Drug evaluation: CP-751871, a human antibody against type I insulin-like growth factor receptor for the potential treatment of cancer.
ABSTRACT Several phase II trials of CP-751871 are currently underway, including a phase Ib/II [corrected] trial of CP-751871 in combination with paclitaxel and carboplatin in patients with advanced NSCLC, a phase II trial of CP-751871 in combination with docetaxel and prednisone in patients with hormone-refractory prostate cancer, and a phase II trial of CP-751871 in combination with exemestane in hormone receptor positive advanced breast cancer [corrected]
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ABSTRACT: Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development of many types of tumors, including prostate, colon, breast, pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR activity may be useful in treatment of patients with various cancers. Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor (IR) was measured in vivo, and the effect on glucose metabolism was evaluated. GSK1904529A selectively inhibits IGF-IR and IR with IC(50)s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity of GSK1904529A on IR in vitro and in vivo, minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity. GSK1904529A is a promising candidate for therapeutic use in IGF-IR-dependent tumors.Clinical Cancer Research 05/2009; 15(9):3058-67. DOI:10.1158/1078-0432.CCR-08-2530 · 8.19 Impact Factor
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ABSTRACT: Background: A greater understanding of the pathogenesis of malignancy has led to the development of novel therapies designed to target aberrant molecular pathways that characterize and distinguish cancer cells from normal tissue. Small molecules are being designed to interfere with specific steps along the deregulated signaling cascade from the cytoplasmic membrane to the nucleus. Viable targets include growth factor receptors and their downstream second messengers, modulators of the cell cycle or apoptosis, regulators of protein trafficking and degradation and transcription regulators. Many reviews had discussed the small molecule signal transduction inhibitors in various stages of development and address the strategic issues relating to clinical trial design with these novel targeted agents. Aim of Work: To verify the Insulin-Like Growth Factor Type 1 Receptor (IGF-IR) and its impact on proliferation of lymphoblasts in Adulthood Acute Lymphoblastic leukemia (ALL). Bone marrow samples from 30 patients with ALL were examined along with 10 healthy donors as controls, a quantitative real time reverse transcriptase polymerase chain reaction (Real time R.T PCR) used to evaluate the concentration of (IGF-IR) correlated with the blast concentration in marrow samples. In our assay (IGF-IR) appeared to have higher to lower expression rate in turn from ALL (27.897) if compared with normal controls (37.883) (p<0.01). This work was carried out to prive the effect of IGF-IR on hematopoie-tic cells in ALL and its relation to the diseases progress. Patients and Methods: The expression of IGF-IR was analyzed in 30 patients with ALL, The patient work over a 3 month's period from February 2008 to May 2008. They were 18 males and 12 females with a male to females' ratio 1.5: 1.0. Their ages ranged from 12 -51 years. All patients were diagnosed as ALL by the routine diagnosis in Egypt national cancer institute with 10 normal age and sex matched healthy controls using a Real-Time Quantitative Reverse-Transcriptase Polymerase Chain Reaction (qRT-PCR) to assess the possible relation, association or correlation between IGF-IR expression and ALL clinical and laboratory features at diagnosis. Results: IGF-IR was expressed in all 30 patients with ALL; the expression levels of IGF-IR was significantly higher in newly diagnosed patients than in patients in complete remission (CR) and controls (p<0.001). There were statistically significant differences in the expression of IGF-IR between patients with blast concentration. Conclusion: IGF-1R seems to play a crucial role in patients with Adulthood and over expression of (IGF-IR) existed in hematopoietic cells in ALL marrows which appeared to be contributed to disease progress. 1-Over expression of (IGF-IR) existed in hematopoietic cells in ALL marrows which appeared to be contributed to disease progress. 2-Over expressed in our patient. 3-Over express contributed to disease progress.
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ABSTRACT: Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor kappaB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.Cancer letters 09/2009; 291(1):1-13. DOI:10.1016/j.canlet.2009.08.012 · 5.02 Impact Factor