CURRENT CLINICAL INTERESTS
Myeloproliferative
and myelodysplastic disorders; acute myeloid leukemia
CURRENT RESEARCH INTERESTS
Mechanisms
of leukemic disease progression and therapy resistance, new agents in
the treatment of chronic myeloid leukemia (CML) and acute myeloid
leukemia (AML)
RESEARCH
DESCRIPTION
The tyrosine kinase
inhibitor imatinib mesylate (Gleevec), and now the second generation
tyrosine kinase inhibitors dasatinib and nilotinib, have dramatically
altered treatment strategies in chronic myeloid leukemia (CML).
Outcomes for early (or chronic phase) disease are excellent.
However, a significant minority of chronic phase CML patients
and many advanced CML patients develop resistance to therapy.
In the laboratory we are examining mechanisms involved in CML disease progression and the effects
of tyrosine kinase inhibitor therapy on the underlying natural history
of CML disease. In the
clinic we are pursuing phase one studies of new agents in the
treatment of CML and AML.
CML
provides a unique disease model in which to apply a translational
approach. Using microarray-based
gene and microRNA expression studies of a large group of CML patients,
we have identified expression changes in patients that are highly
associated with disease progression and therapy resistance.
We are using these data to investigate several questions
including: can we identify
candidates that predict which patients are at risk for early therapy
failure or disease progression and can we determine how these genes
and their targets cause disease progression and therapy resistance?
To answer the first question we are investigating a group of
prognostic markers at diagnosis that can identify patients at
risk for early disease
progression or therapy failure.
Expression of these diagnostic markers is correlated with other
clinical and molecular markers such bcr-abl mRNA response and
the development of ABL tyrosine kinase domain point mutations (a
common mechanism of resistance). To answer the second question, the
most promising candidates derived from our patient-based studies are
examined in vitro and in vivo to better understand their possible
function in disease progression and therapy resistance, and to define
pathways that can be targeted by existing or novel therapies.
We believe the findings and methodologies utilized here can be
extended to the study, monitoring, and treatment of other cancers
SELECTED PUBLICATIONS
Oehler VG*, Yeung KY*, Choi E, Bumgarner RE,
Raftery AE, et al. The
derivation of diagnostic markers of chronic myeloid leukemia
progression from microarray data.
Blood. 2009;
prepublished online August 4, 2009.
PMID 9654405. *
These authors had equal participation in the work.
Oehler VG, Guthrie K, Cummings CL, Sabo K, Wood BL, et al.
Preferentially Expressed Antigen in Melanoma
(PRAME) inhibits myeloid differentiation in normal hematopoietic and
leukemic progenitor cells. Blood.
2009; prepublished online July 22, 2009. PMID 19625708.
Oehler VG, Qin J, Ramakrishnan R, Facer G, Ananthnarayan S,
et al. Absolute
quantitative detection of ABL tyrosine kinase domain point mutations
using a novel nanofluidic platform and mutation-specific PCR. Leukemia.
2009; 23:396-399.
PMID 18615105.
Oehler V and Radich JP.
Monitoring chronic myeloid leukemia in the age of tyrosine
kinase inhibitors. JNCCN. 2007;
5:497-504. PMID 17509253
Oehler V, Radich JP. Monitoring
of patients with chronic myeloid leukemia receiving Abl tyrosine
kinase inhibitor therapy. Clin
Lymphoma Myeloma. 2007;
Suppl 2: S58-63.
PMID 17382014.
Oehler VG, Gooley T, Snyder DS, Johnston L,
Lin A, Cummings CC, et al. The
effects of imatinib mesylate treatment before allogeneic
transplantation for chronic myeloid leukemia.
Blood. 2007; 109:1782-1789.
PMID 17062727.
Radich JP, Dai H, Mao M, Oehler
V, Schelter J, et al. Gene
expression changes associated with progression and response in chronic
myeloid leukemia. Proc Natl Acad Sci USA. 2006;
103:2794-2799. PMID
16477019.
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