Abstract 5305: Characterization of the ovarian tumor transcriptome and microenvironment in pre and post-chemotherapy treated patients
Authors: Jordan Kimberly R. , Slansky Jill , Minic Angela , Richer Jennifer K. , Costello James C. , Clauset Aaron J. , Kumar Rajendra T. , Behbakht Kian , Sikora Matthew J. , Bitler Benjamin G. 
Published: September 2020

Purpose: Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is typically effective, but most patients will experience recurrence and enter a cycle of response and recurrence, ultimately developing resistant disease. Importantly, the understanding of mechanisms contributing to clinical chemoresistance in ovarian cancer is limited. Achieving optimal cytoreduction improves survival. Gynecologic oncologists therefore perform laparoscopy to evaluate resectability and collect tumor biopsies. Patients identified with un-resectable tumor receive three cycles of neoadjuvant platinum/taxane-based chemotherapy (NACT) to improve the likelihood of optimal cytoreductive surgery. NACT offers a previously unavailable window for identifying therapy-induced remodeling of the tumor, potentially providing insight into drivers of chemo-resistance.

Experimental Design: We accessed formalin fixed (FFPE) tumor tissue from high-grade serous ovarian cancer NACT patients (n=6) pre- and post-chemotherapy. RNA was extracted and the mRNA transcript levels were examined for 791 genes via the Immunoncology 360 NanoString panel. Further, using the pre-treated ascites fluid we examined the cytokine environment through MesoScale Discovery multiplex ELISA. Transcriptional and cytokine profiles were correlated to clinical outcomes, such as days to recurrence.

Results: Component analysis found that transcriptional profiles separated based on pre- and post-chemotherapy status. Comparing the pre- (n=6) and post-chemotherapy (n=6), the most upregulated gene following therapy was IL6 (4.1 log2 fold change, adj. p = 0.045) and the most downregulated gene was UBE2C (-3.9 log2 fold change, adj. p = 0.001). Elevated IL-6 within ascites correlated to a shorter time to recurrence. On the patient-by-patient basis we compared transcriptional changes between pre- and post therapy. We correlated these changes to IL6 expression and time to recurrence uncovered that an increase in Immediate Early Response 3 (IER3) is a poor prognostic indicator. IER3/IEX-1 is a NF-κB target gene involved in apoptosis and potentiates MAPK activation.

Conclusion: Using ovarian cancer tumors from NACT patients provides a unique insight into chemo-induced transcriptional changes. To-date little is known of IER3's function in ovarian cancer thus future work will focus on a potential novel IL-6/IER3 signaling axis that protects tumors from chemotherapy-induced apoptosis. Also, computer modeling and integration of transcriptional and cytokine date could also provide an approach to predict recurrence.

Citation Format: Kimberly R. Jordan, Jill Slansky, Angela Minic, Jennifer K. Richer, James C. Costello, Aaron J. Clauset, Rajendra T. Kumar, Kian Behbakht, Matthew J. Sikora, Benjamin G. Bitler. Characterization of the ovarian tumor transcriptome and microenvironment in pre and post-chemotherapy treated patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5305.