Abstract 7302: Effect of estrogen receptor modulator bazedoxifene on progression of carcinogen induced bladder cancer in female F344 rats
Authors: Madka Venkateshwar , Pathuri Gopal , Singh Surya P. , Chiliveru Srikanth , Singh Anil , Bao Anh , Stratton Nicole , Grubbs Clinton J. , Sei Shizuko , Clifford John , Cholewa Brian , Rao Chinthalapally V. 
Published: March 2024

Bladder Cancer (BC) is the second most common genitourinary cancer with high recurrence and mortality rate due to metastatic muscle invasive BC (MIBC). An estimated 82,290 adults in the United States will be diagnosed with BC and one-fifth of the patients will die with this cancer in 2023. Sex disparity of BC is well known with 4 times higher risk in men, but women are more likely to die from it than men. Studies suggest that estrogen receptor (ER)-α and ER-β are over expressed in 18% and 63% of bladder tumors and associated with highly proliferative tumors and reduced overall survival. Hence, ER signaling is considered an important target for intercepting BC. Since the majority of BCs are non-invasive at diagnosis, developing agents that block BC progression may be beneficial for clinical translation. Bazedoxifene (BAZ), a clinically approved second generation SERM, is a co-repressor for both the ER-α and ER-β receptors, and it is a competitive inhibitor of 17-β-estradiol. In this study, BAZ was tested for toxicity and efficacy in an N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced BC rat model. Female F344 rats are administered carcinogen BBN (150mg x twice a week) for 8 weeks to induce BC. For toxicity evaluation, 5 doses of BAZ were fed (2.5 ppm to 12.5 ppm in diet) to BBN treated rats (n=6) for 10 weeks. After termination, serum, various organs, and bladder tissues were evaluated for toxicity biomarkers and histopathology. For efficacy study, Female F344 rats (8 weeks of age) were (n=24) administered BBN as stated above. A week later, rats received either control or BAZ (5 ppm and 10 ppm) containing diets for 33 weeks and terminated. Bladders and other major organs were analyzed grossly for size, weight, and visible abnormalities including tumors. Formalin fixed tumor sections were stained and histopathologically graded. Results showed that BBN-exposed rat bladders were significantly larger and heavier due to tumors (0.77±0.10g, Mean±SEM; p&lt;0.0001) as compared to vehicle treated rats’ normal bladders (0.09±0.02g). Bladder tumor histopathology showed transitional cell carcinoma (TCC) and squamous cell carcinomas (SCC) with non-MIBC (NMIBC) and MIBC tumor grades in the vehicle control group. There was no significant difference in bladder weights between the 5 ppm and 10 ppm BAZ-treated vs. control group (p&gt;0.05). However, histopathological evaluation showed ~20% (p&gt;0.05) reduction in papilloma and NMIBC in the treated rats. Importantly, BAZ 5 ppm and 10 ppm treated rats had significantly less MIBC in a dose dependent manner (50%-70% less respectively; p&lt;0.001) compared to control rats. In summary, our study demonstrates chemopreventive efficacy of bazedoxifene in interception of in BBN-induced rat bladder MIBC and warrants further investigation alone and in combination with complementary pathway targeting agents (Supported by NCI-PREVENT program 75N91019D00020-75N91020F00005).

Citation Format: Venkateshwar Madka, Gopal Pathuri, Surya P. Singh, Srikanth Chiliveru, Anil Singh, Anh Bao, Nicole Stratton, Clinton J. Grubbs, Shizuko Sei, John Clifford, Brian Cholewa, Chinthalapally V. Rao. Effect of estrogen receptor modulator bazedoxifene on progression of carcinogen induced bladder cancer in female F344 rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7302.