Purpose: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a P... more Purpose: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3– or PAX7–FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13–q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS.Experimental Design: We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts.Results: Knockdown of CDK4 abrogated proliferation and transformation of 12q13–14-amplified and nonamplified fusion-positive RMS cells via G1-phase cell-cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell-cycle distri...
Supplementary Table 1 and Figure Legends from Conditional Expression of the CTCF-Paralogous Trans... more Supplementary Table 1 and Figure Legends from Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes
Supplementary Table 1 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erb... more Supplementary Table 1 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line
Supplemental Figure 3. Further evaluation of CDK4/6 inhibitor sensitivity in fusion-positive and ... more Supplemental Figure 3. Further evaluation of CDK4/6 inhibitor sensitivity in fusion-positive and fusion-negative RMS cells.
Additional file 8 : Figure S3. Histology of the 8 MYCN amplified cases. Panels A-H correspond to ... more Additional file 8 : Figure S3. Histology of the 8 MYCN amplified cases. Panels A-H correspond to cases 1–8 in numerical order. All photomicrographs are H&E, 100X, and most show areas with typical perivascular pseudorosettes characteristic of ependymomas.
Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model ... more Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most PLOS GENETICS
Histiocytic disorders are uncommon and often affect multiple organ systems. They pose diagnostic ... more Histiocytic disorders are uncommon and often affect multiple organ systems. They pose diagnostic challenges because of their rarity and the fact that the nosology of these lesions is still being decided. ALK-positive histiocytosis is one of the newest subtypes and was originally described about ten years ago, wherein there was a predilection for neonates and infants with multi-organ involvement [1]. Since then, ten additional cases have been reported, with only one having exclusive intracranial disease, along with involvement of the cavernous sinus [2, 6]. Here, we report two additional cases with exclusive involvement of the central nervous system. Case 1 is a 7-year-old girl who presented with a one-month history of headaches and vomiting. Magnetic resonance imaging (MRI) showed an infiltrating 3 cm mass in the cerebellar vermis. The mass was associated with diffusion restriction and was radiologically suspicious for medulloblastoma (Fig. 1a). She underwent gross total resection followed by observation with MRI every three months. Postoperative whole-body PET-CT scan showed no evidence of systemic disease. At one-year post-operative follow-up, there is no evidence of recurrence on neuroimaging. Her only neurologic deficit is a minimal slurring of speech and difficulty with phonation. Case 2 is a 10-year-old girl who presented with medically refractory seizures and was found to have a homogenously enhancing 1.4 cm mass in the right pericentral cortical region on head MRI (Fig. 1g). She underwent focal corticectomy followed by observation.
Adverse prognosis in Ewing sarcoma (ES) is associated with the presence of metastases, particular... more Adverse prognosis in Ewing sarcoma (ES) is associated with the presence of metastases, particularly in bone, tumor hypoxia and chromosomal instability (CIN). Yet, a mechanistic link between these factors remains unknown. We demonstrate that in ES, tumor hypoxia selectively exacerbates bone metastasis. This process is triggered by hypoxia-induced stimulation of the neuropeptide Y (NPY)/Y5 receptor (Y5R) pathway, which leads to RhoA over-activation and cytokinesis failure. These mitotic defects result in the formation of polyploid ES cells, the progeny of which exhibit high CIN, an ability to invade and colonize bone, and a resistance to chemotherapy. Blocking Y5R in hypoxic ES tumors prevents polyploidization and bone metastasis. Our findings provide evidence for the role of the hypoxia-inducible NPY/Y5R/RhoA axis in promoting genomic changes and subsequent osseous dissemination in ES, and suggest that targeting this pathway may prevent CIN and disease progression in ES and other can...
In this article Sung-Hyeok Hong should have been denoted as an equally contributing author. The o... more In this article Sung-Hyeok Hong should have been denoted as an equally contributing author. The original article has been corrected.
BackgroundDespite recent advances, there is an urgent need for agents targeting HER2-expressing c... more BackgroundDespite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse.Patients and MethodsPart 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evalua...
Purpose: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a P... more Purpose: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3– or PAX7–FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13–q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS.Experimental Design: We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts.Results: Knockdown of CDK4 abrogated proliferation and transformation of 12q13–14-amplified and nonamplified fusion-positive RMS cells via G1-phase cell-cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell-cycle distri...
Supplementary Table 1 and Figure Legends from Conditional Expression of the CTCF-Paralogous Trans... more Supplementary Table 1 and Figure Legends from Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes
Supplementary Table 1 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erb... more Supplementary Table 1 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line
Supplemental Figure 3. Further evaluation of CDK4/6 inhibitor sensitivity in fusion-positive and ... more Supplemental Figure 3. Further evaluation of CDK4/6 inhibitor sensitivity in fusion-positive and fusion-negative RMS cells.
Additional file 8 : Figure S3. Histology of the 8 MYCN amplified cases. Panels A-H correspond to ... more Additional file 8 : Figure S3. Histology of the 8 MYCN amplified cases. Panels A-H correspond to cases 1–8 in numerical order. All photomicrographs are H&E, 100X, and most show areas with typical perivascular pseudorosettes characteristic of ependymomas.
Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model ... more Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most PLOS GENETICS
Histiocytic disorders are uncommon and often affect multiple organ systems. They pose diagnostic ... more Histiocytic disorders are uncommon and often affect multiple organ systems. They pose diagnostic challenges because of their rarity and the fact that the nosology of these lesions is still being decided. ALK-positive histiocytosis is one of the newest subtypes and was originally described about ten years ago, wherein there was a predilection for neonates and infants with multi-organ involvement [1]. Since then, ten additional cases have been reported, with only one having exclusive intracranial disease, along with involvement of the cavernous sinus [2, 6]. Here, we report two additional cases with exclusive involvement of the central nervous system. Case 1 is a 7-year-old girl who presented with a one-month history of headaches and vomiting. Magnetic resonance imaging (MRI) showed an infiltrating 3 cm mass in the cerebellar vermis. The mass was associated with diffusion restriction and was radiologically suspicious for medulloblastoma (Fig. 1a). She underwent gross total resection followed by observation with MRI every three months. Postoperative whole-body PET-CT scan showed no evidence of systemic disease. At one-year post-operative follow-up, there is no evidence of recurrence on neuroimaging. Her only neurologic deficit is a minimal slurring of speech and difficulty with phonation. Case 2 is a 10-year-old girl who presented with medically refractory seizures and was found to have a homogenously enhancing 1.4 cm mass in the right pericentral cortical region on head MRI (Fig. 1g). She underwent focal corticectomy followed by observation.
Adverse prognosis in Ewing sarcoma (ES) is associated with the presence of metastases, particular... more Adverse prognosis in Ewing sarcoma (ES) is associated with the presence of metastases, particularly in bone, tumor hypoxia and chromosomal instability (CIN). Yet, a mechanistic link between these factors remains unknown. We demonstrate that in ES, tumor hypoxia selectively exacerbates bone metastasis. This process is triggered by hypoxia-induced stimulation of the neuropeptide Y (NPY)/Y5 receptor (Y5R) pathway, which leads to RhoA over-activation and cytokinesis failure. These mitotic defects result in the formation of polyploid ES cells, the progeny of which exhibit high CIN, an ability to invade and colonize bone, and a resistance to chemotherapy. Blocking Y5R in hypoxic ES tumors prevents polyploidization and bone metastasis. Our findings provide evidence for the role of the hypoxia-inducible NPY/Y5R/RhoA axis in promoting genomic changes and subsequent osseous dissemination in ES, and suggest that targeting this pathway may prevent CIN and disease progression in ES and other can...
In this article Sung-Hyeok Hong should have been denoted as an equally contributing author. The o... more In this article Sung-Hyeok Hong should have been denoted as an equally contributing author. The original article has been corrected.
BackgroundDespite recent advances, there is an urgent need for agents targeting HER2-expressing c... more BackgroundDespite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse.Patients and MethodsPart 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evalua...
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