A Pilot, Pharmacodynamic Correlate, Multi-Institutional Trial of Sirolimus in Combination With Chemotherapy (Mitoxantrone, Etoposide, Cytarabine) for the Treatment of High Risk, Acute Myelogenous Leukemia
Recent improvements in our understanding of leukemia biology have led to the introduction of
highly effective, molecularly targeted therapies. This is exemplified by the development of
BCR-ABL tyrosine kinase inhibitors such as imatinib as monotherapy for chronic myeloid
leukemia (CML) and in combination with chemotherapy for BCR-ABL+ acute lymphoblastic
leukemia (ALL). Imatinib mesylate blocks the protein made by the BCR-ABL oncogene.
The PI3K (phosphatidylinositol 3-kinases) signaling is critical to leukemia cell survival
and can be targeted. Growth and survival stimulating signal transduction pathways are
abnormally and universally activated in AML (Acute Myeloid Leukemia). This signal cascade is
thought to contribute to survival and growth in tumor cells via downstream effects upon
target proteins AKT/Protein kinase B and mammalian target of rapamycin (mTOR) a protein that
helps control several cell functions.
In AML, we and others have shown that PI3K signaling is constitutively activated in over 85%
of primary samples and that the small molecule PI3K inhibitor LY294002 is cytotoxic in vitro
to virtually all samples tested. As LY294002 is poorly suited for drug development, we have
concentrated upon other ways to inhibit signal transduction through this pathway. Mammalian
target of rapamycin (mTOR) emerged as a reasonable target due to the availability of
clinically available, highly specific inhibitors with favorable safety profiles. Mammalian
target of rapamycin (mTOR) plays a central but complex role in cancer cells' metabolic
regulation and survival. This serine/threonine kinase coordinates several important cellular
functions and its activity is modulated in response to amino acid, glucose, oxygen, and ATP
availability as well as extracellular growth factor ligation. Mammalian target of rapamycin
(mTOR) activity regulates protein translation, nutrient and amino acid uptake, mitochondrial
respiration, glycolysis, cell size regulation, cell cycle entry and progression, ribosome
biogenesis, and autophagy. Constitutive mammalian target of rapamycin (mTOR) activation is
commonly seen in cancer cells and is thought to promote survival in the setting of a wide
variety of cellular insults. Importantly, mTOR opening may cause chemotherapy resistance.
Although regulation of mTOR signaling in leukemia occurs through by several inputs, mTOR
activity in AML is thought to be primarily regulated by PI3K signaling through AKT via the
agent tumor suppressor tuberous sclerosis complex (TSC1& 2) and its target rheb GTPase.
Taken together, mammalian target of rapamycin mTOR is a smart target for molecularly
targeted therapy in AML due to its importance in the growth and survival of AML cells, its
necessity for AML cell survival in certain contexts, and its probable role in chemotherapy
resistance and relapse.
Interventional
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
mTOR Target Inhibition
To determine whether there is an association between the magnitude of mTOR target inhibition post-treatment in leukemic blasts and clinical response in patients with high risk AML treated with sirolimus MEC
1 year
No
Margaret Kasner, MD
Principal Investigator
Thomas Jefferson University
United States: Institutional Review Board
10D.21
NCT01184898
July 2010
September 2013
Name | Location |
---|---|
University of Pennsylvania | Philadelphia, Pennsylvania 19104 |
Thomas Jefferson University | Philadelphia, Pennsylvania 19107-6541 |