Abstract 4580: Personalized treatment selection for therapy-resistant AML by integrating ex-vivo drug sensitivity and resistance testing (DSRT) as well as serial genomic, transcriptomic and phosphoproteomic profiling

Abstract

Abstract Samples from recurrent, treatment-refractory cancers are rarely available, but would be valuable in understanding the molecular drivers of drug resistance. In leukemias, consecutive samples are readily available during treatment. Hence, we explored here the progression of adult acute myeloid leukemias (AML) by serial sampling and by integrating data from multiple platforms. Next-generation exome and RNA sequencing, and phosphoproteomic data were combined with comprehensive 240 cancer drug sensitivity and resistance testing (DSRT) of leukemic blasts ex-vivo before and after clinical relapse. The data were generated in an experimental diagnostic setting, with intent to improve and personalize treatment of patients with recurrent AML. A 54-year old AML-M5 patient with a FLT-3-ITD mutation and a normal karyotype was monitored by serial sampling. The patient was initially refractory to three consecutive high-dose induction treatments and had limited therapy options. AML blasts from the patient were screened with the DSRT platform. Results implied that the blast cells were 710-times more sensitive to temsirolimus and other rapamycin analogs as compared to normal BM cells, and showed a 1100-fold increased sensitivity to dasatinib. Proteomic analysis showed high phosphorylation of several signaling molecules, such as the insulin receptor and mTOR. Sequencing identified WT1 mutations and a NUP98-NSD1 fusion transcript, an infrequent event associated with poor prognosis in AML. Based on the DSRT results, the patient received compassionate off-label treatment with dasatinib, sunitinib and temsirolimus, resulting in a remarkable clinical remission, normalization of blast counts and a rapid recovery of neutrophil counts as a sign of selective elimination of the leukemic cells. The patient relapsed 4 weeks later, and at this point a new DSRT assay was performed, which showed the blast cells to be completely resistant to temsirolimus and less sensitive to dasatinib ex vivo. Consistent with this drug sensitivity profile was a genomic evolution of a distinct AML subclone with new changes, such as NF1 mutation and a microdeletion of the LEF1 gene, which were not observed in the pre-treatment sample. Taken together, we have demonstrated, how molecular profiling and functional ex vivo drug sensitivity and resistance data can be used to individually optimize patient treatment. Remission was achieved in a patient with advanced, treatment-refractory AML. Serial sampling from human AML patients coupled with molecular profiling and drug sensitivity testing may shed light on clonal progression of disease, and the molecular events underlying drug response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4580. doi:1538-7445.AM2012-4580