F all somatic mutations were not detectable across every tumor region

F all somatic mutations were not detectable across every tumor region [10]. The major practical conclusion of this research was that (p. 883) intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development [10]. To be more precise, the major challenge for personalized medicine is that it targets the primary driver of a tumor, and will often successfully defeat or contain that driver. But that only creates an opportunity for genetic sub-populations in a tumor to become the drivers of renewed tumor growth, somewhat in Darwinian fashion. This will usually mean that the targeted therapy is no longer effective; tumors then are described as being resistant. The phenomenon of cancer resistance can be characterized in a variety of ways. In some instances cancers are resistant to first-line traditional chemotherapeutic agents. In other cases resistance developsJ. Pers. Med. 2013,in response to attempted therapies. Efforts to understand this resistance generated the research that has sought to characterize tumors in genetic terms and to identify specific biological pathways connected to specific cancers that were necessary to generate or sustain those tumors. These efforts have been aided by the development of massive Pyrvinium pamoate chemical information parallel sequencing (MPS) capacities that have made possible the sequencing of cancer genomes quickly enough to be clinically useful and cheaply enough to be affordable (roughly 5,000). Sequencing, in turn, allows the order Lixisenatide identification of druggable targets and the rational development of personalized or targeted or precision medicine. Of course, what every cancer researcher knows today is that this is a very oversimplified picture of cancer therapy. As noted earlier, the heterogeneity of many cancers means there is most often no one target, which, if hit precisely, will result in the defeat of that cancer. Garraway and Jaenne conclude (p. 214), The challenge of tumor drug resistance therefore represents a pervasive barrier that confounds the ultimate goal of cure or long-term control of metastatic cancer [3]. They go on to identify the main categories of acquired drug resistance categories. These include: (1) secondary genetic alteration in a drug target; (2) a bypass mechanism, such as the activation of a parallel signaling pathway; (3) alterations in upstream or downstream effectors; (4) a pathway-independent resistance process. At present two broad strategies might be employed to address the problem of resistance. Several drugs might be used in sequence, or several drugs might be used in combination with one another. For many GIST patients imatinib proved very effective in preventing disease progression for long periods of time. But eventually it failed and other tyrosine kinase inhibitors, such as dasatinib or nilotinib, were employed in succession to slow disease progression, usually for briefer intervals. However, as Garraway and Jaenne note (p. 223), if resistance results from activation of a parallel signaling pathway, then a combination of two or more drugs will be necessary to slow disease progression [3]. As noted earlier, this is the same strategy that has successfully contained the AIDS virus for more than a decade in hundreds of thousands of individuals [4]. However, in the case of cancer this combinatorial strategy generates some potentially significant clinical problems. Fi.F all somatic mutations were not detectable across every tumor region [10]. The major practical conclusion of this research was that (p. 883) intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development [10]. To be more precise, the major challenge for personalized medicine is that it targets the primary driver of a tumor, and will often successfully defeat or contain that driver. But that only creates an opportunity for genetic sub-populations in a tumor to become the drivers of renewed tumor growth, somewhat in Darwinian fashion. This will usually mean that the targeted therapy is no longer effective; tumors then are described as being resistant. The phenomenon of cancer resistance can be characterized in a variety of ways. In some instances cancers are resistant to first-line traditional chemotherapeutic agents. In other cases resistance developsJ. Pers. Med. 2013,in response to attempted therapies. Efforts to understand this resistance generated the research that has sought to characterize tumors in genetic terms and to identify specific biological pathways connected to specific cancers that were necessary to generate or sustain those tumors. These efforts have been aided by the development of massive parallel sequencing (MPS) capacities that have made possible the sequencing of cancer genomes quickly enough to be clinically useful and cheaply enough to be affordable (roughly 5,000). Sequencing, in turn, allows the identification of druggable targets and the rational development of personalized or targeted or precision medicine. Of course, what every cancer researcher knows today is that this is a very oversimplified picture of cancer therapy. As noted earlier, the heterogeneity of many cancers means there is most often no one target, which, if hit precisely, will result in the defeat of that cancer. Garraway and Jaenne conclude (p. 214), The challenge of tumor drug resistance therefore represents a pervasive barrier that confounds the ultimate goal of cure or long-term control of metastatic cancer [3]. They go on to identify the main categories of acquired drug resistance categories. These include: (1) secondary genetic alteration in a drug target; (2) a bypass mechanism, such as the activation of a parallel signaling pathway; (3) alterations in upstream or downstream effectors; (4) a pathway-independent resistance process. At present two broad strategies might be employed to address the problem of resistance. Several drugs might be used in sequence, or several drugs might be used in combination with one another. For many GIST patients imatinib proved very effective in preventing disease progression for long periods of time. But eventually it failed and other tyrosine kinase inhibitors, such as dasatinib or nilotinib, were employed in succession to slow disease progression, usually for briefer intervals. However, as Garraway and Jaenne note (p. 223), if resistance results from activation of a parallel signaling pathway, then a combination of two or more drugs will be necessary to slow disease progression [3]. As noted earlier, this is the same strategy that has successfully contained the AIDS virus for more than a decade in hundreds of thousands of individuals [4]. However, in the case of cancer this combinatorial strategy generates some potentially significant clinical problems. Fi.