SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

V I R A L O N C O L O G Y P R O G R A M
prevention of tumor necrosis factor (TNF)-
induced cell death. Together these data suggest
that the cell death pathway in mammalian cells is
not likely to be a simple linear pathway as has
been suggested by C. elegans genetics. They are
currently using biochemical and genetic tools to
dissect this pathway and to determine the interplay
between the Bcl-2 family and the caspase
family. Additionally, from these studies researchers
have determined that many of the changes
that occur to mitochondria during apoptosis are
caspase dependent. These include loss of the mitochondrial
membrane potential. His laboratory
has determined that mitochondria must be inactivated
during apoptosis to prevent excessive production
of reactive oxygen species. They are
currently examining the mechanisms by which
caspases regulate mitochondrial function.
As a product of the laboratory’s studies of
bcl-x expression in drug resistant tumors, they
became interested in the study of arsenic trioxide
as a potential therapeutic agent in the treatment
of multiple myeloma. Dr. Boise and his colleagues
are studying the mechanism by which this agent
can kill chemo refractory myeloma cells as well
as determine the mechanisms of acquired arsenic
resistance in myeloma cell lines. These studies
have led to a new clinical trial initiated at
UM/Sylvester. They also will gather corollary
scientific information from patients on this trial.
SELECTED PUBLICATIONS
2002
Anderson, KC, Boise, LH, Louie, R, and
Waxman, S. Arsenic trioxide in multiple myeloma:
rationale and future directions. Cancer
Journal 8:12-25, 2002.
Bahlis, NJ, McCafferty-Grad, J, Jordan-
McMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,
Eckman, J, Goodman, M, Fernandez, HF, Boise,
LH, and Lee, KP. Feasibility and correlates of arsenic
trioxide combined with ascorbic acid-mediated
depletion of intracellular glutathione for the
treatment of relapsed/refractory multiple myeloma.
Clinical Cancer Research 8:3658-68,
2002.
2003
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,
Cabral, L, Barber, GN, and Harrington, WJ Jr.
Potentiation of TRAIL-induced apoptosis in primary
effusion lymphoma through
azidothymidine-mediated inhibition of NFkappa
B. Blood 101:2321-7, 2003.
McCafferty Grad, J, Bahlis, N, Aguilar, T, Kratt,
N, Lee, KP, and Boise, LH. Arsenic trioxide utilizes
caspase dependent and caspase independent
death pathways in multiple myeloma cells. Molecular
Cancer Therapeutics 2:1155-64, 2003.
Beaupre, DM, McCafferty Grad, J, Bahlis, NJ,
Boise, LH, and Lichtenheld, MG. Farnesyl transferase
inhibitors sensitize to death receptor signals
and induce apoptosis in multiple myeloma cells.
Leukemia & Lymphoma 44:2123-34, 2003.
BEATRIZ M.A. FONTOURA, PH.D.
Assistant Professor of Molecular and
Cellular Pharmacology
DESCRIPTION OF RESEARCH
Signal-mediated nuclear import and export of
molecules occurs through nuclear pore complexes
(NPC). These are highly regulated pathways
that control nuclear entry and exit of
molecules such as transcription factors, RNAs,
kinases, and viral particles. In general, to be imported
or exported from the nucleus, molecules:
1) bind to transport receptors, 2) are transported
through NPC present in the nuclear envelope,
and 3) translocate from NPC to intranuclear or
cytoplasmic target sites. Although progress has
been made regarding the composition and
mechanisms of the nuclear transport machinery,
less is known about the function and regulation
of major constituents of NPC. NPC are composed
of proteins termed nucleoporins or Nups,
which have a role in the structure of NPC and
also in regulating translocation of molecules
through NPC. Nups also are target of viral
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 137