[249]
In Vivo Anti-Tumor Activity of Atiprimod
on SCID Models of Multiple Myeloma.
Session Type: Oral Session
Paola Neri, Pierfrancesco Tassone, Masood A. Shammas,
Ramesh B. Batchu, Simona Blotta, Sushma Samala, Laurence Catley,
Makoto Hamasaki, Teru Hideshima, Gary S. Jacob,
Donald H. Picker, Salvatore Venuta, Kenneth C. Anderson,
Nikhil C. Munshi Jerome Lipper Multiple Myeloma Center,
Dana Farber Cancer Institute, Boston, MA, USA;
VA Boston Healthcare System, Boston, MA, USA;
University Magna Graecia, Catanzaro, Italy;
Callisto Pharmaceuticals, Inc., New York, NY, USA
Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4.5]
decane-2-propanamine) is an orally bio-available cationic
amphiphilic agent previously studied for its
in vivo anti-inflammatory activity.
We previously demonstrated that Atiprimod, in a time-
and dose-dependent manner, inhibits myeloma cell growth
and survival in IL-6 independent (OPM1) as well as
dependent (INA-6) MM cell-lines with an IC50 in
the range of 0.5-2 µM.
We have now further characterized the molecular changes
in MM cells induced by Atiprimod, evaluating the gene
expression profile of INA-6 and OPM-1 cells exposed
to this drug.
Following 24 h treatment, Atiprimod induced significant
down-regulation of genes involved in growth and cell-cycle
control (CDC14, CDC2-like 5, Cyclin-E binding
protein 1 and MDM2), adhesion (ITGA-6, ITGA-X, ADAM-17, CDH-3,
CDH-6, CTNND-1, PECAM-1 and MADCAM-1) cell-signalling
pathways (PRKAB-1, Mapk-7, GPR-125 and GPR-32),
up-regulation of genes implicated in apoptotic
cascades (TNFAIP-3, TNFSF-10, TNFRSF-10c, CDKN2A and CDKN1A)
and in negative regulation of signal
transduction (RGS-4 and IGFBP-5).
We next evaluated the in vivo activity of Atiprimod
using three SCID mouse models of human MM: 1)
To evaluate effects of Atiprimod directly on MM cells,
we used SCID mice bearing subcutaneous OPM1 tumors and
treated i.p. with Atiprimod or vehicle alone (PBS) on
alternate days for 7 days.
In this model 31%, 48% and 55% inhibition of tumor growth were
observed in mice treated with Atiprimod at 20, 30 and 50 mg/kg,
respectively, compared to control group. 2)
To evaluate effects of Atiprimod on MM cells in the context of a
human BM microenvironment, we used SCID mice implanted with a
human fetal bone chip (SCID-hu) engrafted with IL-6-dependant
INA-6 cells and treated i.p. with Atiprimod (40 mg/kg) or
vehicle alone (PBS) for two weeks.
The response was evaluated by detection of serum soluble human
IL-6 receptor (shuIL-6R) released by MM cells in murine serum.
We observed a 60% reduction in shuIL-6R level in mice treated with
Atiprimod versus control group. 3)
Finally, to evaluate effects of Atiprimod on primary patient cells
in a human microenvironment, we used SCID-hu mice engrafted with
patient MM cells (IgG ?) and treated i.p. with
Atiprimod (50 mg/kg) or vehicle alone (PBS) for 4 weeks.
Treatment with Atiprimod induced a reduction in both human IgG
and ? light chain levels in mouse sera, whereas levels of both
proteins continued to rise in mice treated with vehicle alone.
Taken together these data demonstrate the in vivo anti-tumor activity
of Atiprimod and provide a rational for its clinical
evaluation in MM.
Based on these data the drug is presently in a multi-site
Phase I/IIa clinical trial in patients with relapsed or
refractory multiple myeloma (MM).
Abstract #249 appears in Blood, Volume 106, issue 11, November 16, 2005
Keywords: Myeloma|SCID mice|Therapy
Monday, December 12, 2005 8:00 AM
Simultaneous Session: Multiple Myeloma: Novel Therapy
(7:30 AM-9:00 AM) |
