Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
sensitive in the long-term bisphosphonate treatment assays than non-KRAS
mutant cell lines. BRAF or EGFR mutations did not show a differential response
against these inhibitors. Conclusion: In vitro proliferation inhibitory efficacies
of hydrophilic and lipophilic bisphosphonates were not different in lung
adenocarcinoma cells. Nevertheless, due to the different bone accumulation
properties of zoledronic acid and lipophilic bisphosphonates further in vivo
preclinical studies are warranted to evaluate the inhibitory effect in a more
physiological setting.
Conclusion: This result suggests that mRNA concentration of AEG-1 from
liquid biopsy could be a predictive biomarker of tumor response. Increased
expression of AEG-1 contributed to the chemoresistance and caused lung
cancer progression.
Keywords: lung cancer, chemoresistance, AEG-1
POSTER SESSION 2 – P2.01: BIOLOGY/PATHOLOGY
TARGETS FOR TREATMENT PREDICTION –
TUESDAY, DECEMBER 6, 2016
P2.01-089 PREDICTIVE VALUE OF AEG-1 EXPRESSION ON TUMOR
RESPONSE BY LIQUID BIOPSY IN NSCLC PATIENTS TREATED WITH
CHEMOTHERAPY
Ying-Yin Chen 1 , Chung-Yu Chen 1 , Kuan-Yu Chen 2 , Chao-Chi Ho 2 , Jin-Yuan Shih 2 ,
Chong-Jen Yu 2 , Pan-Chyr Yang 2
1 National Taiwan University Hospital Yunlin Branch, Douliou/Taiwan, 2 National
Taiwan University Hospital, Taipei/Taiwan
Background: AEG1 is important in the aggressiveness of NSCLC and also
contributes to induce chemoresistance in treatment of NSCLC. In this study,
we will assess the predictive and prognostic values of AEG-1 expression on
tumor response and survival according to mRNA concentration by liquid
biopsy in NSCLC patients treated with chemotherapy. Methods: Patients
were diagnosed with a advanced NSCLC (stage IIIB and IV). Patients were
enrolled to be treated by chemotherapy as first-line treatment or for
metastatic or recurrent disease with Eastern Cooperative Oncology Group
(ECOG) performance status of 0–1. All patients underwent blood sampling
before any cancer treatment and at first response evaluation. Response to
chemotherapy was assessed using RECIST criteria. mRNA was extracted from
plasma samples using the QIAamp Circulating Nucleic Acid Kit (Qiagen,
Valencia, CA, USA) and quantification of mRNA was performed by real-time
PCR (ABI 7900) with SYBR GREEN reagent expression assay for AEG-1. Results:
A total of 12 patients (9 male and 3 female) with advanced NSCLC received
platinum based doublets chemotherapy. Chemotherapy regimens included 8
cisplatin and 4 carboplatin with 5 pemetrexed, 4 paclitaxel, 2 gemcitabine and
1 vinorelbine. 7 of 12 (58.3%) were adenocarcinoma. The initial response rate of
chemotherapy included 6 partial responses, 1 stable disease and 5 progressive
disease. The expression level of AEG-1 in patients with disease progression
after chemotherapy increased significantly compared with the expression
level at pre-chemotherapy (AEG-1, relative quantification of mRNA,
post-progression, range: 2.14 - 8.61, p = 0.035). In the group of patients with
responsive chemotherapy, the mRNA expression level of AEG-1 was not
increased compared to the baseline expression (Figure 1).
POSTER SESSION 2 – P2.01: BIOLOGY/PATHOLOGY
TARGETS FOR TREATMENT PREDICTION –
TUESDAY, DECEMBER 6, 2016
P2.01-090 PLATIN INDUCED PHOSPHORYLATION OF ATM AND ATM-
DEFICIENCY AS A PREDICTIVE MARKER OF PLATIN SENSITIVITY IN
NON-SMALL CELL LUNG CANCER
Jarrett Moore 1 , Lars Petersen 2 , Anifat Elegbede 3 , D. Gwyn Bebb 2
1 Oncology, Tom Baker Cancer Centre Translational Laboratories, University of
Calgary, Calgary/Canada, 2 Oncology, TBCC Translational Labs, University of
Calgary, Calgary/AB/Canada, 3 Oncology, TBCC Translational Labs, University of
Calgary, Calgary/Canada
Background: Platinum-based antineoplastic therapies (platins) are a first
line treatment for non-small cell lung cancer (NSCLC) that generate DNA
adducts leading to the formation of both single and double stranded DNA
breaks. Effective DNA damage response pathways contribute to cell survival
and resistance to these agents. Ataxia telangiectasia mutated (ATM) is an
important mediator of the DNA damage response involved in the activation
of key components of DNA repair, cell cycle arrest, and apoptosis. Our lab
has demonstrated that cell lines lacking ATM show increased sensitivity to
platins. We hypothesize that platin exposure will activate ATM and that cells
deficient in ATM will be innately sensitivity to platins due to an impaired DNA
damage response. Here we assess the molecular action of ATM in response
to platins to determine if ATM-deficiency is predictive of platin sensitivity.
Methods: ATM status was determined in five NSCLC cell lines using western
blotting and rt-qPCR. Cell lines were treated with varying concentrations
cisplatin, carboplatin and oxaliplatin for 18 hours and assessed for ATM
phosphorylation by western blot. Additionally, downstream targets of ATM
(KAP-1, p53, and g-H2AX) were investigated to determine ATM pathway
activation. Finally, transient and stable ATM knockdowns were generated
using siATM and shATM. These cells were then tested for platin sensitivity by
trypan blue viability or clonogenic assays. Results: NSCLC cell lines NCI-H226,
NCI-H460, and NCI-H522 were found to be ATM-proficient whereas cell lines
NCI-H23 and NCI-H1373 were found to be ATM-deficient. ATM-proficient cell
lines demonstrated an increased level of phosphorylated-ATM in response
to platins. In addition, KAP-1, a downstream target of ATM showed increased
phosphorylation in response to these treatments when compared to nontreated
controls. In contrast, ATM-deficient cell lines showed no increased
levels of phosphorylated ATM or KAP-1 in response to platins. Preliminary
analysis of siATM transient knockdowns in NCI-H226 shows an increased
sensitivity to cisplatin. Conclusion: It is clear that platin exposure activated
an ATM mediated signalling response and that cells lacking ATM showed
deficiencies in the phosphorylation of key downstream targets of this
pathway. Cells deficient in ATM may therefore be more susceptible to platin
therapy due to an impaired DNA damage response. This data suggests that
individuals with low or non-functioning ATM may be candidates for precision
low does therapies that exploit this deficiency.
Keywords: personalized medicine, DNA damage response, chemotherapy,
Ataxia telangiectasia mutated
POSTER SESSION 2 – P2.01: BIOLOGY/PATHOLOGY
TARGETS FOR TREATMENT PREDICTION –
TUESDAY, DECEMBER 6, 2016
P2.01-091 THE ANTICANCER EFFECT OF TECHOIC ACIDS ON LEWIS
LUNG CARCINOMA MODEL
Viktoriia Nikulina, Liudmyla Garmanchuk, Tetiana Nikolaienko, Natalia
Senchylo
Institute of Biology, Taras Shevchenko National University of Kyiv, Kyiv/Ukraine
Background: Ligands of Toll-like receptors (TLR) are often used as adjuvants
in order to enhance the immunogenicity of vaccines in therapy of lung cancer.
Such ligands are cell wall biopolymers of gram-positive microorganisms
Staphylococcus aureus – techoic acids (TAs). They play a significant role
as immunomodulators. Nowadays, agents which, in addition to specific
effect on cellular and molecular targets of tumor growth and ischemia,
posses the ability to inhibit angiogenesis, are attractive for therapeutic
angiogenesis-dependent correction of pathological states, which has
vascular-dependent outcome. Methods: In order to determine possible
S440 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017