A preclinical mouse model for targeted therapy in uterine leiomyosarcoma

Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy that has a low survival rate. Currently, there is no effective treatment for ULMS. We have generated a mouse model of ULMS and demonstrated that the loss of BRCA1 function accelerates the progression of these tumors. Consistent with the hypothesis that BRCA1 plays a role in ULMS, we have shown that the BRCA1 protein is absent in 36% of human ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS. To this end, we will determine the mechanism of BRCA1 downregulation in human tumor samples and test…  Read More »

Therapeutically targeting aberrant chromatin remodeling in sarcomas

SNF5, a core subunit of the SWI/SNF chromatin remodeling complex, is a potent tumor suppressor that is specifically mutated in several types of sarcoma.  It has been thought that oncogenesis in the absence of SNF5 occurs due to a loss of function of the SWI/SNF complex.  However, based upon preliminary data we hypothesize that cancer instead arises due to oncogenic activation of the residual SWI/SNF complex.  We propose to utilize our genetically engineered mouse models to demonstrate this, to further establish that targeted inhibition of residual activity can be therapeutically beneficial, and to establish a pre-clinical model.

Evaluation of the oncogenic potential of genes within the 1q23 amplicon

Comparative genomic hybridization identified amplification of 1q23 to be associated with liposarcomas. Further analyses of 1q23 narrowed down the candidate “driver” genes to two; DUSP12 (encoding a dual-specificity phosphatase) and ATF6 (a transcription factor of the unfolded protein response). We propose to assess the specific consequences of DUSP12/ATF6 over-expression by creating stable inducible cell lines as models of 1q23 amplification. The consequences of specific DUSP12 or ATF6 over-expression on MAP Kinase and other cancer-relevant signaling pathways will be evaluated. Identification of these pathways may expose novel vulnerabilities that can be exploited in the treatment of sarcomas by accelerating translational therapeutics.

Development of novel dual Insulin-like Growth Factor-1 Receptor (IGF-1R)/ Epidermal Growth Factor Receptor (EGFR) inhibitors for treatment of Ewing’s sarcoma

Ewing’s sarcoma, a devastating disease in children and young adults, is in great need for a therapy.  Insulin-like Growth Factor type 1Receptor (IGF-1R) and Epidermal Growth Factor Receptor (EGFR) proved to be interesting targets for different sarcomas.  Here we proposed the development and synthesis of novel dual IGF-1R/EGFR inhibitors based on virtual screening.  We hypothesize that simultaneous targeting of the two receptor tyrosine kinases will be an efficient treatment for Ewing’s sarcoma.  Inhibitory activity and selectivity of the inhibitors will be determined in vitro.

Pharmacodynamic assessment of AKT and SRC inhibitors in primary human sarcoma xenograft models

The poor outcome of patients with advanced sarcomas underscores the rationale supporting novel therapeutic strategies.  Combination treatment with dasatinib and triciribine effectively blocks growth of sarcoma cell lines through inhibition of SRC and AKT pathways, respectively.  We will determine the activity of these drugs against a set of xenografted tumors obtained from sarcoma patients and analyze pharmacodynamic markers of response using a quantitative multiplex assay platform in vivo.  The studies that would be supported by this application are expected to provide a foundation to support rational clinical trial design for these agents to maximize their therapeutic potential in sarcoma.

Targeting kinases to reverse multidrug resistance in human sarcoma

Protein kinases play an important role in the pathogenesis of cancer.  Furthermore, kinases can be targeted by pharmaceutical agents to decrease tumor growth (i.e. EGFR, Her2, c-kit).  This project examines the role of specific kinases as sarcoma cancer cells develop resistance to chemotherapeutic agents.  We aim to: 1) determine the role of kinases in supporting chemoresistance to doxorubicin and methotrexate in sarcoma cell lines; and 2) determine the effectiveness of inhibiting kinases to reverse drug resistance in a sarcoma xenograft mouse model.  We hope to identify the most suitable kinases for future development as new drugs for patients with sarcoma.

Identification of aberrantly methylated genes in Ewing sarcoma

DNA methylation is part of a complex mechanism that regulates genes.  The goal of this proposal is to identify genes that are “turned off” by DNA methylation and contribute to Ewing Sarcoma tumor formation.  We will determine if the methylation pattern of these genes is associated with tumor location, tumor spread, and how the neoplasm responded to treatment.  We hope that this study will lead us to better understanding of the cause of ES and will lead to the development of better diagnostic and therapeutic modalities for these patients.

Targeting the Ras-pathway for the treatment of embryonal rhabdomyosarcoma

A transgenic zebrafish model of embryonal rhabdomyosarcoma was recently created that is molecularly similar to human disease and from which the cancer stem cell has been identified, a cell most similar to the normal muscle stem cell-the actived satellite cell. My hypothesis is that the RAS pathway is responsible for eliciting stem cell self-renewal programs in a subset of the RMS cell types, and that this in turn regulates tumor growth.  Targeting downstream RAS pathways and self-renewal may provide a new way to curb sarcoma growth in patients affected with this devastating disease.

Targeting centrosomes in uterine leiomyosarcoma

Uterine leiomyosarcoma (ULMS) is characterized by its early metastases, frequent recurrences and poor outcome.  Using genome-wide transcriptional profiling, we have found that the Aurora A and B centrosomal kinases are robustly overexpressed in ULMS. AIMS: 1. Assess the clinical significance of Aurora kinase misexpression by correlating levels of expression and surrogates for function with outcome. 2. Determine the biologic impact of targeting Aurora kinases in ULMS using unique cell lines and a novel xenograft model in mice. This work will determine whether a phase I/II trial of Aurora kinase inhibitors currently in clinical testing is warranted for ULMS patients.

Targeting the Wnt pathway in synovial sarcoma

Synovial Sarcoma is an aggressive soft tissue tumor (SS) that afflicts young adults. Its high fatality rate warrants the design of more efficient curative approaches. SS is characterized by a unique translocation that creates the SYT-SSX fusion protein. SYT-SSX plays a central role in the development of SS. Here we present active Wnt/beta-catenin signaling as a downstream cascade of SYT-SSX and as an ideal candidate pathway for targeting in SS. We will generate murine models to assess the extent of Wnt/beta-catenin signaling contribution to SS formation and measure the effect of a specific pharmacological beta-catenin inhibitor on SS tumor growth.