Volume 19 Issue 11, November 2013

Volume 19 Issue 11

In this issue, we are proud to feature a collection of reviews on targeted cancer therapies (pp 1380–1464). Cover image: Plato's Cave by Katie Merz (katiemerz.com).

Editorials

  • Editorial |

    University technology transfer offices are tasked with helping bring the inventions made by academics to the attention of potential investors. But selling off intellectual property to patent aggregators in an effort to bring in money to their institutions could stifle the future development of new technologies.

News

  • News in Brief

  • Q&A

  • Q&A |

    In August, Novartis appointed Ricardo Dolmetsch to be the company's global head of neurosciences—the first new hire for its reincarnated neuroscience division. As a professor at California's Stanford University School of Medicine for the past ten years, Dolmetsch made his name using induced pluripotent stem (iPS) cells to study a rare form of autism known as Timothy syndrome. Elie Dolgin met with Dolmetsch at the Novartis Institutes for BioMedical Research in the Technology Square area of Cambridge to discuss how he plans to succeed where so many others have failed.

  • News Feature

  • News Feature |

    Each year, tens of thousands of young people worldwide die suddenly after their hearts stop beating for no apparent reason. Genetic testing for inherited heart rhythm disorders can potentially offer grief-stricken family members an explanation for the loss of their loved ones and provide actionable diagnostic information to help them avoid the same fate. And yet, such 'molecular autopsies' are rarely performed by the forensic experts who investigate unexplained deaths. Jeanne Erdmann meets the medical professionals who are trying to change that.

    • Jeanne Erdmann
  • Opinion

  • Opinion |

    Better outcomes and lower costs are needed in cancer care. To establish true value for money, researchers must establish what matters most to patients and other relevant stakeholders—including families, employers and even insurance companies.

    • Michael Kolodziej
    • , Ira Klein
    •  & Lonny Reisman

Book Review

News and Views

  • News & Views |

    Autophagy and apoptosis are ancient processes that regulate cell fate under normal and disease conditions. A new study in mice identifies mammalian Ste20-like kinase-1 (Mst-1) as a missing link that interfaces between these pathways for cell survival and death during cardiac stress (pages 1478–1488).

    • Rimpy Dhingra
    •  & Lorrie A Kirshenbaum
  • News & Views |

    An endogenous molecule secreted by macrophages during stress is a new mediator for the wave of inflammation triggered during hemorrhagic and septic shock. This finding suggests a potential drug target to reduce organ injury and death after shock (pages 1489–1495).

    • Peter A Ward
  • News & Views |

    In fragile X syndrome, the absence of fragile X mental retardation protein (FMRP) allows the production of certain proteins to go unchecked in the brain. A recent study in mice suggests that bringing excessive translation into balance may provide a key to treating this syndrome (pages 1473–1477).

    • Laura N Smith
    •  & Christopher W Cowan
  • News & Views |

    Understanding the molecular mechanisms that govern diabetes-induced loss of kidney function is crucial. A new study shows that in mouse models of diabetes, sirtuin 1 (Sirt1) in the proximal tubules of the kidney can modulate the expression of podocyte Claudin-1, a key regulator of albuminuria and glomerular function (pages 1496–1504).

    • Deepak Nihalani
    •  & Katalin Susztak

Community Corner

Research Highlights

Perspective

  • Perspective |

    Synthetic lethality describes a situation in which defects in either one of two genes are not detrimental, but combining defects in the two genes is lethal. The targeting of BRCA-deficient tumors by PARP inhibitors is the first clinical example utilizing the principle of synthetic lethality to treat cancer. Despite the promise of this approach, a number of resistance mechanisms have been identified, and this Perspective describes these mechanisms and their clinical relevance.

    • Christopher J Lord
    •  & Alan Ashworth

Reviews

  • Review Article |

    Despite the initial promise of cancer therapies targeted against the epidermal growth factor receptor (EGFR), tumors treated with these agents eventually develop resistance. In this Review, the authors outline the complex mechanisms by which tumors become resistant to EGFR-targeted drugs and antibodies and offer insights into new strategies that might be employed to circumvent therapeutic resistance.

    • Curtis R Chong
    •  & Pasi A Jänne
  • Review Article |

    Inhibitors of RAF kinase have shown substantial benefits in the clinic for the treatment of people with BRAF-mutant melanoma, but their utility is limited by the emergence of therapeutic resistance. In this Review, the authors provide a synthesis of the currently known mechanisms of resistance to RAF-targeted therapies and show how their model has implications for the development of more effective strategies to treat patients with BRAF-mutant tumors.

    • Piro Lito
    • , Neal Rosen
    •  & David B Solit
  • Review Article |

    There has been substantial progress in understanding the role of Hedgehog (Hh) signaling in cancer in recent years, as exemplified by the approval by the US Food and Drug Administration of the Hh pathway inhibitor vismodegib in 2012 for the treatment of basal cell carcinoma. This Review outlines these advances and charts the development of Hh inhibitors, providing a critical overview of how these drugs have fared in the clinic.

    • Dereck Amakye
    • , Zainab Jagani
    •  & Marion Dorsch
  • Review Article |

    Cancer cells can alter and build a permissive microenvironment that supports the malignant behavior of a growing primary tumor and developing metastases. But the role of the players in the stroma is rather complex, and their functions are intertwined, requiring a strategy to normalize the microenvironment to halt cancer progression. Re-education of stromal cells that interact with tumor cells may be a promising therapeutic avenue to exploit a genetically stable part of the tumor.

    • Daniela F Quail
    •  & Johanna A Joyce
  • Review Article |

    Epithelial-mesenchymal transitions (EMTs) are a key requirement for cancer cells to metastasize and colonize in a new environment. Epithelial-mesenchymal plasticity is mediated by master transcription factors and is also subject to complex epigenetic regulation. This Review outlines our current understanding of the interactions between EMT-inducing transcription factors and epigenetic modulators during cancer progression and the therapeutic implications of exploiting this intricate regulatory process.

    • Wai Leong Tam
    •  & Robert A Weinberg
  • Review Article |

    Increasing understanding of how tumor cells metastasize, what secondary organs are the targets of disseminating tumor cells and what molecular mechanisms are involved in the metastatic cascade can provide a road map to translate new biological insights into clinical practice. As tumor metastasis remains the main cause of death for patients with cancer, this is an unmet clinical need that requires a thorough examination of the most recent and relevant translational research.

    • Liling Wan
    • , Klaus Pantel
    •  & Yibin Kang

Brief Communications

  • Brief Communication |

    The authors employ targeted next-generation sequencing to identify driving oncogenic alterations in patients with lung cancer with no known oncogenes. They discover two gene fusions involving NTRK1 that lead to constitutive activation of the kinase TRKA and can drive transformation. The fusions can be targeted with available kinase inhibitors and may represent therapeutic targets.

    • Aria Vaishnavi
    • , Marzia Capelletti
    • , Anh T Le
    • , Severine Kako
    • , Mohit Butaney
    • , Dalia Ercan
    • , Sakshi Mahale
    • , Kurtis D Davies
    • , Dara L Aisner
    • , Amanda B Pilling
    • , Eamon M Berge
    • , Jhingook Kim
    • , Hidefumi Sasaki
    • , Seung-il Park
    • , Gregory Kryukov
    • , Levi A Garraway
    • , Peter S Hammerman
    • , Julia Haas
    • , Steven W Andrews
    • , Doron Lipson
    • , Philip J Stephens
    • , Vince A Miller
    • , Marileila Varella-Garcia
    • , Pasi A Jänne
    •  & Robert C Doebele
  • Brief Communication |

    Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of the translational repressor protein FMRP. Now, Joel D. Richter and his colleagues report that knocking down the expression of the translational activator protein CPEB can restore normal levels of translation and rescue behavioral deficits in a mouse model of FXS.

    • Tsuyoshi Udagawa
    • , Natalie G Farny
    • , Mira Jakovcevski
    • , Hanoch Kaphzan
    • , Juan Marcos Alarcon
    • , Shobha Anilkumar
    • , Maria Ivshina
    • , Jessica A Hurt
    • , Kentaro Nagaoka
    • , Vijayalaxmi C Nalavadi
    • , Lori J Lorenz
    • , Gary J Bassell
    • , Schahram Akbarian
    • , Sumantra Chattarji
    • , Eric Klann
    •  & Joel D Richter

Articles

  • Article |

    The kinase Mst1, which acts in the Hippo pathway, controls cell proliferation, differentiation and apoptosis. Junichi Sadoshima and his colleagues show that Mst1 in cardiomyocytes phosphorylates the protein Beclin1 to coordinately suppress autophagy and promote apoptosis, thereby having deleterious effects on the heart.

    • Yasuhiro Maejima
    • , Shiori Kyoi
    • , Peiyong Zhai
    • , Tong Liu
    • , Hong Li
    • , Andreas Ivessa
    • , Sebastiano Sciarretta
    • , Dominic P Del Re
    • , Daniela K Zablocki
    • , Chiao-Po Hsu
    • , Dae-Sik Lim
    • , Mitsuaki Isobe
    •  & Junichi Sadoshima
  • Article |

    Cellular stress results in the release of damage-associated molecular pattern (DAMP) molecules that promote inflammatory responses. Here Ping Wang and colleagues show that cold-inducible RNA-binding protein (CIRP) is a DAMP that is released into the circulation in response to hemorrhagic shock and sepsis. It promotes proinflammatory cytokine release by binding to the TLR4-MD2 complex. Blockade of CIRP reduces inflammation, organ injury and mortality in animal models of hemorrhage and sepsis, suggesting that CIRP may be targeted therapeutically in these conditions.

    • Xiaoling Qiang
    • , Weng-Lang Yang
    • , Rongqian Wu
    • , Mian Zhou
    • , Asha Jacob
    • , Weifeng Dong
    • , Michael Kuncewitch
    • , Youxin Ji
    • , Huan Yang
    • , Haichao Wang
    • , Jun Fujita
    • , Jeffrey Nicastro
    • , Gene F Coppa
    • , Kevin J Tracey
    •  & Ping Wang
  • Article |

    Diabetic nephropathy is the most common cause of end-stage renal disease. Shu Wakino and colleagues now show that high-glucose conditions in the renal proximal tubules result in downregulation of Sirt1 expression there and in the glomeruli, resulting in epigentic upregulation of Claudin-1 in the glomeruli and thus proteinuria. They also show that genetic or chemical targeting of Sirt1 in the kidney is sufficient to improve kidney function in a mouse model of diabetic nephropathy.

    • Kazuhiro Hasegawa
    • , Shu Wakino
    • , Petra Simic
    • , Yusuke Sakamaki
    • , Hitoshi Minakuchi
    • , Keiko Fujimura
    • , Kozi Hosoya
    • , Motoaki Komatsu
    • , Yuka Kaneko
    • , Takeshi Kanda
    • , Eiji Kubota
    • , Hirobumi Tokuyama
    • , Koichi Hayashi
    • , Leonard Guarente
    •  & Hiroshi Itoh
  • Article |

    In a new study, Yingzi Yang and her colleagues show that a careful balance between Wnt and Hedgehog signaling is required to maintain proper differentiation of osteogenic precursor cells. Upon mutation of GNAS, this balance is disturbed and severe bone disease develops, including either heterotopic ossification or fibrous dysplasia.

    • Jean B Regard
    • , Deepti Malhotra
    • , Jelena Gvozdenovic-Jeremic
    • , Michelle Josey
    • , Min Chen
    • , Lee S Weinstein
    • , Jianming Lu
    • , Eileen M Shore
    • , Frederick S Kaplan
    •  & Yingzi Yang

Letters

  • Letter |

    Alteration of the bone marrow microenvironment by activation of the parathyroid hormone receptor attenuates chronic myelogenous leukemia (CML) but enhances acute myeloid leukemia (AML) in mouse models, suggesting that the leukemia stem-cell niches in CML and AML are distinct.

    • Daniela S Krause
    • , Keertik Fulzele
    • , André Catic
    • , Chia Chi Sun
    • , David Dombkowski
    • , Michael P Hurley
    • , Sanon Lezeau
    • , Eyal Attar
    • , Joy Y Wu
    • , Herbert Y Lin
    • , Paola Divieti-Pajevic
    • , Robert P Hasserjian
    • , Ernestina Schipani
    • , Richard A Van Etten
    •  & David T Scadden
  • Letter |

    This study identifies the concurrent activation of SHH and PI3K signaling by loss of PTEN as a frequent event in glioblastoma tumors that can be targeted with combination treatments using approved drugs to achieve antitumor responses in vivo. The results could potentially lead to the exploration of much needed new combination therapies for human brain tumors.

    • Mariella Gruber Filbin
    • , Sukriti K Dabral
    • , Maria F Pazyra-Murphy
    • , Shakti Ramkissoon
    • , Andrew L Kung
    • , Ekaterina Pak
    • , Jarom Chung
    • , Matthew A Theisen
    • , Yanping Sun
    • , Yoko Franchetti
    • , Yu Sun
    • , David S Shulman
    • , Navid Redjal
    • , Barbara Tabak
    • , Rameen Beroukhim
    • , Qi Wang
    • , Jean Zhao
    • , Marion Dorsch
    • , Silvia Buonamici
    • , Keith L Ligon
    • , Joseph F Kelleher
    •  & Rosalind A Segal
  • Letter |

    Dysfunction of the potassium-chloride cotransporter KCC2 has been linked to many neurological diseases, including pain, anxiety and epilepsy. Now, Yves De Koninck and his colleagues report that they have developed a novel small-molecule compound that is orally bioavailable and can activate KCC2 and reduce chronic pain in rats.

    • Martin Gagnon
    • , Marc J Bergeron
    • , Guillaume Lavertu
    • , Annie Castonguay
    • , Sasmita Tripathy
    • , Robert P Bonin
    • , Jimena Perez-Sanchez
    • , Dominic Boudreau
    • , Bin Wang
    • , Lionel Dumas
    • , Isabelle Valade
    • , Karine Bachand
    • , Mariève Jacob-Wagner
    • , Christian Tardif
    • , Irenej Kianicka
    • , Paul Isenring
    • , Giorgio Attardo
    • , Jeffrey A M Coull
    •  & Yves De Koninck
  • Letter |

    Hepatitis C virus (HCV) levels are known to be higher during pregnancy, suggesting loss of T cell–mediated control. Here, Honegger et al. study two HCV-infected women through two consecutive pregnancies and chronicle T cell escape mutations in viral proteins that revert during pregnancy and reappear postpartum. The findings highlight the dynamic between T cell–mediated pressure and viral fitness, with implications for vertical transmission of HCV.

    • Jonathan R Honegger
    • , Seungtaek Kim
    • , Aryn A Price
    • , Jennifer A Kohout
    • , Kevin L McKnight
    • , Mona R Prasad
    • , Stanley M Lemon
    • , Arash Grakoui
    •  & Christopher M Walker

Technical Reports

  • Technical Report |

    The lack of robust and high-throughput technologies to analyze the human TCR repertoire has been a bottleneck in the analysis of human T cell responses. Linnemann and colleagues have addressed this issue by using a TCR gene capture technology that, because of its quantitative nature, allows the rapid identification of TCRab pairs from bulk populations of cells without the need for single-cell cloning. Such an approach should be useful in obtaining defined antigen-reactive TCRs for therapeutic purposes.

    • Carsten Linnemann
    • , Bianca Heemskerk
    • , Pia Kvistborg
    • , Roelof J C Kluin
    • , Dmitriy A Bolotin
    • , Xiaojing Chen
    • , Kaspar Bresser
    • , Marja Nieuwland
    • , Remko Schotte
    • , Samira Michels
    • , Raquel Gomez-Eerland
    • , Lorenz Jahn
    • , Pleun Hombrink
    • , Nicolas Legrand
    • , Chengyi Jenny Shu
    • , Ilgar Z Mamedov
    • , Arno Velds
    • , Christian U Blank
    • , John B A G Haanen
    • , Maria A Turchaninova
    • , Ron M Kerkhoven
    • , Hergen Spits
    • , Sine Reker Hadrup
    • , Mirjam H M Heemskerk
    • , Thomas Blankenstein
    • , Dmitriy M Chudakov
    • , Gavin M Bendle
    •  & Ton N M Schumacher
  • Technical Report |

    Progress in T cell receptor (TCR) gene therapy has been hampered by the lack of a rapid and efficient screening system for antigen-specific TCRs. Here, Kobayashi et al. have developed a direct single-cell TCR cloning system for cloning antigen-specific TCRs from peripheral blood in 10 d. The approach is used to clone and analyze Epstein-Barr virus–specific TCRs from healthy donors with latent Epstein-Barr virus infection, as well as TCRs from peptide-vaccinated patients with hepatocellular carcinoma.

    • Eiji Kobayashi
    • , Eishiro Mizukoshi
    • , Hiroyuki Kishi
    • , Tatsuhiko Ozawa
    • , Hiroshi Hamana
    • , Terumi Nagai
    • , Hidetoshi Nakagawa
    • , Aishun Jin
    • , Shuichi Kaneko
    •  & Atsushi Muraguchi

Focus

  • Focus |

    Targeted Cancer Therapies

    At the interface between basic and clinical sciences, we move steadily toward a better understanding and treatment of cancer. Nature Medicine is proud to present a collection of Reviews on some of the most exciting current trends in cancer research.