Rapamycin and thalidomide treatment of a patient with refractory metastatic gastroesophageal adenocarcinoma: a case report.
- SourceAvailable from: Christina Hackl[show abstract] [hide abstract]
ABSTRACT: Inhibition of mTORC1 with the mTOR inhibitor rapamycin may lead to an induction of Akt phosphorylation in cancer cells via mTORC2 activation. Using gastric and pancreatic cancer cells, we further investigated this paradoxical signaling response and found that rapamycin additionally up-regulates both IGF-IR and Her2 expression. Using RNAi for down-regulating RICTOR, this induction of receptor kinase expression was identified to be mediated via an mTORC2-induced Akt activation. Moreover, mTORC2 inhibition reduced the phosphorylation of GSK-3 and NF-kappaB, and significantly impaired cancer cell motility. In conclusion, inhibition of mTORC2 may abrogate unfavorable signaling effects of mTOR inhibitors, hence providing a novel rationale for therapy.Biochimica et Biophysica Acta 04/2010; 1803(4):435-42. · 4.66 Impact Factor
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ABSTRACT: Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid-induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving I kappaB kinases beta (IKK beta), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKK beta inhibitor Bay 11-7082 suppressed bile acid-induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKK beta (pIKK beta) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKK beta expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKK beta signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus-associated EAC.Cancer Research 05/2008; 68(8):2632-40. · 8.65 Impact Factor
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ABSTRACT: Medical management of severe gastrointestinal bleeding can present a therapeutic challenge. We describe a case of bleeding secondary to gastric cancer that failed to settle, despite treatment with tranexamic acid, etamsylate and sucralfate. Thalidomide was prescribed for its antiangiogenic properties. Bleeding settled within 1 week of starting 300 mg of thalidomide nocte. The effect appeared to be dose dependent, with bleeding recurring only when the dose was reduced to 100 mg of thalidomide nocte.Palliative Medicine 04/2009; 23(5):473-5. · 2.61 Impact Factor
Rapamycin and Thalidomide Treatment of a Patient with Refractory
Metastatic Gastroesophageal Adenocarcinoma: A Case Report
SIN JEN ONG,aMARISSA TEO,bKIAT HON LIM,cSU PIN CHOO,aHAN CHONG TOHa,b
aDepartment of Medical Oncology andbLaboratory of Cell Therapy and Cancer Vaccine, National Cancer
Centre Singapore, Singapore;cDepartment of Pathology, Singapore General Hospital, Singapore
Key Words. Rapamycin • mTOR • Thalidomide • Gastroesophageal carcinoma
Disclosures: Sin Jen Ong: None; Marissa Teo: None; Kiat Hon Lim: None; Su Pin Choo: None; Han Chong Toh: None.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from
commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent
Aberrant activation of mammalian target of rapamycin
(mTOR) has been found in malignancies including gastric
cancer  and esophageal cancer . A high level of phos-
phorylated mTOR (p-mTOR) expression is associated with
a poor prognosis in gastric cancer patients. mTOR is a
serine/threonine protein kinase and regulates protein trans-
kinase ? (IKK?) results in deregulation of the tuberous
sclerosis complex 1 (TSC1)–mTOR pathway. Rapamycin
is a macrolide antibiotic derived from the fungus Strepto-
myces. In vitro studies have shown that it inhibits mTOR
cer growth and metastasis.
We report the use of rapamycin and thalidomide in a 43-
year-old Malay male with metastatic gastroesophageal car-
cinoma. In April 2005, he presented with dysphagia and
ageal adenocarcinoma. He declined surgery then and opted
for alternative therapy instead.
ing dysphagia, and symptomatic anemia secondary to a
larger gastroesophageal junction tumor. A computed to-
mography (CT) scan demonstrated new liver and left adre-
nal metastases. He was treated with argon plasma
coagulation, palliative radiotherapy, and chemotherapy
(capecitabine with oxaliplatin). He improved clinically
with resolution of dysphagia, increased appetite, and in-
creased weight. Six months later, the liver metastases had
increased in size. Capecitabine and docetaxel were initi-
ated but he tolerated the treatment poorly and declined
further chemotherapy. A trial of rapamycin was started at
2 mg/day in March 2009. By then, his cancer antigen
(CA) 19–9 level was 19,269 U/ml. This decreased to
16,216 U/ml 1 month later, and then thalidomide was
added at 50 mg/day (Fig. 1).
ble liver metastases with central necrosis. By August 2009,
his CA 19–9 level had dropped significantly by about 70%
to 6,176 U/ml and it had reached 3,855 U/ml by October
Correspondence: Sin Jen Ong, MBBS, MRCP, MMed (Int Med), Department of Medical Oncology, National Cancer Centre Singapore,
2010; accepted for publication July 13, 2010; first published online in The Oncologist Express on August 26, 2010. ©AlphaMed Press
1083-7159/2010/$30.00/0 doi: 10.1634/theoncologist.2010-0118
treatment well. His weight also increased by 4 kg. Both
rapamycin and thalidomide were continued at the same
doses and achieved good disease control before eventual
progression 7 months later.
Immunohistochemistry was performed retrospectively
on tissue taken before his treatment. This showed overex-
mTOR (Fig. 2), and vascular endothelial growth factor
receptor (VEGFR) (Fig. 3). Human epidermal growth fac-
tor receptor (HER)-2 staining was 2? but the fluorescence
in situ hybridization was negative.
Overexpression of mTOR presents a potential role for its
ageal cancer. Bile acid and a low pH environment were
found to activate IKK?, with subsequent phosphorylation
and suppression of TSC1. This then leads to activation of
the mTOR pathway in esophageal adenocarcinoma .
A retrospective review of 108 cases of esophageal can-
cer showed aberrant p-mTOR expression in 25% of speci-
mens. There was an association with a lesser degree of
Figure 2. Cytoplasmic stains of phosphorylated mammalian
target of rapamycin showing overexpression in 40% of adeno-
carcinoma cells (magnification, 20?).
Figure 1. Trend of tumor marker cancer antigen (CA) 19-9.
Abbreviation: od, once daily.
Rapamycin and Thalidomide in GEJ Adenocarcinoma
differentiation but not with tumor location, tumor–node–
metastasis stage, lymph node metastases, or expression of
al.  evaluated 1,072 cases of gastric cancer and found a
p-mTOR overexpression rate of 46.5%. This was associ-
ated with lymph node metastases, advanced-stage disease,
and a shorter median survival time at every stage. In fact,
strong expression of p-mTOR was reported in up to 64% of
diffuse-type and 60% of intestinal-type gastric cancers .
A phase II trial involving everolimus (an oral inhibitor
of mTOR) monotherapy in 53 patients with previously
treated metastatic gastric cancer showed a disease control
rate of 56% and median progression-free survival interval
of 2.7 months. The treatment was generally well tolerated
and the median overall survival time was 10.1 months .
Thalidomide is a known inhibitor of angiogenesis 
duced microvessel density in mice implanted with esopha-
geal cancer cells that expressed VEGF and/or basic
lean body mass and weight loss .
The combination of an antiangiogenic agent, bevaci-
zumab, and rapamycin was shown to reduce tumor growth
in mouse models of hepatocellular carcinoma more signif-
icantly than either bevacizumab or rapamycin alone .
Similarly, the combination of rapamycin and a thalidomide
showed much synergism. This combination overcame both
resistance to conventional chemotherapy in MM cell lines
and the protective effects on tumor cells by interleukin-6,
Given the evidence of potential synergy, an antiangio-
genic agent was considered, and thalidomide, rather than
bevacizumab, was chosen because of cost concerns. To our
knowledge, there are no known clinical benefits of thalido-
mide monotherapy in gastric cancer, aside from the appar-
ent dose-dependent effects on recurrent bleeding in one
case of gastric cancer .
Rapamycin is known to upregulate HER-2 expression
paradoxically via mTOR complex 2 activation ,
whereas trastuzumab, a monoclonal antibody against
patients . Treatment of mice bearing HER-2?mam-
mary tumors with both trastuzumab and rapamycin was
more effective than treatment with either alone . How-
ever, positive HER-2 expression was not detected in that
tric cancer series (unpublished data), a frequency lower
than in the ToGA trial.
In our patient, the tumor marker CA 19–9 responded
has continued so far. The beneficial effect may, however,
be confounded or consolidated by the later addition of tha-
lidomide. Scan evidence of disease progression was appar-
ent only after approximately 7 months of treatment.
Prior staining of biomarkers could have identified po-
tential responders to targeted agents and, in the future,
could permit better individualization of treatment.
The combination of rapamycin and thalidomide in our pa-
tient with metastatic gastroesophageal carcinoma demon-
strated disease stability associated with a significant tumor
marker response and improved clinical quality of life. This
suggests a potential for further evaluation of mTOR inhibi-
tion with an antiangiogenic agent in gastroesophageal car-
cinomas upon identification of the appropriate biomarkers.
Conception/Design: Han Chong Toh
Provision of study material or patients: Han Chong Toh
Data analysis and interpretation: Sin Jen Ong, Marissa Teo, Kiat Hon Lim
Manuscript writing: Sin Jen Ong, Su Pin Choo
Final approval of manuscript: Han Chong Toh
receptor showing overexpression in 60% of adenocarcinoma
cells (magnification, 20?).
Ong, Teo, Lim et al.
1Yu GZ, Wang JJ, Chen Y et al. Overexpression of phosphorylated mam-
malian target of rapamycin predicts lymph node metastasis and prognosis
of Chinese patients with gastric cancer. Clin Cancer Res 2009;15:1821–
2 Yen CJ, Izzo JG, Lee DF et al. Bile acid exposure up-regulates tuberous
sclerosis complex 1/mammalian target of rapamycin pathway in Barrett’s-
associated esophageal adenocarcinoma. Cancer Res 2008;68:2632–2640.
3 Boone J, Ten Kate FJW, Offerhaus GJA et al. mTOR in squamous cell car-
cinoma of the oesophagus: A potential target for molecular therapy? J Clin
4Lang SA, Gaumann A, Koehl GE et al. Mammalian target of rapamycin is
activated in human gastric cancer and serves as a target for therapy in an
experimental model. Int J Cancer 2007;120:1803–1810.
5 Doi T, Muro K, Boku N et al. Multicenter phase II study of everolimus in
patients with previously treated metastatic gastric cancer. J Clin Oncol
6 D’Amato RJ, Loughnan MS, Flynn E et al. Thalidomide is an inhibitor of
angiogenesis. Proc Natl Acad Sci U S A 1994;91:4082–4085.
7 Kotoh T, Dhar DK, Masunaga R et al. Antiangiogenic therapy of human
8Khan ZH, Simpson EJ, Cole AT et al. Oesophageal cancer and cachexia:
body mass. Aliment Pharmacol Ther 2003;17:677–682.
9 Huynh H, Chow PK, Palanisamy N et al. Bevacizumab and rapamycin in-
duce growth suppression in mouse models of hepatocellular carcinoma.
J Hepatol 2008;49:52–60.
10 Raje N, Kumar S, Hideshima T et al. Combination of the mTOR inhibitor
rapamycin and CC-5013 has synergistic activity in multiple myeloma.
11 Lambert K, Ward J. The use of thalidomide in the management of bleeding
from a gastric cancer. Palliat Med 2009;23:473–475.
12 Lang SA, Hackl C, Moser C et al. Implication of RICTOR in the mTOR
inhibitor-mediated induction of insulin-like growth factor-I receptor (IGF-
IR) and human epidermal growth factor receptor-2 (Her2) expression in
gastrointestinal cancer cells. Biochim Biophys Acta 2010;1803:435–442.
13 Van Cutsem E, Kang Y, Chung H et al. Efficacy results from the ToGA
trial: A phase III study of trastuzumab added to standard chemotherapy
(CT) in first-line human epidermal growth factor receptor 2 (HER2)-
positive advanced gastric cancer (GC). J Clin Oncol 2009;27(18 suppl):
mycin is required for optimal antitumor effect of HER2 inhibitors against
HER2-overexpressing cancer cells. Clin Cancer Res 2009;15:7266–7276.
Rapamycin and Thalidomide in GEJ Adenocarcinoma