Dataset Information

Targeting angiogenesis in gastrointestinal tumors: current challenges.

ABSTRACT: Colorectal cancer (CRC) is one of the few cancers where screening modalities are standardized, but it still remains the third leading cause of cancer related mortality. For more than a decade now, the approval of anti-angiogenic therapy has led to an increase in the rate of overall survival (OS) of patients with advanced colon cancer. The drawback of the anti-angiogenic therapy is that their effect is short-lived and many patients progress through these therapies. Various mechanisms of resistance have been hypothesized, but overcoming this has been challenging. Also, there are no standardized predictive biomarkers that could aid in selecting patients who responds to the therapy upfront. This review focuses on the basis of angiogenesis, describing the approved anti-angiogenic therapies, discusses the challenges in terms of resistance to anti-angiogenic therapy and also the role of biomarkers. In the future, hopefully newer targeted therapies, immunotherapy, combination therapies and the standardization of biomarkers may result in improved outcomes and cure rates.

SUBMITTER: Nandikolla AG

PROVIDER: S-EPMC5244743 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Targeting angiogenesis in gastrointestinal tumors: current challenges.

Nandikolla Amara G AG Rajdev Lakshmi L

Translational gastroenterology and hepatology 20160906

Colorectal cancer (CRC) is one of the few cancers where screening modalities are standardized, but it still remains the third leading cause of cancer related mortality. For more than a decade now, the approval of anti-angiogenic therapy has led to an increase in the rate of overall survival (OS) of patients with advanced colon cancer. The drawback of the anti-angiogenic therapy is that their effect is short-lived and many patients progress through these therapies. Various mechanisms of resistanc ...[more]

PMID: 28138633

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Project description:UnlabelledSummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype.SignificanceGastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors.

Dataset Information

Targeting angiogenesis in gastrointestinal tumors: current challenges.

Publications

Targeting angiogenesis in gastrointestinal tumors: current challenges.

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