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)

Positron emission tomography (PET) with epidermal growth factor receptor (EGFR) kinase-specific radiolabeled tracers could provide the means for noninvasive and repetitive imaging of heterogeneity of EGFR expression and signaling activity in tumors in individual patients before and during therapy with EGFR signaling inhibitors. We developed the synthesis and (124)I-radiolabeling of the (E)-But-2-enedioic acid [4-(3-[(124)I]iodoanilino)-quinazolin-6-yl]-amide-(3-morpholin-4-yl-propyl)-amide (morpholino-[(124)I]-IPQA), which selectively, irreversibly, and covalently binds the adenosine-triphosphate-binding site to the activated (phosphorylated) EGFR kinase, but not to the inactive EGFR kinase. The latter was demonstrated using in silico modeling with crystal structures of the wild type and different gain-of-function mutants of EGFR kinases. Also, this was demonstrated by selective radiolabeling of the EGFR kinase domain with morpholino-[(131)I]-IPQA in A431 human epidermoid carcinoma cells and Western blot autoradiography. In vitro radiotracer accumulation and washout studies demonstrated a rapid accumulation and progressive retention postwashout of morpholino-[(131)I]-IPQA in A431 epidermoid carcinoma and in U87 human glioma cells genetically modified to express the EGFRvIII mutant receptor, but not in the wild-type U87MG glioma cells under serum-starved conditions. Using morpholino-[(124)I]-IPQA, we obtained noninvasive PET images of EGFR activity in A431 subcutaneous tumor xenografts, but not in subcutaneous tumor xenografts grown from K562 human chronic myeloid leukemia cells in immunocompromised rats and mice. Based on these observations, we suggest that PET imaging with morpholino-[(124)I]-IPQA should allow for identification of tumors with high EGFR kinase signaling activity, including brain tumors expressing EGFRvIII mutants and nonsmall-cell lung cancer expressing gain-of-function EGFR kinase mutants. Because of significant hepatobiliary clearance and intestinal reuptake of the morpholino-[(124)I]-IPQA, additional [(124)I]-IPQA derivatives with improved water solubility may be required to optimize the pharmacokinetics of this class of molecular imaging agents.
 ...
PMID:Molecular imaging of EGFR kinase activity in tumors with 124I-labeled small molecular tracer and positron emission tomography. 1689 20

A growing number of tumors are characterized by simple genetic changes that activate important biochemical pathways, which are involved in their pathogenesis. These findings have led to the concept of targeted small molecule inhibitor treatment. The prototype for this type of therapy has been treatment of chronic myelogenous leukemia with imatinib mesylate (Gleevec), which targets BCR-ABL kinase. More recently, imatinib has been used to inhibit KIT in gastrointestinal (GI) stromal tumor, a mesenchymal tumor that arises in the GI tract. Furthermore, it has been possible to target EGFR in non-small-cell lung cancer with gefitinib and erlotinib. While initial results have been encouraging, resistance to small molecule kinase inhibitors is a substantial drawback. This paper focuses on what is known about mechanisms of resistance in the treatment of solid tumors by small molecule kinase inhibitors.
 ...
PMID:Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. 1692 45

A MESSAGE FROM ASCO's PRESIDENT For the second consecutive year, the American Society of Clinical Oncology (ASCO) is publishing Clinical Cancer Advances: Major Research Advances in Cancer Treatment, Prevention, and Screening, an annual review of the most significant cancer research presented or published over the past year. ASCO developed this report to demonstrate the enormous progress being made on the front lines of cancer research today. The report is intended to give all those with an interest in cancer care-the general public, cancer patients and physicians, policymakers, oncologists, and other medical professionals-an accessible summary of the year's most important cancer research advances. These pages report on new targeted therapies that are improving survival and response rates in hard-to-treat cancers such as kidney cancer, HER-2-positive breast cancer, head and neck cancer, and chronic myelogenous leukemia; the FDA's approval of the world's first preventive vaccine for human papillomavirus (HPV), which has the potential to dramatically reduce the global burden of cervical cancer; and advances in the fast-growing field of personalized medicine, including a new lung cancer test that could help physicians better target treatments and predict prognosis. These advances are only part of the landscape. Survival rates are on the rise, the number of cancer deaths in the United States began declining for the first time since 1930, and new research is showing that the rates of certain common cancers, such as those of the breast and colon, have stabilized, and may have even begun to decline. However, cancer research still faces a number of major obstacles. At a time of extraordinary scientific potential, declining federal funding of cancer research threatens to stall or even reverse recent progress. Such funding cuts have already led to fewer clinical trials, fewer talented young physicians entering the field, and a growing bottleneck of basic science discoveries waiting to be "translated" into useful therapies and diagnostics. In addition to highlighting the major research advances over the past year, this report also identifies key barriers to accelerating the pace of cancer research and outlines ASCO's recommendations for overcoming them. Despite these and other challenges, there is much good news on the front lines of cancer research. This report demonstrates the essential role of clinical cancer research in finding new and better ways to treat, diagnose, and prevent a group of diseases that strike half of men and one-third of women in the United States.
 ...
PMID:Clinical cancer advances 2006: major research advances in cancer treatment, prevention, and screening--a report from the American Society of Clinical Oncology. 1715 28

Dasatinib is a multitargeted kinase inhibitor that was recently approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. It is also in clinical trials for treating patients with solid tumors. The identification of molecular markers predictive of response to dasatinib could assist in clinical development by selecting patients most likely to derive clinical benefit. Using baseline gene expression profiling of a panel of 23 breast cancer cell lines, we identified genomic signatures highly correlated with in vitro sensitivity to dasatinib. The ability of these signatures to predict dasatinib sensitivity was further confirmed and validated in independent test cell lines. A six-gene model was used to correctly predict dasatinib sensitivity in 11 out of 12 (92%) additional breast and 19 out of 23 (83%) lung cancer cell lines. Quantitative real-time PCR and immunohistochemical assays further confirmed the differential expression pattern of selected markers. Finally, these gene signatures were observed in a subset of primary breast, lung, and ovarian tumors suggesting potential utility in patient selection. The subset of breast cancer patients expressing the dasatinib-sensitive signature includes a distinct clinical and molecular subgroup: the so-called "triple negative" (i.e., estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) or "basal" breast cancer subtype. This patient population has a poor prognosis and currently has few effective treatment options. Our results implicate that dasatinib may represent a valuable treatment option in this difficult-to-treat population. To test this hypothesis, clinical studies are now under way to determine the activity of dasatinib in these patients.
 ...
PMID:Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. 1733 53

The BCR-ABL inhibitor dasatinib achieves clinical remissions in chronic myeloid leukemia (CML) patients using a dosing schedule that achieves potent but transient BCR-ABL inhibition. In vitro, transient potent BCR-ABL inhibition with either dasatinib or imatinib is cytotoxic to CML cell lines, as is transient potent EGFR inhibition with erlotinib in a lung cancer cell line. Cytotoxicity correlates with the magnitude as well as the duration of kinase inhibition. Moreover, cytotoxicity with transient potent target inhibition is equivalent to prolonged target inhibition and in both cases is associated with BIM activation and rescued by BCL-2 overexpression. In CML patients receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, thereby demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy.
 ...
PMID:Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. 1906 39

Recently, there is an increasing evidence supporting the theory of cancer stem cells not only in leukemia but also in solid cancer. To date, the existence of cancer stem cells has been proven in acute and chronic myeloid leukemia, in breast cancer, in brain tumors, in lung cancer and gastrointestinal tumors. This review is focusing on the recent discovery of stem cells in leukemia, human brain tumors and breast cancer. A small population of cells in the tumor (less than 1%) shows the potential to give rise to the tumor and its growth. These cells have a substantial characteristic of stem cells--ability for self-renewal without loss of proliferation capacity with each cell division. Furthermore they are immortal, rather resistant to treatment and express typical markers of stem cells. The origin of these resident cancer stem cells is not clear. Whether the cancer stem cells originate from normal stem cells in consequence of genetic and epigenetic changes and/or redifferentiation from somatic tumor cells to the stem-like cells remains to be investigated. We propose the idea of the relation between normal tissue stem cells and cancer stem cells and their populations--progenitor cells. Based on this we highlight one of the major characteristic of stem cell--plasticity, which is equally important in the physiological regeneration process as well as carcinogenesis. Furthermore, we consider the microenvironment as a limiting factor for tumor genesis in AML, breast cancer and brain tumors. Thus the biological properties of cancer stem cells are just beginning to be revealed, the continuation of these studies should lead to the development of cancer stem cells target therapies for cancer treatment.
 ...
PMID:Cancer stem cells--new approach to cancerogenensis and treatment. 1927 80

Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non-small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.
 ...
PMID:Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors. 1936 96

Lung cancer is the leading cause of cancer-related death in the United States. Outcomes for patients with lung cancer have reached a plateau with cytotoxic chemotherapy. Lung cancer remains very much at the vanguard of the new revolution in cancer therapy using molecular targets. Although striking improvements in survival have been observed in the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors, and in a subset of breast cancer using this approach, the impact of targeted therapies in lung cancer is quite modest. Along with advances in imaging and cancer genomics, there is now considerable optimism that the pace of progress in the treatment of lung cancer will accelerate in the next 10 years. As has been the custom for the past 8 years, leading experts in the biology, diagnosis and treatment of lung cancer met for three days to discuss current areas of research and future directions. This summary provides a brief snapshot of the discussions held at the 8th Annual Meeting on Targeted Therapies for Lung Cancer sponsored by the International Association for the Study of Lung Cancer in Santa Monica in early February 2008.
 ...
PMID:Summary of selected presentations from the 8th annual targeted therapy in lung cancer symposium. 1955 Feb 49

The 2008 American Society of Clinical Oncology Meeting, the 44th and the largest so far in its history, hosted 34,000 oncologists and industry exhibitors, with 312 journalists on-site. Among more than 11,000 abstracts presented, key sessions touched on the pharmacological treatment of breast cancer, renal cell carcinoma, chronic myelogenous leukemia, non-small-cell lung cancer, bone resorption, and advanced melanoma.
 ...
PMID:American society of clinical oncology. 1975 Jan 18

DNA amplifications, leading to the overexpression of oncogenes, are a cardinal feature of lung cancer and directly contribute to its pathogenesis. To uncover such novel alterations, we performed an array-based comparative genomic hybridization survey of 128 non-small-cell lung cancer cell lines and tumors. Prominent among our findings, we identified recurrent high-level amplification at cytoband 22q11.21 in 3% of lung cancer specimens, with another 11% of specimens exhibiting low-level gain spanning that locus. The 22q11.21 amplicon core contained eight named genes, only four of which were overexpressed (by transcript profiling) when amplified. Among these, CRKL encodes an adapter protein functioning in signal transduction, best known as a substrate of the BCR-ABL kinase in chronic myelogenous leukemia. RNA-interference-mediated knockdown of CRKL in lung cancer cell lines with (but not without) amplification led to significantly decreased cell proliferation, cell-cycle progression, cell survival, and cell motility and invasion. In addition, overexpression of CRKL in immortalized human bronchial epithelial cells led to enhanced growth factor-independent cell growth. Our findings indicate that amplification and resultant overexpression of CRKL contribute to diverse oncogenic phenotypes in lung cancer, with implications for targeted therapy, and highlight a role of adapter proteins as primary genetic drivers of tumorigenesis.
 ...
PMID:Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer. 1996 67


<< Previous 1 2 3 4 5 6 7 8 9 Next >>