**6. Conclusions and Future Directions**

In summary, this review accomplishes the aim of the study to investigate the effectiveness of quinazoline-based α1-adrenoceptor antagonists in the treatment of RCC by demonstrating the translational value of quinazoline-based α1-adrenoceptor-antagonists as anti-tumor-modalities with potential efficacy at all stages of the RCC patients' journey (neoadjuvant, adjuvant, salvage and metastatic). Retrospective epidemiological studies are underway to assess the impact of quinazoline-derived α1 adrenoceptor antagonists as chemopreventive agents, and prospective clinical trials designed to investigate their efficacy in pre-surgical, post-surgical, and in-patient settings of metastatic disease. There is high translational significance in the repurposing of the α1-adrenoceptor antagonists (FDA-approved drugs) to establish their therapeutic benefit as effective treatment modalities for patients with metastatic renal cell carcinoma (RCC). Our current research efforts pursue this drug repurposing at three levels: (a) the mechanistic level, by interrogating the functional exchanges between anoikis signaling and phenotypic EMT within the kidney TME to define novel mechanisms of action; (b) the translational level by directly examing precision combination therapies in pre-clinical models of RCC with and without VHL mutations; and (c). at the clinical setting by undertaking retrospective epidemiological studies to determine the impact of the use of quinazoline-derived α1 adrenoceptor antagonists as chemopreventive agents in RCC cancan also by prospective clinical trials designed to investigate their efficacy in pre-surgical, post-surgical, and in-patient settings of RCC patients with metastatic disease [54]. If such investigative efforts demonstrate clear efficacy, RCC patients with advanced disease can therapeutically benefit from their clinical use in the near future. With the international initiatives in place encouraging the use of repurposed drugs, the introduction of new, effective RCC treatment modalities based on α1-blockade can rapidly be integrated into clinical use and markedly improve oncological outcomes of RCC patients.

**Author Contributions:** Conceptualization, M.M., Z.D., K.K.B. and N.K.; methodology, M.M., Z.D., M.A., T.G.K.; software, M.A., K.E.O., W.N., H.F.; validation, M.M., A.R., N.M., and N.K.; formal analysis, M.M., Z.D., T.G.K., S.A.K., R.M., D.L., C.-K.T., K.K.B.; investigation, M.M., Z.D., K.E.O., R.M., K.K.B., N.K.; resources, S.A.K., C.-K.T., K.K.B., N.K.; data curation, Z.D., N.M., D.L., N.K.; writing—original draft preparation, M.M., Z.D., S.A.K., R.M., K.K.B., N.K.; writing—review and editing, M.M., Z.D., N.K.; visualization, M.M., M.A., T.G.K.; supervision, N.K.; project administration, K.K.B., N.K.; funding acquisition, N.K. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received support from an NIH/NCI R01 grant CA232574 (NK).

**Acknowledgments:** The authors wish to acknowledge the support of the Department of Urology and the Kidney Cancer Center of Excellence at the Icahn School of Medicine at Mount Sinai for the completion of this work.

**Conflicts of Interest:** The authors declare no conflict of interest.
