This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACT HYPOTHESIS Epidermal growth factor receptor inhibitors will have an antitumor effect in recurrent or refractory childhood tumors. This antitumor effect will be greater when the EGFR inhibitor is combined with a cytotoxic agent.
SPECIFIC AIMS Primary Aims:To estimate the maximum tolerable dose (MTD) of single agent daily OSI-774 administered as an oral solution to children with selected refractory/recurrent solid tumors, including brain tumors.To determine the dose-limiting toxicities (DLT) of OSI-774 given as an oral solution on this schedule as a single agent and in combination with temozolomide.To evaluate the tolerability of the combination of OSI-774 with temozolomide.To characterize the pharmacokinetic behavior of OSI-774 given as an oral solution in children with selected refractory/recurrent solid tumors, including brain tumors.Secondary Aims:To preliminarily define the antitumor activity of OSI-774 in combination with temozolomide within the confines of a Phase I study.To determine in archival tumor tissues the expression and activation (phosphorylation) of ERBB1 and ERBB2 and downstream cell signal targets including phospho-AKT, phospho- p70s6kBACKGROUND AND SIGNIFICANCE In the advanced stages of the disease, many malignancies become increasingly resistant to the DNA-damaging effects of standard cytotoxic chemotherapy. An increased understanding of cancer biology has led to the development of a new class of anticancer agents, which act by a completely different mechanism. Signal transduction pathways are now widely recognized as an important target for anticancer agents. Inhibitors of these pathways affect the cellular signaling which is critical to the life cycle and biologic functions of the cell.Receptors of the tyrosine kinase family play a principal role in the signal transduction process as they serve to integrate a large number of external stimuli with specific internal signals and responses. The receptor tyrosine kinases (RTKs), also known as ERBB or type 1 receptors are involved at an early stage in the transmission of proliferation and differentiation signals from the cell surface to the nucleus. The ERBB family consists of four closely related transmembrane receptors (ERBB1 or EGFR, ERBB2 or HER2, ERBB3 and ERBB4) which interact to form a complex signaling network of transmembrane homo- and heterodimers. With the exception only of hematopoietic cells, the ERBB receptors are expressed in cells of mesodermal and ectodermal origins.EGFR and its ligands EGF and TGF-alpha are important in cell proliferation, as well as motility, adhesion, invasion, survival and angiogenesis. The importance of EGFR in the development and progression of malignancies is supported by a number of observations: 1) hyperactivation or dysregulation of the ERBB pathway, either through overproduction of receptors or ligands and/or constitutive activation of receptors leads to malignant transformation 2) EGFR is expressed, overexpressed or mutated in many solid malignancies and expression of EGFR has been correlated with poor prognosis; 3) treatment of tumor cells in vitro with anti-EGFR antibody induces arrest of cells in G1 with an increase in the cyclin-dependent kinase inhibitor P27 and a decrease in retinoblastoma protein (RB) phosphorylation; 4) down-regulation of EGFR using antisense strategies reduces the proliferation and invasive properties of a human colon tumor cell line and blocks proliferation of human rhabdomyosarcoma cells; 5) blockade of the EGFR by an anti-receptor antibody triggers apoptosis; 6) ERBB2 signaling upregulates expression of vascular endothelial growth factor in mouse 3T3 and human MCF-7 breast cancer cells, indicating a role in angiogenesis; 7) ERBB2 enhances tumor cell motility; 8) human colon cancer metastases had fivefold greater levels of ERBB1 mRNA than those from non-metastatic tumors. Although tumor growth delay is most typical, inhibitors of EGFR can cause striking tumor regression in certain xenograft models, suggesting that for at least some tumors, the EGFR pathway is important to cell survival.OSI-774 is an oral epidermal growth factor receptor tyrosine kinase inhibitor, which inhibits the activity of purified EGFR TK and EGFR autophosphorylation in tumor cells with an IC50 of 20nM. The effect of OSI-774 on cell division is 1000 fold more potent against EGF than most other human kinases, requiring only sub-micromolar concentrations to inhibit cell division induced by EGF and block cell cycle progression at the G1 phase. In addition, there is mounting evidence to say that the small molecule EGFR inhibitors (such as OSI-774 and ZD1839) also inhibit ERBB2 signaling and suppress the growth of tumor cells, including pediatric tumors, which utilize this pathway.ERBB1 receptor over-expression has been reported in 81% (n=22/27) of pediatric high-grade gliomas, with over half demonstrating overexpression in greater than 90% of tumor cells. 19 ERBB2 protein expression has been detected in 80% of pediatric medulloblastomas 20 and in over 75% of childhood ependymomas studied. EGFR expression and overexpression has also been observed in neuroblastomas and rhabdomyosarcomas and a functional EGFR pathway was demonstrated in a panel of rhabdomyosarcoma and neuroblastoma cell lines. The presence of HER- 2/neu positivity was a significant predictor of shorter median survival in patients with neuroblastoma.Overexpression of EGFR and HER-2/neu has also been shown in osteogenic sarcomas. EGFR was expressed in 30/37 (81%) osteosarcomas studied and over expression of HER2 was found in 42 % of patients with osteogenic sarcoma with the level of HER2 expression inversely correlated with EFS. Many tumors with EGFR expression below the level of detection over express EGFR-activating ligands such as transforming growth factor alpha, also suggesting that EGFR inhibitors may be appropriate treatments for these diseases. For example, increased expression of TGF- alpha in Wilm's tumor correlated with a higher stage and greater likelihood of clinical progression. TGF-alpha and EGFR were found in 48% and 44% of Wilm's tumors tested.
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