Download 2016 department of medicine research day

2016 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: Targeting the FGFR Pathway in Liposarcoma
Presenter: Arun Singh
Division: Hematology-Oncology
☒ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☐Other
Principal Investigator/Mentor: Arun Singh
Co-Investigators: Bartosz Chmielowski, Weiping Jia, Kareem
Clarke, Lee Anderson, Fritz C. Eilber , Richard Finn, Claudia Lebedinsky and Dennis J. Slamon
Thematic Poster Category:
Pharmacology and Drug Development
Abstract
Background: Liposarcomas are a rare group of neoplasms which can be locally controlled with
surgery and radiation therapy. However, for patients who relapse or present with metastatic disease,
efficacious systemic therapy options are an unmet need. The objective response rate to systemic
chemotherapy is only 12-15% and there are no approved drugs for this disease in the United States.
Searches for the molecular underpinnings of this disease have revealed the frequent amplification of
12q13-15 in liposarcomas. Two putative driving oncogenes, MDM2 and CDK4 are found in this
amplicon and have been the targeted, with the CDK4 inhibitor meeting its endpoint in a phase 2
trial.(1) Recently, two reports have elucidated that the follicular growth factor receptor [FGFR]
adaptor protein, FRS2, as another amplified gene found in the 12q13-15 amplicon.(2, 3) The signaling
network for the FGFR family is complex, but works primarily through the PI3Kinase and MAP Kinase
pathways, with FRS2 as a key modulator of FGFR signaling. It is plausible that targeting FGFR
signaling may be a valid therapeutic strategy.
Methods: High-resolution genome-wide oligonucleotide (aCGH) with matched gene expression
analyses was performed on an Agilent 105K oligonucleotide array on liposarcoma cell lines and
primary patient tissue in order to identify FGFR pathway alterations. We determined the IC50G of FGFR
inhibitors TKI258(Novartis) and BGJ(Novartis) across 50 human soft tissue and bone sarcoma cell
lines representing 5 main histologies by exposing the lines to six drug concentrations over a 6-day
incubation and using direct cell counts. These compounds were were assayed, alone and in
combination with inhibitors of the MAP Kinase pathway (MEK-162, Novartis) and PI3Kinase pathways
(BKM, Novartis) and synergy was determined by calculating cell growth inhibition. Single agent and
combination TKIs were assessed for their effects on the cell cycle and apoptosis. Optimization of
FGFR/PI3K or MAPK inhibitor combinations from the in vitro experiments will be corroborated for
efficacy in xenograft experiments. Ewing’s sarcoma lines were used as a control.
Results: We have found that FRS2 is amplified in primary liposarcoma samples, but not in lipomas.
We have screened 2 tyrosine kinase inhibitors that target FGFR, TKI258 and BGJ (Novartis), against a
panel of 50 sarcoma cell lines and have found that the liposarcoma samples were relatively more
sensitive to these drugs as compared to other bony and soft tissue sarcomas. BGJ, in combination
with MEK162 resulted in growth inhibition that was more potent than either drug alone. Apoptosis is
increased in liposarcoma lines treated with BGJ, and is augmented with the addition of MEK162.
Conclusions: FRS2 is amplified and activated in liposarcomas. This genetic lesion may be targeted
via inhibition with the FGFR inhibitor BGJ and this effect seems to be augmented by the addition of
MEK162. Ongoing studies are looking at combinging BGJ with mTOR inhibition and in vivo
combinations.
References:
1.
Dickson MA, et al. (2013) Phase II trial of the CDK4 inhibitor PD0332991 in patients with
advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. (Translated from
eng) J Clin Oncol 31(16):2024-2028 (in eng).
2.
Wang X, et al. (2011) High-resolution genomic mapping reveals consistent amplification of the
fibroblast growth factor receptor substrate 2 gene in well-differentiated and dedifferentiated
liposarcoma. (Translated from eng) Genes Chromosomes Cancer 50(11):849-858 (in eng).
3.
Zhang K, et al. (2013) Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in
high-grade liposarcoma. (Translated from eng) Cancer Res 73(4):1298-1307 (in eng).