Re-purposing beta-blockers to improve chemotherapy response

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ABSTRACT Metastatic tumors often develop chemoresistance, which makes chemotherapy ineffective. We have exciting evidence that beta-blockers, which are widely used cardiac drugs, can be repurposed to improve the effects of chemotherapy. If we could understand how beta-blockers enhance the effects of chemotherapy, this would expedite the translation of beta-blockers for treatment of patients with metastatic cancer, who are at high risk for anxiety and depression and tend to have elevated levels of endogenous stress hormones including epinephrine. Here we will test the hypothesis that beta-blockers can improve access of chemotherapy drugs to the tumor by decreasing tumor density or stiffness to improve chemotherapy response. Our recent work shows that beta- blockers modulate the physical tension of tumor cells. Building on these findings, we will test if beta-blockers can be used to make tumors more porous to increase the delivery of chemotherapy drugs to tumor cells and enhance the response of tumor cells to chemotherapy agents, paclitaxel and doxorubicin. We will also determine how the effects of ?-blockers on tumor cell chemosensitivity are modulated by matrix stiffness through RhoA and ROCK. Beta-blockers are already well established for clinical use for heart disease, and are showing promising effects on tumor biology in prospective clinical trials, which provides strong rationale for continued biological analysis of the basic mechanisms involved to guide biomarker selection as this field advances toward Phase III clinical trials. Repurposing beta-blockers to enhance chemotherapy response could thus have patient-related outcomes on a short timescale of 5 years.