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 demonstrated by molecular evolution through space (primary tumor to metastasis) and time (after therapy). These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents. Classic trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic 'oncogenic driver' aberrations with adequate power. Usual accrual difficulties to clinical trials are exacerbated by low frequencies of any given molecular driver. To address these challenges, there is need for innovative clinical trial designs and strategies implementing novel diagnostic biomarker technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for pre-defined treatment priority algorithms given numerous aberrations commonly observed within any one individual sample. Access to multiple available therapeutic agents simultaneously is crucial. Finally intra-patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression. This report discusses various 'next-generation' biomarker-driven trial designs and their potentials and limitations to tackle these recognized molecular heterogeneity challenges. Regulatory hurdles, with respect to drug and companion diagnostic development and approval, are considered. Focus is on the 'Expansion Platform Design Types I and II', the latter demonstrated with a first example, 'PANGEA: Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma'. Applying integral medium-throughput genomic and proteomic assays along with a practical biomarker assessment and treatment algorithm, 'PANGEA' attempts to address the problem of heterogeneity towards successful implementation of molecularly targeted therapies.
journal_name
Mol Oncoljournal_title
Molecular oncologyauthors
Catenacci DVdoi
10.1016/j.molonc.2014.09.011subject
Has Abstractpub_date
2015-05-01 00:00:00pages
967-96issue
5eissn
1574-7891issn
1878-0261pii
S1574-7891(14)00235-Xjournal_volume
9pub_type
杂志文章,评审abstract::Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12193
更新日期:2018-05-01 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
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2015.10.021
更新日期:2016-02-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12088
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1002/1878-0261.12441
更新日期:2019-03-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12491
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.12.009
更新日期:2015-04-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12879
更新日期:2020-12-13 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2007.06.001
更新日期:2007-09-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2010.09.005
更新日期:2010-12-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1002/1878-0261.12095
更新日期:2017-07-01 00:00:00
abstract:BACKGROUND:The association between nuclear factor I/B (NFIB) gene and triple negative breast cancer has been previously suggested. METHODS:We investigated the relationship between NFIB mRNA and protein expression and molecular subtypes of breast cancer as well as the effect of NFIB silencing on the proliferation and a...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2011.08.002
更新日期:2011-12-01 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::Angiogenin (ANG), a 14-kDa pro-angiogenic secreted protein, has been shown to play a role in cell migration and tumor invasion, which involve proteolytic cleavage of plasminogen to generate plasmin. However, the mechanism by which ANG regulates plasmin formation and cell migration was not known. Our studies here detec...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2013.12.017
更新日期:2014-05-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12057
更新日期:2017-09-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12562
更新日期:2019-12-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12812
更新日期:2020-10-05 00:00:00
abstract::Protein inhibitor of activated STAT3 (PIAS3) is an endogenous suppressor of signal transducer and activator of transcription 3 (STAT3) signaling. By directly interacting with phosphorylated STAT3, PIAS3 can block the downstream transcriptional activity of STAT3, which is hyper-activated in various cancers. We previous...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12386
更新日期:2018-12-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12053
更新日期:2017-05-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12889
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journal_title:Molecular oncology
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doi:10.1002/1878-0261.12756
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12810
更新日期:2020-12-01 00:00:00
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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
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2013.12.003
更新日期:2014-03-01 00:00:00
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journal_title:Molecular oncology
pub_type:
doi:10.1002/1878-0261.12436
更新日期:2019-03-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2013.05.002
更新日期:2013-10-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2012.07.001
更新日期:2012-10-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2015.04.006
更新日期:2015-08-01 00:00:00
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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