Critical reviews in oncology/hematology
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Crit. Rev. Oncol. Hematol. · Feb 2014
ReviewTargeting the MET gene for the treatment of non-small-cell lung cancer.
Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era. ⋯ Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.
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Crit. Rev. Oncol. Hematol. · Jan 2014
ReviewTargeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities.
A dynamic interplay exists between host and tumor, and the ability of the tumor to evade immune recognition often determines the clinical course of the disease. Significant enthusiasm currently exists for a new immunotherapeutic strategy: the use of immunomodulatory monoclonal antibodies that directly enhance the function of components of the anti-tumor immune response such as T cells, or block immunologic checkpoints that would otherwise restrain effective anti-tumor immunity. This strategy is based on the evidence that development of cancer is facilitated by the dis-regulation and exploitation of otherwise physiological pathways that, under normal circumstances, down-regulate immune activation and maintain tolerance to self. ⋯ An emerging concept in cancer immunology is that inhibitory ligands such as PD-L1 are induced in response to immune attack, a mechanism termed "adaptive resistance". This potential mechanism of immune resistance by tumors suggests that therapy directed at blocking the interaction between PD-1 and PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity. The anti-PD-1 strategy can be effective in several solid tumors such as renal cell carcinoma (RCC) or non-small cell lung cancer (NSCLC), however in this review we summarize the biological role of PD-1/PD-L1 on cancer by focusing our attention in the biological rationale, clinical challenges and opportunities to target the PD-1/PD-L1 axis in melanoma.
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Crit. Rev. Oncol. Hematol. · Dec 2013
ReviewChemokine receptor CXCR4: role in gastrointestinal cancer.
Chemokines (CK)s, small proinflammatory chemoattractant cytokines that bind to specific G-protein coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The CXCL12 [stromal cell-derived factor-1 (SDF-1)] binds primarily to CXC receptor 4 (CXCR4; CD184). The binding of CXCL12 to CXCR4 induces intracellular signaling through several divergent pathways initiating signals related to chemotaxis, cell survival and/or proliferation, increase in intracellular calcium, and gene transcription. ⋯ In this review, we mainly focus on the roles of chemokines CXCL12 and its cognate receptors CXCR4 as they pertain to cancer progression. In particular, we summarizes our current understanding regarding the contribution of CXCR4 and SDF-1 to gastrointestinal tumor behavior and its role in local progression, dissemination, and immune evasion of tumor cells. Also, describes recent therapeutic approaches that target these receptors or their ligands.
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Crit. Rev. Oncol. Hematol. · Oct 2013
Review Meta AnalysisLate effects of adjuvant chemotherapy for adult onset non-CNS cancer; cognitive impairment, brain structure and risk of dementia.
Few studies have investigated the late (i.e. ≥ 5 years post-treatment) effects of chemotherapy for non-central nervous system (non-CNS) cancer on the brain. Here we discuss the studies that have investigated the late effects of adjuvant chemotherapy for non-CNS cancer on cognitive function (n=6); brain structure and function (n=5); and incidence of dementia (n=4). ⋯ The studies exploring the association between chemotherapy and the incidence of dementia were contradictive and showed no clear relationship between the two phenomena. Although several methodological issues limit the validity and interpretation of some of the results of these studies, they suggest that chemotherapy is associated with subtle, yet long-lasting cognitive deficits, possibly related to brain structural and functional differences, but as yet not with an increased risk of dementia.
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Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults accounting for 31% of all NHL in Western Countries. Following, morphological, biological and clinical studies have allowed the subdivision of DLBCLs into morphological variants, molecular and immunophenotypic subgroups and distinct disease entities. However, a large number of cases still remain biologically and clinically heterogeneous, for which there are no clear and accepted criteria for subclassification; these are collectively termed DLBCL, not otherwise specified (NOS). ⋯ Overall results in patients who cannot be managed with HDC/ASCT due to age or comorbidity are disappointing. New effective and less toxic chemotherapy drugs or biological agents are also worth considering for this specific and broad group of patients. Several novel agents are undergoing evaluation in DLBCL; among other, immunomodulating agents (lenalidomide), m-TOR inhibitors (temsirolimus and everolimus), proteasome inhibitors (bortezomib), histone deacetylase inhibitors (vorinostat), and anti-angiogenetic agents (bevacizumab) are being investigated in prospective trials.