Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer.

Renal cancer ranks twelfth in incidence among cancers worldwide. Despite improving outcomes due to better therapeutic options and strategies, prognosis for those with metastatic disease remains poor. Current systemic therapeutic approaches include inhibiting pathways of angiogenesis, immune checkpoint blockade, and mTOR inhibition, but inevitably resistance develops for those with metastatic disease, and novel treatment strategies are urgently needed. Emerging molecular and epidemiological evidence suggests that quinazoline-based alpha 1-adrenoceptor-antagonists may have both chemopreventive and direct therapeutic actions in the treatment of urological cancers, including renal cancer. In human renal cancer cell models, quinazoline-based alpha 1-adrenoceptor antagonists were shown to significantly reduce the invasion and metastatic potential of renal tumors by targeting focal adhesion survival signaling to induce anoikis. Mechanistically these drugs overcome anoikis resistance in tumor cells by targeting cell survival regulators AKT and FAK, disrupting integrin adhesion (alpha 5 beta 1 and alpha 2 beta 1) and engaging extracellular matrix (ECM)-associated tumor suppressors. In this review, we discuss the current evidence for the use of quinazoline-based alpha 1-adrenoceptor antagonists as novel therapies for renal cell carcinoma (RCC) and highlight their potential therapeutic action through overcoming anoikis resistance of tumor epithelial and endothelial cells in metastatic RCC. These findings provide a platform for future studies that will retrospectively and prospectively test repurposing of quinazoline-based alpha 1-adrenoceptor-antagonists for the treatment of advanced RCC and the prevention of metastasis in neoadjuvant, adjuvant, salvage and metastatic settings.