Abstract:
:The ability to predict responsiveness to drugs in individual patients is limited. We hypothesized that integrating molecular information from databases would yield predictions that could be experimentally tested to develop transcriptomic signatures for specific drugs. We analyzed lung adenocarcinoma patient data from The Cancer Genome Atlas and identified a subset of patients in which xanthine dehydrogenase (XDH) expression correlated with decreased survival. We tested allopurinol, an FDA-approved drug that inhibits XDH, on human non-small-cell lung cancer (NSCLC) cell lines obtained from the Broad Institute Cancer Cell Line Encyclopedia and identified sensitive and resistant cell lines. We utilized the transcriptomic profiles of these cell lines to identify six-gene signatures for allopurinol-sensitive and allopurinol-resistant cell lines. Transcriptomic networks identified JAK2 as an additional target in allopurinol-resistant lines. Treatment of resistant cell lines with allopurinol and CEP-33779 (a JAK2 inhibitor) resulted in cell death. The effectiveness of allopurinol alone or allopurinol and CEP-33779 was verified in vivo using tumor formation in NCR-nude mice. We utilized the six-gene signatures to predict five additional allopurinol-sensitive NSCLC cell lines and four allopurinol-resistant cell lines susceptible to combination therapy. We searched the transcriptomic data from a library of patient-derived NSCLC tumors from the Jackson Laboratory to identify tumors that would be predicted to be sensitive to allopurinol or allopurinol + CEP-33779 treatment. Patient-derived tumors showed the predicted drug sensitivity in vivo. These data indicate that we can use integrated molecular information from cancer databases to predict drug responsiveness in individual patients and thus enable precision medicine.
journal_name
Mol Oncoljournal_title
Molecular oncologyauthors
Tavassoly I,Hu Y,Zhao S,Mariottini C,Boran A,Chen Y,Li L,Tolentino RE,Jayaraman G,Goldfarb J,Gallo J,Iyengar Rdoi
10.1002/1878-0261.12521subject
Has Abstractpub_date
2019-08-01 00:00:00pages
1725-1743issue
8eissn
1574-7891issn
1878-0261journal_volume
13pub_type
杂志文章abstract::Short arm of chromosome 8 is a hot spot for chromosomal breaks, losses and amplifications in breast cancer. Although such genetic changes may have phenotypic consequences, the identity of candidate gene(s) remains to be clearly defined. Pol β gene is localized to chromosome 8p12-p11 and encodes a key DNA base excision...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.01.001
更新日期:2014-05-01 00:00:00
abstract::Patient derived xenografts (PDXs) are increasingly appreciated models in cancer research, particularly for preclinical testing, as they reflect the patient's tumor biology more accurately than cancer cell lines. We have established a collection of 20 breast PDXs and characterized their biological and clinical features...
journal_title:Molecular oncology
pub_type: 临床试验,杂志文章
doi:10.1016/j.molonc.2013.11.010
更新日期:2014-03-01 00:00:00
abstract::The MYC protein is a transcription factor with oncogenic potential controlling fundamental cellular processes such as cell proliferation, metabolism, differentiation, and apoptosis. The MYC gene is a major cancer driver, and elevated MYC protein levels are a hallmark of most human cancers. We have previously shown tha...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12636
更新日期:2020-03-01 00:00:00
abstract::The elevated expression and activation of human telomerase reverse transcriptase (hTERT) is associated with the unlimited proliferation of cancer cells. However, the excise mechanism of hTERT regulation during carcinogenesis is not well understood. In this study, we discovered cleavage and polyadenylation specific fac...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.02.001
更新日期:2014-05-01 00:00:00
abstract:BACKGROUND:Breast cancer is a heterogeneous disease with different molecular subtypes that have varying responses to therapy. An ongoing challenge in breast cancer research is to distinguish high-risk patients from good prognosis patients. This is particularly difficult in the low-grade, ER-positive luminal A tumors, w...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.11.002
更新日期:2015-03-01 00:00:00
abstract::miRNAs in circulating extracellular vesicles (EVs) are promising biomarkers for cancer. However, their diagnostic ability for early-stage non-small-cell lung cancer (NSCLC) is not well known. In this study, the circulating EV miRNAs profiling was initially performed in 36 untreated NSCLC patients and 36 healthy contro...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12889
更新日期:2020-12-19 00:00:00
abstract::The absence of biomarkers to accurately predict anticancer therapy response remains a major obstacle in clinical oncology. We applied a genome-wide loss-of-function screening approach in human haploid cells to characterize genetic vulnerabilities to classical microtubule-targeting agents. Using docetaxel and vinorelbi...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12307
更新日期:2018-06-01 00:00:00
abstract::Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK+ ) T-cell lymphoma is an aggressive neoplasm that is more commonly seen in children and young adults. The pathogenesis of NPM-ALK+ T-cell lymphoma is not completely understood. Wild-type ALK is a receptor tyrosine kinase that is physiologically expressed in ...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12088
更新日期:2017-09-01 00:00:00
abstract::Triple-negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer-related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesen...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12167
更新日期:2018-04-01 00:00:00
abstract::Deregulation of the insulin-like growth factor (IGF) axis and dysbalance of components of the IGF system as potential therapeutic targets have been described in different tumor types. IGF2 is a major embryonic growth factor and an important activator of IGF signaling. It is regulated by imprinting in a development- an...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12164
更新日期:2018-02-01 00:00:00
abstract::Breast cancer tissue overexpresses fucosylated glycans, such as sialyl-Lewis X/A (sLeX/A ), and α-1,3/4-fucosyltransferases (FUTs) in relation to increased disease progression and metastasis. These glycans in tumor circulating cells mediate binding to vascular E-selectin, initiating tumor extravasation. However, their...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12163
更新日期:2018-05-01 00:00:00
abstract::The PI3K/Akt signaling pathway, the most frequently altered signaling system in human cancer, is a crucial inducer of dysregulated proliferation and neoplastic processes; however, few therapeutic strategies using PI3K/Akt inhibitors singly have been shown to be effective. The purpose of this paper was to underline the...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12888
更新日期:2020-12-18 00:00:00
abstract::Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of pro...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12365
更新日期:2018-10-01 00:00:00
abstract::Chimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton-interfering pharmacophores, in testicular germ cell tumors (T...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12582
更新日期:2019-12-01 00:00:00
abstract::C13ORF18 is frequently hypermethylated in cervical cancer but not in normal cervix and might serve as a biomarker for the early detection of cervical cancer in scrapings. As hypermethylation is often observed for silenced tumor suppressor genes (TSGs), hypermethylated biomarker genes might exhibit tumor suppressive ac...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2013.02.017
更新日期:2013-06-01 00:00:00
abstract::Cullin 4B, a member of the Cullins, which serve as scaffolds to facilitate the assembly of E3 ligase complexes, is aberrantly expressed in many cancers, including osteosarcoma. Recently, we observed that CUL4B forms the CRL4BDCAF11 E3 ligase, which specifically ubiquitinates and degrades the cyclin-dependent kinase (C...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12176
更新日期:2018-04-01 00:00:00
abstract::Poly-ADP-ribose-polymerase inhibitors (PARPi) are considered to be optimal tools for specifically enhancing radiosensitivity. This effect has been shown to be replication-dependent and more profound in HR-deficient tumors. Here, we present a new mode of PARPi-mediated radiosensitization which was observed in four out ...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.06.008
更新日期:2014-12-01 00:00:00
abstract::It is well known that different racial groups have significantly different incidence and mortality rates for certain cancers. It has been suggested that biological factors play a major role in these cancer racial disparities. Previous studies on the biological factors contributing to cancer racial disparity have gener...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12799
更新日期:2020-09-13 00:00:00
abstract::ERBB2 amplification and overexpression are strongly associated with invasive cancer with high recurrence and poor prognosis. Enhanced ErbB2 signaling induces cysteine cathepsin B and L expression leading to their higher proteolytic activity (zFRase activity), which is crucial for the invasion of ErbB2-positive breast ...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.07.004
更新日期:2014-12-01 00:00:00
abstract::Pancreatic adenocarcinomas express neurotensin receptors in up to 90% of cases, however, their role in tumor biology and as a drug target is not clear. In the present study, a stable neurotensin (NT) analog induced intracellular calcium release and intracellular alkalinization in BxPC-3 and PANC-1 pancreatic cancer ce...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2009.01.006
更新日期:2009-06-01 00:00:00
abstract::Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.10.011
更新日期:2015-03-01 00:00:00
abstract::The presence of circulating tumor cells (CTCs) in the blood of ovarian cancer patients was shown to correlate with decreased overall survival, whereby CTCs with epithelial-mesenchymal-transition (EMT) or stem-like traits are supposed to be involved in metastatic progression and recurrence. Thus, investigating the tran...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2016.04.002
更新日期:2016-08-01 00:00:00
abstract::The promise of 'personalized cancer care' with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized heterogeneity within any given tumor-type from patient to patient (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) as demon...
journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2014.09.011
更新日期:2015-05-01 00:00:00
abstract::Prostate cancer (PCa) remains an important public health concern in Western countries. Metabolic syndrome (MeS) is a cluster of pathophysiological disorders with increasing prevalence in the general population that is a risk factor for PCa. Several studies have determined that a crosstalk between white adipose tissue ...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12788
更新日期:2020-09-02 00:00:00
abstract::Gain-of-function (GOF) mutants of p53 upregulate genes implicated in cell proliferation and oncogenesis. Here, we report that GOF p53 induces tumorigenicity through simultaneous activation of key oncogenic pathways including those controlling putative tumor-initiating cell functions. We determined that in cells expres...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12068
更新日期:2017-06-01 00:00:00
abstract::Autophagy, a well-described cellular mechanism for lysosomal degradation of cytoplasmic content, has emerged as a tumour suppression pathway. Recent evidence indicates that the tumour suppressor function of autophagy is mediated by scavenging of damaged oxidative organelles, thereby preventing accumulation of toxic ox...
journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2009.05.007
更新日期:2009-08-01 00:00:00
abstract::The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life ...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2016.03.004
更新日期:2016-06-01 00:00:00
abstract::CDC25 (cell division cycle 25) phosphatases are essential for cell cycle control under normal conditions and in response to DNA damage. They are represented by three isoforms, CDC25A, B and C, each of them being submitted to an alternative splicing mechanism. Alternative splicing of many genes is affected in response ...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2012.06.003
更新日期:2012-10-01 00:00:00
abstract::Comprehensive Cancer Centres (CCCs) serve as critical drivers for improving cancer survival. In Europe, we have developed an Excellence Designation System (EDS) consisting of criteria to assess "excellence" of CCCs in translational research (bench to bedside and back), with the expectation that many European CCCs will...
journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2015.12.007
更新日期:2016-05-01 00:00:00
abstract::Cancer is a massive challenge with a significant impact on society, healthcare systems, the economy and an increasing number of patients and their families. To help meet this societal challenge, the European Commission has recently proposed a mission-oriented approach to cancer in Horizon Europe, and about 60 particip...
journal_title:Molecular oncology
pub_type:
doi:10.1002/1878-0261.12436
更新日期:2019-03-01 00:00:00