Abstract 117: Anti-proliferative and cytotoxic effects of verteporfin in endometrial cancer cells
Authors: Gogoi Radhika P. , Castañeda-Gill Jessica M. , Metpally Raghu P. , Krishnamurthy Sarath B. , Vishwanatha Jamboor K. , Carey David J. , Nash John D. , Dasari Venkata Ramesh 
Published: July 2017

Endometrial cancer (EMCA) is the most prevalent gynecologic cancer in women in the United States. The relatively poor prognosis and limited therapeutic options in advanced endometrial cancer underscores the urgency in developing new and more effective treatment modalities. On the basis of clinical and histopathological features, EMCA is classified into type I and type II disease groups. Type 1 is estrogen potentiated, estrogen receptor (ER) and progesterone receptor (PR) positive, and generally carries a favorable prognosis. Type 2 is ER/PR negative and carries a much poorer prognosis. We investigated the therapeutic efficacy and mechanism of action of Verteporfin (VP), a benzoporphyrin derivative in EMCA. Treatment with VP resulted in a decrease in cell viability, invasion and an increase in cytotoxicity of EMCA cells. Similarly, VP treatment increased apoptosis in organoids, developed from patient-derived xenografts. Since the half-life of verteporfin is very short, we evaluated the longer duration efficacy of VP, encapsulated in mPEG-PLGA polymers. Our results demonstrated that VP nanoparticles (NP) decreased cell viability in both Type 1 (HEC-1-B) and Type 2 (ARK-1) EMCA cell lines over a period of 4 days. We did not observe any lethal effects of blank NP to the EMCA cells. In order to determine the efficacy of VP in changing cellular transcriptome, we performed RNASeq of EMCA cells after treatment with VP. RNASeq data analysis was carried out using latest version of Kallisto and Sleuth software. Based on the global gene expression whole transcriptome analysis, we observed that HEC-1-A VP treated cells show 225 differentially expressed transcripts (out of 204 genes); whereas HEC-1-B VP treated cells show 12315 differentially expressed transcripts (out of 7870 genes). There were 114 differentially expressed transcripts (out of 105 genes) common to both the cell lines. We observed that ATM, ATR, BRCA2, CDK4, ERBB2, JAK2, NF1, NOTCH and TET2 are some of the differentially expressed genes after VP treatment. To test the efficacy of VP under in vivo conditions, we developed a subcutaneous mouse model of EMCA using HEC-1-B-GFP cells. IP administration of VP in this model achieved 21% tumor regression. To more accurately simulate the results in vivo in a clinically relevant model, we have developed an orthotopic tumor model with IV injection of VP. Taken together, our results suggest that VP is a promising chemotherapeutic agent for the treatment of endometrial cancer.

Citation Format: Radhika P. Gogoi, Jessica M. Castañeda-Gill, Raghu P. Metpally, Sarath B. Krishnamurthy, Jamboor K. Vishwanatha, David J. Carey, John D. Nash, Venkata Ramesh Dasari. Anti-proliferative and cytotoxic effects of verteporfin in endometrial 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 117. doi:10.1158/1538-7445.AM2017-117