12th Congress of the European Hematology ... - Haematologica

12 th Congress of the European Hematology Association
median of 3 lines, range 2-6 (37% BMT and 40% Thalidomide).Treatment
was administered till disease progression, unacceptable toxicity or
complete response (CR), up to a maximum of 8 cycles. Results. 321 cycles
were administered; median 4 cycles (range 2-10). Dose reductions were
done in 18% of cycles, mainly due to neuropathic pain or peripheral neuropathy.
The most frequent grade 3-4 toxicity was thrombocytopenia
in 28% of patients. The most frequent grade 1-2 non-hematological toxicity
was neuropathic pain and peripheral neuropathy (in 25% of
patients) and asthenia in 17% of them. Response rate by treatment
branch are shown in Table 1. Median TtPD was 200 days in the group
of patients treated in third or subsequent lines of therapy, and was not
reached in the second line group. Conclusions. Treatment with bortezomib
and dexamethasone is hignly efficacious in patients with refractory
MM. Earlier treatment produced better results.
Table 1.
98 | haematologica/the hematology journal | 2007; 92(s1)
Myeloma and other monoclonal gammopathies -
Plasma cell biology
0269
IN VITRO AND IN VIVO ACTIVITY OF THE VEGF INHIBITOR PAZOPANIB IN MULTIPLE
MYELOMA
K. Podar, 1 G. Tonon, 1 M. Sattler, 1 Y.-T. Tai, 1 S. Le Gouill, 2 H. Yasui, 1
K. Ishitsuka, 1 S. Kumar, 3 R. Kumar, 4 L.N. Pandite, 4 T. Hideshima, 1
D. Chauhan, 1 K.C. Anderson1 1 Dana-Farber Cancer Institute, BOSTON, USA; 2 Hotel-Dieu Centre Hospitalier
University, NANTES, France; 3 Mayo Clinic, ROCHESTER, USA;
4 GlaxoSmithKline, RESEARCH TRIANGLE PARK, USA
Background. Vascular endothelial growth factor (VEGF) and its receptors
play an important role in the pathogenesis of multiple myeloma
(MM). VEGF present in the MM bone marrow microenvironment
induces neovascularization; triggers tumor cell growth, survival and
migration; inhibits dendritic cell maturation; and promotes osteoclastogenesis.
VEGF therefore provides a potential therapeutic target in MM.
Aims. To evaluate the therapeutic potential of the novel, potent VEGF
receptor inhibitor pazopanib in MM. Methods. Effects of pazopanib on
MM and endothelial cell growth, survival, and migration were evaluated
using western blot analysis, 3H-thymidine uptake, Boyden- modified
chamber, tubule formation assays, FACS analysis as well as microarray
analysis, RT- PCR, and specific cMyc knockdown by siRNA. in vivo
effects of pazopanib were evaluated using a MM xenograft mouse model.
Results. In vitro, pazopanib inhibits VEGF- triggered VEGF receptor
phosphorylation and activation of downstream signaling molecules
including Src kinase in MM cells and blocks MM cell migration, growth,
and survival. Moreover, gene expression and signaling network analysis
in pazopanib- treated cells demonstrate transcriptional changes of
several signaling pathways, including marked downregulation of cMyc.
siRNA targeting cMyc blocked VEGF production and secretion in MM
cell lines. In addition, pazopanib reduced VEGF in the microenvironment
and directly inhibited endothelial cell growth, migration, and vessel formation.
Furthermore, pazopanib inhibited VEGF- induced upregulation
of adhesion proteins on both endothelial and MM cells, thereby abrogating
endothelial cell -MM cell adhesion and associated tumor cell proliferation.
Pazopanib also strongly sensitized tumor cells bound to
endothelial cells to DNA- damaging chemotherapeutic agents (i.e. melphalan),
immunomodulatory drugs, and bortezomib. Similar activity of
pazopanib was demonstrated in vivo using a MM xenograft mouse model.
Ongoing studies evaluate effects of pazopanib on MM bone disease
and immune deficiency. Summary and Conclusions. In summary, this is the
first report showing anti- MM activity of an anti-VEGF compound in
both in vitro and in vivo, strongly supporting its clinical evaluation either
as a single agent or in combination with other therapies.
0270
IDENTIFICATION AND CHARACTERIZATION OF HLA CLASS I RESTRICTED T-CELL
EPITOPES IN THE PUTATIVE TUMOR ASSOCIATED ANTIGENS P21 ACTIVATED SERIN
KINASE 2 (PAK2) AND CYCLIN DEPENDENT KINASE INHIBITOR 1A (CDKN1A)
M. Witzens-Harig, G. Li, M. Hundemer, S. Wolfrum, A.D. Ho,
H. Goldschmidt
University of Heidelberg Hospital, HEIDELBERG, Germany
Multiple myeloma (MM) is one of the most common hematological
malignancies. Despite a variety of therapeutical approaches including
high dose cytostatic treatment with subsequent autologous or allogeneic
stem cell transplantation, as well as vaccination, cures remain rare
exceptions. An important issue for future immunological treatments is
the identification and characterization of appropriate tumor associated
antigens. However, the number of tumor associated antigens in MM is
limited. PBK/TOPK and activated serin kinase 2 (PAK2) are novel serin
kinases that have recently been identified. PBK/TOPK is overexpressed
in Burkitt Lymphoma, acute lymphoblastic leukemia and MM, PAK2 is
expressed on malignant lymphatic cells. The cyclin kinase inhibitor 1A
(CDKN1A) is overexpressed in MM compared to normal plasma cells.
We here identified and characterized for the first time HLA class I
restricted immunogenic peptides in the amino acid sequences of PAK2
and CDKN1A. Using two independent prediction algorithms we identified
2 peptides in PAK2 and 3 peptides in CDK1NA with high binding
to HLA-A2. Using an IFN-γ Elispot assay we could demonstrate the pres-