Targeting the Hedgehog pathway to inhibit osteosarcoma growth through dual effects on tumor and microenvironment cells

Targeting the Hedgehog pathway to inhibit osteosarcoma growth through dual effects on tumor and microenvironment cells

While the 5-year survival rate for localized osteosarcoma (OS), the most common primary bone cancer, is approximately 70%, metastasis decreases this to under 30%, highlighting the need for novel and targeted treatments. We have developed a model of high penetrant, spontaneous occurring OS in Tax+Arf-/- mice that recapitulates many aspects of human disease. Compared to normal osteoblasts, Tax+Arf-/- OS cells have increased expression of Hedgehog (Hh) pathway genes and exhibit increased susceptibility to Hh inhibitors (SMO antagonists). Furthermore, the high rate of bone turnover in Arf-/- mice may support OS growth, mimicking the adolescent growth spurts during which OS is…  Read More »

Oncogenic Targets of Hedgehog-GL/1 Activation in Ewing Sarcoma

Ewing Tumors are addicted to aberrant oncogenic transcription factors of the EWS/FLI1 class. Means to target these proteins face substantial technical and economic obstacles. However, my lab and others have shown the importance of Hedgehog-GLI (HH-GLI) signaling in Ewing tumor biology. More recently, data from my lab has shown that a majority of targets transcriptionally deregulated by EWS/FLI1 are co-regulated by GLI1, demonstrating the central importance of HH-GLI in Ewings. We now have evidence that the reason for this tremendous target overlap involves a novel mechanism in which GLI1 interacts with EWS/FLI1 to synergistically upregulate jointly-targeted promoters. This synergism represents…  Read More »

Differentiation Therapy for Rhabdoid Tumors

Malignant rhabdoid tumors are uncommon but extremely aggressive childhood sarcomas for which there is no adequate therapy. Since rhabdoid tumors are characterized by defects in mesenchymal progenitor cell differentiation, therapies that target and correct these defects and induce terminal differentiation are an attractive alternative to the cytotoxic therapies currently used to treat these tumors. However, little is known about the molecular changes that occur in rhabdoid tumors, which limits the development of targeted therapies. We observed frequent expression of the HOXB13 gene in rhabdoid tumors. HOXB13 is known to play an important role in cell determination during embryogenesis but its…  Read More »

ROS1 kinase as a candidate molecular target in angiosarcoma

Angiosarcomas are an uncommon type of soft tissue tumor, but are clinically aggressive and associated with relatively poor survival. New targets for molecularly-directed therapy are needed. In preliminary genomic analyses, we discovered presumptive oncogenic rearrangements of ROS1, a receptor tyrosine kinase previously linked to a subset of brain and lung tumors, but not to sarcomas. The objectives of the proposed study are to determine whether ROS1 functions as an oncogenic driver in angiosarcoma (by overexpression studies in cultured cells), whether angiosarcomas are addicted to ROS1 (by RNA interference knockdown and small molecule inhibitor studies in cultured cells), and whether ROS1…  Read More »

C-MYC Target Gene Network in the Ewing’s Sarcoma Cancer Stem Cell

Tumors are not homogenous in nature, but are heterogeneous populations of cells.  One population, the cancer stem cell (CSC), is thought to be responsible for the initiation and progression of the disease as well as contain inherent properties that make it more resistant to modern therapies.  One of the key regulatory genes in these cells may be the oncogenic transcription factor c-Myc.  We propose to study the regulatory and functional role c-Myc has in the Ewing’s sarcoma cancer stem cells (ESSCs) to increase our understanding of the genetic and molecular landscape of these cells.  These studies can enhance our insights…  Read More »

Desmoplastic small round cell tumor: validation and further development of novel active compounds emerging from high-throughput chemical screens and establishment of xenografts for preclinical studies

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive tumor of adolescents and young adults characterized by the chromosomal translocation t(11:22)(p13;q12) that generates a novel, chimeric transcription factor EWS-WT1.  DSRCT has a dismal prognosis in the setting of current treatment options.  The first Aim of this project is to better define the cellular pathways targeted by 5 compounds that we have recently identified as potent inhibitors of DSRCT cell growth in a large scale chemical screen by using microarray-based gene expression analysis to generate compound-specific signatures.  This work should, firstly, help us prioritize compounds for further pre-clinical drug development;…  Read More »

Preclinical Testing of Compounds Identified in a High Throughput Screen as Potential Chordoma Therapies

Chordoma is a rare tumor presumed to be derived from remnants of the notochord.  Conventional chordoma is a low-grade malignancy that can be cured with surgery alone, but because chordomas usually arise in places where resection with negative margins is not feasible, recurrent disease is a problem. There is no effective chemotherapy for recurrent chordoma. Dedifferentiated chordoma is a higher grade malignancy with a moderate metastatic potential. There is no effective systemic therapy for dedifferentiated chordoma, either. Our laboratory (DL) has created the first primary human dedifferentiated chordoma xenograft, and our collaborator (AQ-H) has created a primary chordoma cell line…  Read More »

Polarity and Ploidy in Peripheral Chondrosarcoma

Peripheral chondrosarcoma (PCS) remains a malignancy for which no treatments other than radical surgery have proven effective.  Nonetheless, PCS is one of very few sarcomas which arise from known precursor lesions in the setting of a genetically well-understood heritable syndrome.  PCS frequently demonstrates grossly invasive lobular growth patterns and aneuploidy despite generally low-grade histology.  One possible explanation is that chondrosarcoma cells have lost their sense of direction.  As preliminary data, we found not only misorientation, but a decrease in the presence of primary cilia in the osteochondromas that form in our previously published mouse genetic model of multiple osteochondromas by…  Read More »

Study of miR-26a-2 gene as a therapeutic target of human liposarcoma

Despite its high occurrence, human liposarcoma (LPS) lacks effective treatment options except surgical resection of localized tumor mass.  Progressive disease may have a temporary response to chemotherapy.  Approximately 90% of well-differentiated/de-differentiated LPS (WDLPS/DDLPS), the most common LPS subtype, have chromosomal amplification at 12q13-q15.  Many protein-coding genes in the region, such as MDM2 and CDK4, have been studied as potential therapeutic targets for LPS treatment with minimal success to date.  Within this amplicon near to the MDM2 gene, our preliminary data showed that a microRNA (miRNA), miR-26a-2, was amplified. miRNAs are short, non-coding RNAs that can provide the coordinated regulation of…  Read More »

Targeting ETV1 in Gastrointestinal Stromal Tumor (GIST)

ETS family transcription factors (e.g. ERG, ETV1) are well-established oncogenes involved in recurrent genomic alterations in prostate cancer, Ewing sarcoma and melanoma.  Recently, we uncovered an oncogenic role of ETV1 in GIST – one of the most common types of human sarcoma.  GIST is primarily defined by activating mutations in the KIT or PDGFRA receptor tyrosine kinases.  KIT is highly expressed in the interstitial cells of Cajal (ICCs) – the presumed cell of origin of GIST – as well as in hematopoietic stem cells, melanocytes, mast cells and germ cells.  Yet, humans and mice with germline activating KIT mutations exclusively…  Read More »