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Metropolitan Government of Nashville-Davidson (balance), TN, United States

Lovly C.M.,Vanderbilt University | Pao W.,Vanderbilt University | Pao W.,Vanderbilt Ingram Cancer Center
Science Translational Medicine | Year: 2012

Mutated anaplastic lymphoma kinase (ALK) drives the development of multiple tumor types, and ALK tyrosine kinase inhibitors such as crizotinib have been validated as targeted therapeutics. Unfortunately, as with other oncogene-driven tumors, therapeutic resistance invariably develops. In Science Translational Medicine, two recent studies provide new insight into mechanisms of resistance to ALK tyrosine kinase inhibitors and possible strategies to overcome this resistance.

Pao W.,Vanderbilt Ingram Cancer Center
Proceedings of the American Thoracic Society | Year: 2012

This brief report summarizes Dr. Pao's talk at the 54th Annual Meeting of the Thomas L. Petty Aspen Lung Conference, in Aspen, Colorado, on June 11, 2011. In this talk, Dr. Pao discussed three main topics: (1) DETECT (DNA Evaluation of Tumors for Enhanced Cancer Treatment), (2) MyCancerGenome.org (web-based decision support), and (3) DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment). Copyright © 2012 by the American Thoracic Society.

Pao W.,Vanderbilt Ingram Cancer Center | Girard N.,University of Lyon
The Lancet Oncology | Year: 2011

Treatment decisions for patients with lung cancer have historically been based on tumour histology. Some understanding of the molecular composition of tumours has led to the development of targeted agents, for which initial findings are promising. Clearer understanding of mutations in relevant genes and their effects on cancer cell proliferation and survival, is, therefore, of substantial interest. We review current knowledge about molecular subsets in non-small-cell lung cancer that have been identified as potentially having clinical relevance to targeted therapies. Since mutations in EGFR and KRAS have been extensively reviewed elsewhere, here, we discuss subsets defined by so-called driver mutations in ALK, HER2 (also known as ERBB2), BRAF, PIK3CA, AKT1, MAP2K1, and MET. The adoption of treatment tailored according to the genetic make-up of individual tumours would involve a paradigm shift, but might lead to substantial therapeutic improvements. © 2011 Elsevier Ltd.

Pao W.,Vanderbilt Ingram Cancer Center | Chmielecki J.,The New School
Nature Reviews Cancer | Year: 2010

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease. © 2010 Macmillan Publishers Limited. All rights reserved.

Boice Jr. J.D.,Vanderbilt Ingram Cancer Center
Journal of Radiological Protection | Year: 2012

For nearly 100 years, epidemiologic studies of human populations exposed to ionising radiation have provided quantitative information on health risks. High dose deterministic (tissue reaction) effects result when sufficient numbers of functioning cells are killed, such as in bone marrow depression that can lead to death. Lower dose stochastic effects are probabilistic in nature and include an increased risk of cancer later in life and heritable genetic defects, although genetic conditions in the children of irradiated parents have yet to be convincingly demonstrated. Radiation studies are of diverse populations and include not only the Japanese atomic bomb survivors, but also patients treated with radiation for malignant and non-malignant disease; patients exposed for diagnostic purposes; persons with intakes of radionuclides; workers occupationally exposed; and communities exposed to environmental and accidentally released sources of radiation. Much is known about radiation and its risks. The major unanswered question in radiation epidemiology, however, is not whether radiation causes cancer, but what the level of risk is following low dose (<100mSv) or low dose rate exposures. Paracelsus is credited with first articulating that the 'poison is in the dose', which for radiation epidemiology translates as 'the lower the dose, the lower the risk' and, an important corollary, the lower the dose, the greater the difficulty in detecting any increase in the number of cancers possibly attributable to radiation. In contrast to the Chernobyl reactor accident, the Fukushima reactor accident has to date resulted in no deterministic effects and no worker deaths. Estimates to date of population doses suggest very low uptakes of radioactive iodine which was a major determinant of the epidemic of thyroid cancer following childhood exposures around Chernobyl. The estimates to date of population doses are also much lower (and the distribution much narrower) than the doses for which cancer excesses have been detected among atomic bomb survivors after 60 years of follow-up. Studies of populations exposed to low doses are also limited in their ability to account for important lifestyle factors, such as cigarette smoking and medical x-ray exposures, which could distort findings. Studies of the Fukushima population should be and are being considered for reassurance and health care reasons. Apart from as regards the extreme psychological stress caused by the horrific loss of life following the tsunami and the large-scale evacuation from homes and villages, such studies have limited to no chance of providing information on possible health risks following low dose exposures received gradually over time - the estimated doses (to date) are just too small. © 2012 IOP Publishing Ltd.

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