Abstract 38P
Background
The treatment of metastatic renal cell carcinoma (mRCC) has evolved dramatically, however, biomarkers suggesting initial treatment selection do not yet exist. We have previously reported the therapeutic potential of JX-594 (pexastimogene devacirepvec, Pexa-vec) in mRCC. The purpose of this study is to develop four cell-line derived xenograft (CDX) mouse models for most commonly mutated genes; VHL, PBRM1, SETD2, and BAP1 in clear cell RCC (ccRCC), and compare the response to JX-594.
Methods
Four CDX mouse models have been developed using the ccRCC cell lines representative of each four mutations (786-O (VHL mutation), ACHN (PBRM1 mutation), Caki-1 (SETD2 mutation), and 769-P (BAP1 mutation)). Tumors were implanted by subcutaneous injection of 2-10x106 cells into the right flank of wild-type BALB/c nude mice. When tumors reached >50 mm3, mice were treated with either PBS or 1x107 plaque-forming units of JX-594 by intratumoral injection in day 0, 3, and 6. Tumor volume was calculated with digital calipers. mRNA expressions of PBRM1, SETD2, and BAP1 were measured with qRT-PCR after the JX-594 treatment in 786-O CDX model.
Results
All four CDX models demonstrated significant decrease in tumor size by the JX-594 treatment compared to control. Most rapid tumor growth was noted at BAP1 mutation tumors while PBRM1 mutation tumor demonstrated the slowest growth. The decrease of tumor volume was most significant in BAP1 mutation tumors compared to tumors with VHL, PBRM1, and SETD2 mutations. In terms of relative therapeutic response ratio, calculated as decreased tumor volume x tumor growth rate, which adjusted the relative difference in a tumor growth rate of each cell line, BAP1 mutation was also associated with a better relative therapeutic response ratio. Meanwhile, expression levels of SETD2 and BAP1 were significantly reduced in the process of oncolysis.
Conclusions
Our study has demonstrated that BAP1 mutation was associated with rapid tumor progression and JX-594 was best fit for BAP1 mutation tumor. Although further studies are needed, SETD2 and BAP1 were reduced in the process of oncolysis. BAP1 was found to be a predictive therapeutic biomarker for JX-594 treatment response.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI17C1095], and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number: 2019R1A2C1002863 and 2022R1A2C2003831].
Disclosure
All authors have declared no conflicts of interest.