Mdr Expression/Activity May Serve As Potential Biomarker In Developing Therapeutic Drugs For Aml Therapy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Multidrug resistance may play a critical role in developing cancer therapeutics for acute leukemia. The expression of the ATP binding cassette (ABC) transporter Pgp/MDR1 (also known as ABCB1) has been reported in AML patients and correlates with poor clinical outcome. Additional transporters like MRP1 and BCRP also appeared to contribute towards this resistance mechanism. We have profiled a panel of AML tumor cell lines and tumor xenografts for both expression and activity of Pgp/MDR1 via FACS and MSD;. Our profiling also includes analysis of the known SNPs associated with these transporters in key models. We have evaluated the sensitivity of the AML models to a series of standard of care therapies, including auristatins, in both in vitro and in vivo studies. These payloads alone or when conjugated to antibodies as antibody drug conjugates (ADCs) are known substrates of the ABC transporters, Using Pgp inhibitors, we could restore the sensitivity of the MDR expressing cells to the cytotoxic drugs and ADCs, which confirmed that the drugs were MDR substrates. These inhibitors could also block the activity of the Pgp pump. We have also observed limited activity in vivo with these ADCs when used in a MDR positive model. Our initial observation indicates that a threshold level of activity of MDR1 may be critical to confer resistance to these standard of care molecules and antibody drug conjugates using similar payloads. Currently, we are investigating the contribution of other efflux pumps in this mechanism of drug resistance MRP1 and BCRP, in similar manner. This can also aid in identifying cytotoxic drugs that are able to bypass the resistance mediated by these efflux pumps. Additional work is underway to characterize patient samples and identify MDR threshold level of activity as a potential predictive biomarker in developing AML therapeutics. Citation Format: Nandini Rudra-Ganguly, Christine Lowe, Mukta Shiwalkar, Claudia I. Guevara, Christopher Kemball, Min Michelle Wu, Cyrus Virata, Alla Verlinsky, Ssucheng J Hsu, Michael Mattie, William Yeh, Peng Yang, Sung-Ju Moon, Ingrid Joseph, David R. Stover, Daniel S. Pereira, Dowdy Jacksosn. MDR expression/ activity may serve as potential biomarker in developing therapeutic drugs for AML therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1976. doi:10.1158/1538-7445.AM2014-1976