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.
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...
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.
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...
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...
Uploads
Papers by Svetlana Pack