The goal of this proposal is to establish pre-clinical evidence of synergism between glucocorticoids such as dexamethasone (Dex) and the MEK inhibitors such as PD184352 in the induction of apoptosis in acute lymphoblastic leukemia (ALL) cells. Glucocorticoids (GC) represent common components of many chemotherapeutic regimens for lymphoid malignancies including ALL. GC-induced apoptosis involves the intrinsic mitochondria-dependent pathway, but the signaling pathways and downstream target molecules involved in GC-induced cell death are not entirely clear. We and others have previously shown that BIM (BCL- 2 Interacting Mediator of cell death), a pro-apoptotic BCL-2 family protein, is up-regulated by Dex treatment in ALL cells and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation by survival/growth factors. We therefore hypothesize that co-treatment with Dex and MEK/ERK inhibitors will promote apoptosis in ALL cells through BIM up-regulation and activation, resulting in cell death. Significantly, preliminary data from our laboratory demonstrate that MEK inhibitors synergistically promote DEX lethality in a variety of ALL cell lines. We now propose to elucidate the mechanisms by which MEK/ERK inhibition enhances the activity of BIM and perturbs other pro- and anti-apoptotic BCL-2 family members to enhance Dex efficacy in ALL cells.
The specific aims are to 1) evaluate the significance of BIM-dependent/-independent pathways and the BIM phosphorylation status in apoptosis with Dex and MEK inhibitors co-treatment;2) determine the molecular mechanisms how BIM is induced by dexamethasone treatment;3) employ in vivo murine models of ALL to establish a basis for the efficacy of the strategy. The main concept is that we have a novel and potentially effective way to increase GC activity against leukemia cells, which may reflect the fact that a) GCs up-regulate BIM;and b) pharmacologic MEK inhibitors further potentiate BIM activation by blocking BIM phosphorylation and degradation. Information derived from this proposal will provide a rational foundation for future attempts to improve the activity of glucocorticoids such as dexamethasone with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies.

Public Health Relevance

The main concept is that we have a novel and potentially effective way to increase glucocorticoids (GC) activity against acute lymphoblastic leukemia (ALL) cells, which may reflect the fact that a) GC up-regulate a pro-death molecule, BIM;and b) pharmacologic MEK/ERK inhibitors further potentiate BIM activation. In this proposal, we will establish the mechanistic evidence how MEK/ERK-BIM pathway involves the synergistic interaction of dexamethasone (Dex) and MEK/ERK inhibitors. Information derived from this proposal will provide a rational foundation for future attempts to improve the activity of glucocorticoids such as Dex with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134473-04
Application #
8278032
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Duglas-Tabor, Yvonne
Project Start
2009-07-17
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$237,412
Indirect Cost
$78,607
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Nakajima, W; Hicks, M A; Tanaka, N et al. (2014) Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer. Cell Death Dis 5:e1052
Miller, Anna V; Hicks, Mark A; Nakajima, Wataru et al. (2013) Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor. PLoS One 8:e60685