Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
POSTER SESSION 3 – P3.01: BIOLOGY/PATHOLOGY
APOPTOSIS IN LUNG CANCER –
WEDNESDAY, DECEMBER 7, 2016
P3.01-064 THE OVEREXPRESSION AND CLEAVAGE OF SASH1 BY
CASPASE-3 STIMULATES CELL DEATH IN LUNG CANCER CELLS
Joshua Burgess 1 , Emma Bolderson 1 , Steven Gray 2 , Martin Barr 2 , Kathy Gately 3 ,
Shu-Dong Zhang 4 , Anne-Marie Baird 1 , Derek Richard 1 , Kenneth O’Byrne 1
1 Cancer Ageing and Research Program, Queensland University of Technology,
Brisbane/QLD/Australia, 2 Thoracic Oncology Research Group, Trinity College
Dublin/st. James’ Hospital, Dublin/Ireland, 3 Clinical Medicine, Trinity College
Dublin/st. James’ Hospital, Dublin/Ireland, 4 Queen’s University Belfast, Belfast/
United Kingdom
Background: SASH1 (SAM and SH3 domain-containing protein 1) is a
recently identified gene with tumour suppressor properties and has a
role in induction of apoptosis. Previous work has shown that 90 % of lung
cancer cell lines have a decrease in SASH1 mRNA levels (Zeller et al., 2003),
however little characterisation of SASH1 function in lung cancer has been
undertaken. Methods: We evaluated SASH1 expression in transformed
normal and malignant non-small cell lung cancer cell lines. We also utilised
cell based assays to study the effects of altered SASH1 levels on cell survival
and proliferation. Identification of a novel SASH1 targeting drug was
performed through connectivity mapping. Results: SASH1 protein expression
was down regulated in two of the five lung cancer cell lines compared to
immortalized normal bronchial epithelial cells. Prognoscan assessment
identified decreased SASH1 mRNA expression reduced patient survival.
The depletion of SASH1 in lung cells resulted in a significant increase in
cellular proliferation in cancer lung cells. Connectivity mapping predicted
the drug Chloropyramine would lead to an increase in SASH1 expression.
We demonstrated that Chloropyramine upregulates SASH1 in malignant
cell lines. In keeping with this we have demonstrated the Chloropyramine
inhibited lung cancer proliferation in vitro. We also explored the role of
SASH1 in apoptosis. Following ultraviolet light exposure SASH1 is cleaved
by Caspase-3. The C-terminal fragment of SASH1 then translocates from
the cytoplasm to the nucleus where it associates with chromatin. The
overexpression of wild type SASH1 or cleaved SASH1 amino acids 231-1247
leads to an increase in apoptosis, however loss of the SASH1 cleavage site and/
or nuclear translocation prevents this initiation of apoptosis. Mechanistically
SASH1 cleavage is required for the translocation of the transcription factor
NF-κB to the nucleus. The use of the NF-κB inhibitor DHMEQ demonstrated
that the effect of SASH1 on apoptosis was dependent on NF-κB, indicating
a co-dependence between SASH1 and NF-κB for this process. Conclusion:
We have shown that SASH1 contributes to apoptosis via a NF-κB-dependent
mechanism. Agents that upregulate SASH1, such as chloropyramine or SASH1
gene therapy, are potential novel approaches to the management of NSCLC in
the future.
Keywords: SASH1, Chloropyramine, lung cancer, apoptosis
POSTER SESSION 3 – P3.02a: ADVANCED NSCLC & CHEMO-
THERAPY/TARGETED THERAPY/IMMUNOTHERAPY
ALK –
WEDNESDAY, DECEMBER 7, 2016
P3.02A-001 RESPONSE AND PLASMA GENOTYPING FROM PHASE
I/II TRIAL OF ENSARTINIB (X-396) IN PATIENTS (PTS) WITH ALK+
NSCLC
Leora Horn 1 , Heather Wakelee 2 , Karen Reckamp 3 , George Blumenschein 4 ,
Jeffrey Infante 5 , Corey Carter 6 , Saiama Waqar 7 , Joel Neal 2 , Jon Gockerman 8 ,
Kimberly Harrow 9 , Gary Dukart 9 , Chris Liang 9 , James Gibbons 9 , Jennifer
Hernandez 10 , Tera Newman-Eerkes 10 , Lee Lim 11 , Christine Lovly 12
1 Vanderbilt University, Nashville/TN/United States of America, 2 Stanford Cancer
Institute, Stanford/United States of America, 3 City of Hope Comprehensive Cancer
Center, Duarte/CA/United States of America, 4 University of Texas MD Anderson
Cancer Center, Houston/TX/United States of America, 5 Sarah Cannon Research
Institute, Nashville/TN/United States of America, 6 Walter Reed National Military
Medical Center, Germantown/United States of America, 7 Internal Medicine/
Oncology, Washington University, St. Louis/United States of America, 8 Novella
Clinical, Morrisville/NC/United States of America, 9 Xcovery Holding Company, Llc,
Palm Beach Gardens/FL/United States of America, 10 Resolution Bio, Bellevue/WA/
United States of America, 11 Resolution Bio, Bellevue/United States of America,
12 Department of Medicine/division of Hematology-Oncology, Vanderbilt University
School of Medicine, Nashville/TN/United States of America
Background: Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase
(ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity
against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report data on the
ALK TKI-naïve and crizotinib (C)-resistant NSCLC pts treated with ensartinib.
Clinical trial information: NCT01625234 Methods: In this multicenter
expansion study, pts with ALK+ NSCLC were treated with ensartinib 225
mg daily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1,
and adequate organ function. Untreated brain metastases (CNS) and
leptomeningeal disease were allowed. Next Generation Sequencing (NGS)
was performed on plasma samples collected at baseline and on study and
compared with central tissue results (FISH/IHC). All pts were assessed for
response to therapy using RECIST 1.1 and for adverse events (AEs) using CTCAE
version 4.03. Results: 80 pts (51% female) have been enrolled. Median age 54
(20-79) years, 64% ECOG PS 1. Of 40 ALK+ NSCLC pts evaluable for response;
partial response (PR) was achieved in 23 pts (58%) and stable disease (SD) in
8 pts (20%). In the C-naïve pts (n = 8), PRs were observed in 7 pts (88%). In the
22 pts with prior C but no other ALK TKI, 14 pts (64%) achieved PR and 6 (27%)
SD. In the 10 pts who had received two or more prior ALK TKIs, there was 2 PR,
2 SD (40% DCR). CNS responses (50% PR) have been observed in both C-naïve
and C-resistant pts. Plasma and tissue genotyping were available on 27 pts
(26 ALK+ and 1 ALK-). ALK was detected in plasma in 16 pts, all of whom had a
response to therapy. 2 pts with PD were tissue +ve and plasma -ve. 9 plasma
samples were unevaluable. Serial sequencing demonstrated a decrease in
ALK in pts responding and an increase at the time of progression. The most
common drug-related AEs (≥ 20% of pts) included rash (53%), nausea (32%),
vomiting (26%), fatigue (23%), and pruritus (21%). Most AEs were Grade (G)
1-2. The G3 treatment-related AEs were rash (8 pts), fatigue (2 pts), pruritus
(2 pts), edema (2 pts), decreased appetite (1 pt), nausea (1pt), and vomiting
(1pt). Conclusion: Ensartinib is well-tolerated with response in both C-naïve
and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma
sequencing appears to be promising to select pts for therapy and monitor for
response and development of acquired resistance.
Keywords: Nextgen Sequencing, ALK, NSCLC
POSTER SESSION 3 – P3.02A: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
ALK –
WEDNESDAY, DECEMBER 7, 2016
P3.02A-002 PULMONARY SARCOMATOID CARCINOMA WITH
ALK REARRANGEMENT: FREQUENCY, CLINICAL-PATHOLOGIC
CHARACTERISTICS, AND RESPONSE TO ALK INHIBITOR
Xinru Chen 1 , Yu Zhang 2 , Jiabin Lu 3 , Chunwei Xu 4 , Jianzhong Liang 3 , Fang
Wang 3 , Wenyong Sun 5 , Jingping Yuan 6 , Sangao Fang 7 , Huijuan Wang 8 , Hui
Wang 9 , Xuewen Liu 9 , Likun Chen 10
1 Sun Yat-Sen University Cancer Center, Dongfeng Road East, Guangzhou
,guangdong, P. R. China/China, 2 Sun Yat-Sen University Cancer Center, Dongfeng
Road East, Guangzhou ,guangdong, P. R. China./China, 3 Sun Yat-Sen University
Cancer Center, Guangzhou/China, 4 Affiliated Hospital of Academy of Military
Medical Sciences, Beijing/China, 5 Zhejiang Cancer Hospital, Zhejiang/China,
6 Renmin Hospital of Wuhan University, Wuhan/China, 7 Daping Hospital and
Research Institute of Surgery, the Third Military Medical University, Chongqing/
China, 8 Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou/China,
9 Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School
of Medicine, Changsha/China, 10 Department of Medical Oncology, Sun Yat-Sen
University Cancer Center, Guangzhou/China
Background: Pulmonary sarcomatoid carcinoma (PSC) is a poorly
differentiated subtype of non-small cell lung cancer (NSCLC). Compared with
other subtypes of NSCLC, PSC has higher aggressive courses and far worse
survival. The incidence of anaplastic lymphoma kinase (ALK) rearrangement
is controversial, and clinical benefit from anti-ALK treatment in PSC remains
unknown.This study aimed to reveal the reliable frequency and the clinicalpathologic
characteristics of pulmonary sarcomatoid carcinoma (PSC) with
anaplastic lymphoma kinase (ALK) rearrangement, and to provide insight
into the translatability of anti-ALK treatment in this treatment-refractory
disease. Methods: Immunohistochemistry (IHC) staining using a Ventana anti-
ALK (D5F3) rabbit monoclonal antibody was performed in 141 PSC specimens
collected from multiple medical centers. IHC-positive cases were then
confirmed using ALK fluorescent in situ hybridization (FISH). The incidence
rates and clinical-pathologic characteristics of ALK-rearranged PSC were
then analyzed. Response to the ALK inhibitor crizotinib in a patient with ALKrearranged
PSC was evaluated according to the response evaluation criteria
for solid tumors (RECIST) version 1.1. Results: A total of 5 of 141 (3.5%) of PSCs
showed ALK rearrangement-positive by IHC and then were confirmed by FISH.
Two were carcinosarcomas and the other three were pulmonary pleomorphic
carcinoma (PPC). Strong positive ALK rearrangement was observed in both
the epithelioid and sarcomatoid components. ALK rearrangement was
mutually exclusive with mutations in EGFR and KRAS. The median age of
ALK-positive patients was younger than that of ALK-negative patients. PSCs
in never-smokers was more likely to harbor ALK rearrangement than those
in former or current smokers (P