Abstract P220: Reactivation of the tumor suppressor SPARC in bladder cancer by verteporfin

Abstract

Abstract Bladder cancer (BCa) is the most common malignancy of urinary system and is one of the top 10 cancers in terms of new cases and deaths in the United States. While most patients present with non-muscle invasive (NMI) that is treated with bladder preserving approaches, recurrence with a muscle invasive (MI) disease with occult or detectable metastases is frequently encountered with poor prognosis. Because of its protracted natural history, BCa is among the most expensive malignancies from diagnosis to death. Limited advances have been achieved in treatment of MI disease in the past 30 years with a few drugs approved as second line of therapy. This limitation is mainly because the current approaches of drug development do not represent the complex heterogeneous BCa ecosystem that influences tumor behavior, treatment response, and disease outcome. In this respect, we have identified SPARC is a potent tumor suppressor in BCa whose expression is downregulated/lost in the cancerous compartment in advanced stage disease. We reported that SPARC inhibits BCa through inhibition of the multistep cascade of carcinogenesis, tumor invasiveness and metastasis, with multifaceted inhibitory effect on BCa cells, and their interactions with stromal cells. To date the mechanism of downregulation of SPARC during the evolution of BCa is still unraveled. To overcome this knowledge gap, we developed a comprehensive approach to identify drugs that reactivate SPARC expression in BCa cell lines, and restore its tumor suppressor effect in the BCa ecosystem. We identified verteporfin (VP) as a potent inducer of SPARC expression in established BCa cells and confirmed that VP exerts its anti-cancer effect through reactivation of SPARC. Specifically, VP inhibited BCa cell proliferation, clonogenic survival as well as repopulation on normal urothelial cells, fibroblasts as well as bladder smooth muscle cells. In addition, VP inhibited invasiveness of BCa cell lines through primary bladder smooth cells. In vivo, VP inhibited growth of UMUC3 cell lines in xenografts in nude mice; an effect that was partially and significantly mitigated by knockdown of SPARC in UMUC3 cells. Mechanistically, we found that VP-induces SPARC expression in BCa cells through inhibition of the association of histone modifying enzymes KDM4A, and HDAC1 with SPARC promoter. KDM4A, and HDAC1 are upregulated in BCa patients’ tumors, and their nuclear expression inversely correlated with SPARC expression. Our data shine the light not only on novel mechanism of the anti-cancer effect of VP through reactivation of a BCa tumor suppressor “SPARC”, but also on novel mechanism of repression of “SPARC” by histone modifying enzymes KDM4A and HDAC1, as well as identification of KDM4A and HDAC1 as targets of VP. Citation Format: Neveen A. Said. Reactivation of the tumor suppressor SPARC in bladder cancer by verteporfin [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P220.