**5. The Repurposing of** α**1-Blockade in the Management of RCC**

Drug repurposing refers to the development of new applications and uses for existing drugs. The advantage of this method is that the drugs under investigation have already been "de-risked," have been approved by the FDA, have an established safety/toxicity profile and their subsequent development timelines and costs are significantly reduced. Historically, the concept of drug repurposing has been based on incidental discoveries, but a more formal approach has been proposed internationally to realize the potential in reusing currently available drugs. Emerging recommendations for integrative platforms of data analysis to systematically synthesize results from industry drug trials for more efficient discovery of new therapeutic uses and effects of novel compounds, advance combinatorial approaches for efficacy and treatment optimization. Drug repurposing has also been accelerated by the removal of patency and regulatory barriers that may prevent clinical use and the increasing funding opportunities for drug repurposing initiatives, particularly for less common diseases [54].

Quinazoline-based α1-adrenoceptor-antagonists represent an important category of drug repurposing, having already been FDA approved, with an established safety profile and extensively prescribed for the treatment of HTN and BPH for the last 30 years. Moreover, RCC patients, who have an average age at diagnosis of 65 years, commonly suffer from comorbidities including HTN and BPH (if male), notwithstanding the common association of HTN with RCC as a paraneoplastic syndrome secondary to renin and adrenocorticotropic hormone (ACTH) secretion, parenchymal or ureteral compression, and polycythaemia or an arterio-venous fistula. This would lend itself to the use of quinazoline-α1-adrenoceptor-antagonists as a logical choice in RCC patients with HTN for a potential bimodal treatment effect. Clinicians treating patients with RCC have a strong advantage to further explore such treatment and impact patient survival.

Analogous to the observational cohort study in prostate cancer discussed earlier, epidemiology studies retrospectively exploring the use of quinazoline-based α1-adrenoceptor-antagonists for the treatment of HTN or BPH for patients who were subsequently diagnosed with RCC would allow comparisons of cumulative incidence with populations of RCC patients who were unexposed, thus providing insight into the chemopreventive effects of the drug [17,46]. In a surgical setting, retrospective analyses of patient cohorts who underwent nephrectomy for renal masses with and without extensive exposure to α1-adrenoceptors for the treatment of HTN or BPH pre-operatively, as well as patients who continued α1 blockade for a period of time post-surgery, would allow an assessment of the efficacy of neoadjuvant or adjuvant quinazoline-based α1-adrenoceptor-antagonists

on long-term RCC oncological outcomes. Moreover, immunohistochemical profiling of renal tumors may establish a novel anoikis signature that could correlate with the effects of α1 blockade on clinical outcome and survival in patients with high-risk RCC, potentially contributing to risk stratification and treatment decisions. Finally, applying translational research to further investigate the mechanisms of quinazoline-induced anoikis in RCC and its influence on both the tumor microenvironment and EMT may reveal additional actions on alternative signaling pathways and guide the development of combination regimes with other emerging targeted therapies.
