Abstract LB018: Therapeutic efficacy of inhibition of specific sirtuins against melanoma in BrafV600E/PtenNULL and PDX models
Authors: Aldrete Karla Anaya , Zaemisch Gabriella R. , Ndiaye Mary A. , Chhabra Gagan , Ahmad Nihal 
Published: April 2023

Abstract
Melanoma is a highly immunogenic malignancy and one of the deadliest skin cancers due to its ability to metastasize and its resistance to existing therapies. Current treatment regimens include immunotherapies as well as targeted therapies (e.g. BRAF and MEK inhibitors). However, these immuno- or targeted therapies have been associated with acquired resistance and, therefore, failure of therapy. Therefore, development of novel mechanistically-targeted therapies is of paramount importance for an efficient management of this neoplasm. Sirtuins, a seven-member family of class III histone deacetylases, have been implicated in the development/progression of multiple cancers, including melanoma. Previous studies from our laboratory and elsewhere have shown the pro-proliferative functions of sirtuins SIRT1 and SIRT3 in melanoma. We have also shown that the small molecule inhibitor 4’-bromoresveratrol (4’-BR; co-inhibitor of SIRT1 and SIRT3) has antiproliferative effects in melanoma cell lines as well as in a BrafV600E/PtenNULL mouse model of melanoma. This study was designed to further expand on our previous findings and to determine the therapeutic significance of SIRT1 and SIRT3 in melanoma. To determine the effect of specific inhibition of SIRT3 on melanoma progression, we treated BrafV600E/PtenNULL mice with 100 μg small interfering RNA (siRNA) against SIRT3 (siSIRT3) or its non-targeting control (siNTC) twice weekly (intraperitoneal injections for 5 weeks). We found a trend of decreased tumor volumes in the siSIRT3-treated mice, though not significant. A similar trend was seen in the final tumor weight of these mice. In the next series of experiments, we used two human melanoma patient-derived xenografts (PDXes) to compare the effect of 4’-BR or siSIRT3 on melanoma tumor growth. Similar to our published study in the BrafV600E/PtenNULL mice, we found that 4’-BR treatment (50 mg/kg, via intraperitoneal injection, twice weekly for 5 weeks) resulted in a significant decrease in tumor growth when compared to vehicle control mice. Additionally, the final tumor weight was significantly decreased in the 4’-BR group. However, the siSIRT3 treatments resulted in a decrease but non-significant decrease in melanoma tumor growth or final weights, supporting our observations in BrafV600E/PtenNULL mice. Considering the lung is a common site for metastasis in melanoma, metastatic nodules in the lungs were quantified in one of our PDX models. We observed a decreased number in both the siSIRT3 and 4’-BR groups vs their respective controls. Overall, our data suggests that targeting SIRT3 alone may not be sufficient for melanoma treatment, and that the concomitant inhibition of SIRT1 and SIRT3 (and potential other sirtuins with pro-proliferative functions in melanocytic cells) may be better for melanoma management. Indeed, additional research is needed to validate our findings in relevant models.
Citation Format: Karla Anaya Aldrete, Gabriella R. Zaemisch, Mary A. Ndiaye, Gagan Chhabra, Nihal Ahmad. Therapeutic efficacy of inhibition of specific sirtuins against melanoma in BrafV600E/PtenNULL and PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB018.