K inhibitors), Akt (allosteric and kinase inhibitors of Akt), and mTOR ( Figure 1 ). Drugs targeting mTOR include

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Jill Corre and Hervé Avet-Loiseau

Myeloma is a complex disease, characterized by a wide heterogeneity in clinical presentation, evolution, and molecular portraits. The successive use of cytogenetics, molecular cytogenetics, expression genomics, copy number genomics, and, more recently, deep sequencing, has shown that this heterogeneity can be used to identify markers usable for not only prognostication but also therapeutic choice and, ultimately, discovery of druggable targets. The use of some of these techniques is now mandatory for the management of patients. Although risk-adapted therapy is not yet a routine practice in myeloma, these molecular changes are essential for the definition of the prognosis.

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Wing C. Chan and James O. Armitage

The application of gene expression profiling to the study of lymphomas will significantly influence the way these tumors are diagnosed and treated. Diffuse large B-cell lymphoma is now known to consist of several different genetic entities with different clinical presentations and therapeutic outcomes. In both follicular and diffuse large B-cell lymphoma, these studies have shown that host–tumor interactions have a major impact on the clinical course. Findings of gene expression profiling in diffuse large B-cell lymphoma has indicated the frequent up-regulation of the nuclear factor-κB and B-cell receptor signaling pathways in the activated B-cell type. Drugs targeting these pathways may be effective in the treatment of these cases and clinical trials have been initiated based on these findings. Gene expression profiling may assist in the selection of treatments based on specific metabolic pathways shown to be active in a particular lymphoma. These techniques offer the promise of truly personalized medicine for patients with lymphoma.

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Prithviraj Bose and Srdan Verstovsek

The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of “clinical improvement” in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations.

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Michael Deininger

Imatinib, a specific small molecule inhibitor of the Abl kinase, has become the standard drug therapy for chronic myelogenous leukemia in all phases. More than 80% of newly diagnosed patients with chronic phase attain a complete cytogenetic response (CCR). Although remissions in patients with early disease are generally durable, acquired resistance after an initial response is common in advanced disease. Reactivation of Bcr-Abl signaling is almost invariably present at the time of relapse, consistent with re-establishment of the initial pathogenetic mechanism. Mutations in the kinase domain (KD) of Bcr-Abl that impair drug binding and increased expression of Bcr-Abl have been identified as major mechanism of acquired drug resistance. The fact that Bcr-Abl remains central to disease pathogenesis at the time of relapse implies that it also remains the optimal drug target. Alternative Abl kinase inhibitors with increased potency and activity against most Bcr-Abl KD mutants are currently undergoing phase I/II clinical testing, with encouraging early results. Despite the high rates of CCR, persistence of residual leukemia as assessed by reverse transcription polymerase chain reaction is the rule even in patients with chronic phase, suggesting that even these patients may remain at risk of relapse. Understanding the mechanisms underlying disease persistence will be crucial for developing strategies to eradicate residual leukemia.

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Gregory P. Kalemkerian

physicians tell me that, at every meeting, they are told they aren’t practicing modern medicine if they don’t routinely check for mutations of gene X , despite little evidence that drugs targeting gene X improve outcomes. A horde of commercial entities

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Lyndsay J. Willmott, Daniele A. Sumner and Bradley J. Monk

adverse events being gastrointestinal, fatigue, and rash. The authors concluded that erlotinib was inactive as monotherapy in patients with recurrent squamous cell carcinoma of the uterine cervix. 30 Cetuximab is another drug targeting EGFR that has been

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Toni K. Choueiri and Robert J. Motzer

therefore been characterized as a possible resistance mechanism to drugs targeting angiogenesis. 7 One small prospective clinical trial (N=25) showed a promising PFS of 12.9 months and a response rate of 28% with cabozantinib, a receptor tyrosine kinase

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Tianhong Li

agents to first FDA approval to approximately 4 years. In recent years, the FDA has approved an increasing number of precision oncology drugs targeted to individual molecular biomarkers across many cancer types based on early-stage (phase I or II