Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oncologist dream is to provide more benefit with lower toxicity. The increasing knowledge of molecular mechanism for survival and proliferation of cancer cells leads to the development of targeted therapies with impressive results for some cancers even if not associated with chemotherapy. These targeted treatments could be monoclonal antibodies or tyrosine kinase inhibitors. Inactivation of only one oncogene can lead to the regression of tumours as well as the inhibition of only one pathway with one or more inhibitors. This result is related to the oncogenic addiction of these tumours. Examples are imatinib in CML and GIST, trastuzumab in HER2 positive breast cancer, gefitinib in mutated EGFR, crizotinib in EML4-ALK positive lung cancer and, also, vemurafenib in BRAF 600E mutated metastatic melanoma. We shall specifically discuss HER2 positive breast cancer, which represent some 15-20% of breast cancers and the recent targeted and bi-targeted therapies. Trastuzumab, an anti-HER2 monoclonal antibody has changed the prognosis of the disease improving survival in the metastatic and adjuvant setting. Lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2 is approved with capecitabine in trastuzumab resistant patients and in combination with letrozole in first line. Unfortunately, 20% of patients receiving adjuvant trastuzumab relapse and metastatic patients only transienly respond to trastuzumab or lapatinib combined with chemotherapy. New HER2 targeted drugs are currently in development like pertuzumab, T-DMI or mTOR and PI3K inhibitors. New strategies combining these drugs with or without chemotherapy showed interesting results in metastatic and neoadjuvant trials. The selection of patients who will most benefit from these combinations is still a challenge. Currently, chemotherapy in association with anti-HER2 therapy remains the most effective treatment option.
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PMID:[Will targeted therapies replace chemotherapy?]. 2269 Apr 83

The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries for leukemic cells. In murine chronic myeloid leukemia (CML) CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of CML-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in CML after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with CML via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1+ cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and proto-oncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as an indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human CML. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - which could be exploited therapeutically in the future.
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PMID:The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis. 3189 93