Jennifer Scalici

Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin

OBJECTIVE The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves α4β1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin α4β1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of α4β1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-α4β1 integrin function-blocking antibody. METHODS Integrin α4β1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-α4β1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines. RESULTS Treatment of tumor-bearing mice with human-specific α4β1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-α4β1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-α4β1 integrin antibodies resulted in increased cell death and doubling time. CONCLUSIONS Our findings support a role for α4β1 integrin in regulating treatment response to carboplatin, implicating α4β1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.

Imaging VCAM-1 as an Indicator of Treatment Efficacy in Metastatic Ovarian Cancer

The inability to successfully treat women with ovarian cancer is due in large part to the advanced stage of disease at diagnosis, the development of platinum resistance, and the lack of sensitive methods to monitor tumor progression and response to treatment. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the mesothelium of ovarian cancer patients. We investigated VCAM-1 expression as a marker of peritoneal metastasis and tumor response to platinum-based chemotherapy. Methods: Peritoneal or omental biopsies obtained from women diagnosed with stage I, stage II, or stage III/IV ovarian cancer were evaluated by immunohistochemistry. The effects of carboplatin on mesothelial VCAM-1 expression were determined in cultured cells by Western blot. Radiolabeled VCAM-1–specific peptide imaging probes and SPECT were used in a mouse model of ovarian cancer peritoneal metastasis to identify VCAM-1 as a viable imaging target. Results: VCAM-1 expression correlated with tumor stage. All specimens from stage I patients were negative, whereas 29% of stage II patients and 73% of stage III/IV patients were positive. Although most women with advanced stage disease expressed VCAM-1, the incidence of expression was reduced among women who received neoadjuvant chemotherapy, suggesting a role for chemotherapy in regulating VCAM-1 expression. Treatment of mesothelial cells in culture with carboplatin resulted in a transient decrease in VCAM-1 expression 4 h after treatment that returned to baseline within 16–24 h. In vivo imaging of VCAM-1 also demonstrated an acute decrease in expression 4 h after carboplatin administration that recovered within 48 h in mice harboring platinum-resistant tumors. Chronic VCAM-1 expression reflected the effect of platinum-based treatment on tumor burden. Specifically, carboplatin treatment of mice with platinum-sensitive tumors showed reduced VCAM-1 expression, which correlated with reduced tumor burden; mice with platinum-resistant tumors retained elevated VCAM-1 expression and tumor burden after treatment. Conclusion: Clinically relevant VCAM-1–specific imaging probes identify VCAM-1 expression as an indicator of ovarian cancer peritoneal metastasis and therapeutic response to platinum-based agents. These observations support testing the utility of VCAM-1 imaging probes to monitor treatment response in ovarian cancer patients, thus providing the potential to improve management of women with this disease.

Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC)

Mesothelium vascular cell adhesion molecule‐1 (VCAM‐1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM‐1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM‐1 expression and prospectively evaluate whether soluble VCAM‐1 (sVCAM‐1) is a surrogate for mesothelium expression.

Vulvar necrotizing soft tissue infection: A review of a multi-disciplinary surgical emergency and management in the modern era

Highlights ► Mortality from necrotizing soft tissue infections of the vulva is 14% in this study. ► Multi-disciplinary care may contribute to the lower mortality in this case series.

Abstract 5174: Phosphodiesterase 10A inhibition as a novel approach to suppress β-catenin signaling in ovarian cancer cells

Canonical Wnt/β-catenin signaling is known to be associated with platinum resistance in ovarian cancer in which inhibitors hold promise for the treatment of refractory disease. Phosphodiesterase 10A (PDE10A) is a dual cyclic AMP and cyclic GMP phosphodiesterase isozyme recently implicated in colon cancer. PDE10A inhibition in colon cancer cells by siRNA or small molecule inhibitors increased cGMP levels and activated PKG to inhibit β-catenin signaling. A novel PDE10 inhibitor, ADT-061, was identified by screening a library of indene derivatives, and showed strong antineoplastic activity in the Apc+/min-FCCC mouse (Lee K et al., unpublished data). Cyclic GMP and phosphodiesterases participate in the ovarian follicular development, although little is known about PDE10A expression in ovaries, especially with regard to a potential role in ovarian tumorigenesis. PDE10A protein was found to be expressed in various established ovarian cancer cell lines at higher levels than immortalized or primary ovarian surface epithelial cell lines. Pf-2545920, a known PDE10A inhibitor, and ADT-061 inhibited the growth of multiple ovarian tumor cell lines with IC50s around 20µM and 0.5µM, respectively. Both compounds induced apoptosis after 24h treatment, as measured by PI/Annexin-V staining and PARP cleavage. Pf-2545920 and ADT-061 induced phosphorylation of VASP at Ser157 and Ser239 in various ovarian cancer cell lines, indicating activation of cyclic AMP and cyclic GMP signaling, respectively. Treatment also decreased levels of β-catenin and downstream targets of TCF-dependent transcription, including c-MYC, survivin and cyclin-D1. Homozygous knockout PDE10A clones of OV-90 ovarian cancer cells obtained using CRISPR/Cas9 showed decreased clonogenic potential, decreased Pf-2545920-mediated VASP phosphorylation and β-catenin, c-MYC and survivin expression. Ongoing efforts are focused on the development of more potent ADT-061 analogs. These observations support further study of a role of PDE10 in ovarian tumorigenesis and the development of ADT-061 or analogs for the treatment of refractory ovarian cancer as well as the prevention of malignant recurrence. Citation Format: Luciana Madeira Da Silva, Elaine Gavin, Kevin J. Lee, Veronica Ramirez-Alcantara, Kristy L. Berry, Holly T. Taylor, Alla Musiyenko, Ileana V. Aragon, Adam B. Keeton, Jennifer Scalici, Rodney P. Rocconi, Gary A. Piazza. Phosphodiesterase 10A inhibition as a novel approach to suppress β-catenin signaling in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5174. doi:10.1158/1538-7445.AM2017-5174

Abstract 845: Vascular cell adhesion molecule-1 (VCAM-1) expression in patients with ovarian tumors of low malignant potential

The molecular basis for gynecologic tumor dissemination into the peritoneum is not well understood, however it is the primary mechanism of death in advanced stage ovarian cancers. Although serous borderline and serous invasive ovarian cancers are similar, they differ in their ability to implant and invade peritoneal structures. Vascular cell adhesion molecule-1 (VCAM-1), a cell surface receptor expressed on activated endothelial and mesothelial cells, regulates leukocyte attachment and extravasation at sites of inflammation. Recent studies by our group demonstrated the ability of ovarian carcinoma to induce the expression of VCAM-1 on mesothelial cells, and correlated the presence of VCAM-1 with peritoneal dissemination of the tumor. We undertook the current study to determine whether VCAM-1 is expressed on the mesothelium of patients with borderline ovarian tumors. After IRB approval was obtained, cell blocks containing peritoneum and omentum from 10 patients with borderline tumors were processed and stained using antibodies to VCAM-1. Mesothelial expression of VCAM-1 was determined by a single pathologist blinded to tumor type and stage. Samples were determined to be positive if mesothelial cells demonstrated membrane staining. Cytoplasmic staining for VCAM-1 was not considered positive, nor was staining of non-mesothelial cells. Of the 10 patients, four were stage 1a and six were stage 1c serous borderline tumors. Nine of 10 had peritoneal or omental biopsies that did not stain for VCAM-1. The one sample which did stain positively was micropapillary type, which is an invasive sub-type of borderline ovarian cancers. Together, these observations support the hypothesis that VCAM-1 expression correlates with ovarian cancer peritoneal invasion and offers a possible explanation for the inability of borderline tumors to invade peritoneal structures. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 845.

Abstract 848: VCAM-1 expression in epithelial ovarian cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Vascular cell adhesion molecule-1 (VCAM-1) is a cell surface adhesion molecule with known expression on the peritoneum of some advanced stage epithelial ovarian cancer patients. Previous study by our group has implicated VCAM-1 as a mediator of metastatic invasion of peritoneal surfaces by tumor cells in advanced disease, as inhibition of its function resulted in decreased tumor burden and improved overall survival in an animal model. We propose that VCAM-1 expression is a potential site of targeted therapy and in addition, expression may also serve as an early indicator of disease recurrence. We aim to correlate VCAM-1 expression with disease stage and histology to determine when in the course of disease expression begins. After IRB approval, archived tissue blocks from 1998-2008 containing samples of tumor, omentum, and peritoneum were evaluated for the presence of mesothelial cells. IHC staining of VCAM-1 was performed. Samples were evaluated and scored by a single pathologist blinded to stage and tumor type. All tissue samples from stage 1 patients were negative for VCAM-1 expression. The majority of samples from stages 3 and 4 were positive. Of the stage 2 samples, 50% were positive; those were primarily of serous histology. This suggests that there is an increase in peritoneal VCAM-1 expression as tumor cells leave the confines of the ovary and may serve as a marker of metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 848.

Abstract 2346: Contribution of VLA-4 to ovarian cancer metastasis and platinum resistance

Ovarian cancer is the fourth leading cause of cancer-related death among women. The relatively poor prognosis for ovarian cancer (5-year survival of 30-40%) reflects 1) the advanced stage of disease at diagnosis and 2) the frequent development of recurrent disease refractory to front line therapy. Ovarian cancers metastasize by attaching to and invading through the mesothelium, a single cell layer of mesothelial cells lining the peritoneal cavity. The presence of invasive peritoneal metastases is associated with a poor prognosis for ovarian cancer (5 yr survival Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2346.