Abstract 1958: Early treatment response detected in a murine clear cell renal cell carcinoma model in response to combination therapy with antiangiogenic and notch inhibition therapy using a non-invasive imaging tool
Authors: Rojas Juan D. , Papadopoulou Virginie , Czernuszewicz Tomasz , Rajamahendiran Rajalekha , Chytil Anna , Chiang Yun-Chen , Chong Diana , Bautch Victoria L. , Rathmell Wendy K. , Aylward Stephen , Gessner Ryan , Dayton Paul 
Published: August 2019

Background: Functional and molecular changes often precede gross anatomical changes in cancer, so early assessment of a tumor’s functional and molecular response to therapy can help reduce a patient’s exposure to the side effects of ineffective chemotherapeutics or other treatment strategies. Clear-cell renal cell carcinoma (ccRCC) is an aggressive and hyper-vascular form of renal cancer that is often treated with anti-angiogenic and Notch Inhibition therapies, which target the vasculature feeding the disease. The purpose of this work is to show that ultrasound microvascular imaging can provide indications of response to antiangiogenic and Notch Inhibition therapies prior to measurable changes in tumor size.

Methods: Mice bearing 786-O ccRCC xenograft tumors were treated with SU (Sunitnib malate, Selleckchem, TX), an antiangiogenic drug, and a combination of SU and the Notch inhibitor GSI (Gamma secretase inhibitor, PF-03084014, Pfizer, New York, NY) therapies (n=8). A 3D ultrasound system (SonoVol Inc., Research Triangle Park, NC), in addition to microbubble ultrasound contrast agents, was used to obtain a measurement of microvascular density over time and assess the response of the tumors to the therapies. CD31 immunohistochemistry was performed to serve as a gold standard for comparison against imaging results. Statistical tests included: Spearman correlation to compare imaging and histology; Kruskal-Wallis analysis with Tukey multiple comparison post-test to determine if the vessel density or tumor volume were significantly different between the treatment groups; and receiver operating characteristic (ROC) curve analysis to determine sensitivity/specificity for separating treated/untreated groups.

Results: Data indicated that ultrasound-derived microvascular density can detect response to antiangiogenic and Notch inhibition therapies a week prior to changes in tumor volume. Furthermore, the imaging measurements of vasculature are strongly correlated with physiological characteristics of the tumors as measured by histology (p=0.75). Moreover, data demonstrated that ultrasound measurements of vascular density can determine response to therapy and classify between-treatment groups 1 week after the start of treatment with a high sensitivity and specificity of 94% and 86%, respectively.

Conclusion: This work shows vascular density measurements that are strongly correlated with histology can be obtained using ultrasound, and that imaging-derived vessel density metrics may be a better tool for assessing the response of ccRCC to antiangiogenic and Notch inhibition therapies than anatomical size measurements.

Note: This abstract was not presented at the meeting.

Citation Format: Juan D. Rojas, Virginie Papadopoulou, Tomasz Czernuszewicz, Rajalekha Rajamahendiran, Anna Chytil, Yun-Chen Chiang, Diana Chong, Victoria L. Bautch, Wendy K. Rathmell, Stephen Aylward, Ryan Gessner, Paul Dayton. Early treatment response detected in a murine clear cell renal cell carcinoma model in response to combination therapy with antiangiogenic and notch inhibition therapy using a non-invasive imaging tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1958.