Repositioning Antimalarial Drug Quinacrine to Enhance Carboplatin Sensitivity in Ovarian Cancer
Abstract
Rationale and Objectives: Despite the enormous resources being invested in cancer prevention and treatment, new drug development has lagged behind. The reason for this is that drug development requires an average of 13-15 years of research and investment of $1.8 billion to bring a single drug from bench to bedside. The high rate of failure to bring experimental drugs from bench to bedside has compelled the need for alternative efforts in drug development. One of the approaches in drug development is to find new uses of existing non-cancer drugs and use them for cancer treatment. This concept of repositioning or repurposing of non-cancer drugs to treat cancer provides an opportunity to rapidly advance therapeutic strategies into clinical trials. Other advantages to this approach of Food and Drug Administration-approved drugs is it costs less, it has less risk of failure due to its already established safety record, and has a much shorter time to progress from bench to bedside. Consequently, the National Institutes of Health recognized drug repositioning as a priority in drug development in 2011. We have been successful in adopting this "repositioning" approach to test the effect of the anti-diabetic drug metformin in ovarian cancer. Furthermore, based on our studies with metformin, the Ovarian SPORE (Specialized Program of Research Excellence) at the Mayo Clinic is poised to open a clinical trial with metformin in the near future. Building on this success, we decided to test the effect of other repurposing drugs and decided to test the effect of an antimalarial drug quinacrine (QC) on ovarian cancer cells. Why choose QC as a repurposing drug? Quinacrine was originally used as an anti-protozoal, antiparasitic, and antibacterial compound until penicillin was discovered in the 1940s. The interest in QC was revived during the Second World War when it replaced quinine as an antimalarial agent. QC was later replaced with chloroquine. But before this substitution, millions of military personnel took it as a prophylactic. Thus, it has a long history of safety record. My interest in choosing QC to test on ovarian cancer cells stems from the fact that it has shown antitumor effect both in tissue culture and animal studies in breast, colon, lung, head and neck cancers, but there are no reports in ovarian cancer. To date, Quinacrine (Atabrine?, Mepacrine, NSC14229) has been shown to have anti-cancer effects for androgen independent prostate cancer [ClinicalTrials.gov Identifier: NCT00417274]. The results showed that one patient had a partial response and 50% of the patients exhibited a decrease or stabilization in the rate of prostate cancer progression. QC (CBL0102) was well-tolerated with no serious adverse events. Phase1/2 clinical trials have also been initiated in combination with Erlotinib in patients with non-small cell lung cancer, hepatocellular carcinoma and colorectal adenocarcinomas [(http://www.cbiolabs.com/cbl0102 and ClinicalTrials.gov Identifier: NCT01844076 respectively]. More importantly, we postulated that because of the high rate of recurrence and chemotherapy resistance in ovarian cancer (OVCa), repurposed drugs that synergize with cis/carboplatin (Pt) and paclitaxel in recurrent tumors will have an enormous impact in prolonging the survival of OVCa patients. The relevance of repurposing QC for OVCa treatment: QC targets several signaling pathways simultaneously by affecting autophagy, apoptosis, p53, NFkB, heat shock response (HSF1), AKT, and methylation pathways, and alterations in all these key pathways are implicated in conferring chemoresistance in OVCa. To our knowledge, there are no in vitro and in vivo studies of QC against OVCa alone or in combination with standard therapy. Our preliminary data show that (1) QC enhances sensitivity to carboplatin (Pt) in chemoresistant cells, (2) irrespective of their p53 mutational status, QC induces autophagy in OVCa cells by upregulating the ea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510347
Entities
People
- Vijayalakshmi Shridhar
Organizations
- Mayo Clinic
- United States Army