Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

Autor: Kasner MT; Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Mick R; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Jeschke GR; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Carabasi M; Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Filicko-O'Hara J; Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Flomenberg N; Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Frey NV; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Hexner EO; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Luger SM; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Loren AW; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Mangan JK; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Wagner JL; Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Weiss M; Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Carroll M; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Perl AE; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. alexander.perl@uphs.upenn.edu.; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. alexander.perl@uphs.upenn.edu.
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2018 Aug; Vol. 36 (4), pp. 657-666. Date of Electronic Publication: 2018 Apr 02.
DOI: 10.1007/s10637-018-0585-x
Abstrakt: Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.
Databáze: MEDLINE
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