Anti-Angiogenesis Therapy in Pancreatic

Muhammad Wasif Saif
Yale University School of Medicine. New Haven, CT, USA
Pancreatic adenocarcinoma is a leading cause
of cancer death in the United States and
represents a challenging chemotherapeutic
problem. The treatment of advanced
pancreatic cancer with gemcitabine has only
modest activity with a small survival benefit,
and toxicity continues to be a major obstacle.
New therapeutic strategies that notably lack
cross resistance with established treatment
regimens are much needed in pancreatic
cancer. One such approach is the
pharmacological control of angiogenesis that
represents a novel approach to the
management of pancreas cancer, since the
pathological development of vascular supply
is a critical step for tumor growth and may
affect its prognosis. Since pancreatic
carcinoma show strong tumor neoangio-
genesis, overexpression of vascular
endothelial growth factor (VEGF), a key
mediator of angiogenesis, in pancreatic cancer
and consequently are highly vascularized, the
role of anti-angiogenic therapies is under
exploration at present. Hence, this review
covers the summary of the development of
anti-angiogenesis as anti-antitumor therapy in
pancreatic carcinoma, including matrix-
metalloproteinase inhibitors (MMPIs), such as
marimastat and BAY 12-9566, anti-VEGF
agent, bevacizumab (Avastin, Genentech,
South San Francisco, CA, USA), celecoxib (a
cyclooxygenase-2 inhibitor), thalidomide and
others. Role of markers of angiogenesis in
predicting response to therapy is also
Exocrine pancreatic carcinoma is now the
fifth leading cause of cancer in the United
States, Japan and Europe, with an overall 5-
year survival rate of less than 5% [1]. One of
the major causes of death is peritoneal
dissemination and liver metastasis [2]. Akin
to other solid tumors, pancreatic carcinoma
also depends on the development of an
adequate blood supply through angiogenesis
for growth at both primary and secondary
sites. The pivotal role of angiogenesis in
primary tumor growth and metastasis has
been recognized many years before. It is also
thought that new blood vessels in tumor are
highly permeable and provide a route for
cancer cells to enter the circulation [3].
Inhibition of neo-angiogenesis is a new and
attractive target for tumor therapy, since it
theoretically offers the hope of long-term
control of tumor progression. Antiangiogenic
therapy offers a number of potential benefits
including lack of resistance to some agents,
synergistic interaction to other modalities,
lack of significant toxicity compared with
conventional agents, and a potent antitumor
effect [4, 5, 6]. However, the anti-neoplastic
actions and side effects of angiogenesis
inhibitors and cytotoxic agents were clearly
different [4]. Administration of angiogenesis
inhibitors might keep the tumor and its
metastases dormant (rather than killing it),
and co-administration of cytotoxic drugs
might kill it [5, 6]. Many studies have been
conducted to evaluate the therapeutic effects

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of angiogenic inhibitors with in combination
with cytotoxic agents. Therefore, angio-
cytotoxic therapy has been gradually accepted
worldwide in recent years.
Recently, a number of new drugs have been
developed for treating patients with pancreatic
carcinoma. Early studies with gemcitabine
suggested a modest antitumor activity with
significant improvement in disease-related
symptoms [7]. Therefore, gemcitabine has
been generally considered to be the first-line
therapy for pancreatic cancer, and is now
widely used. The anti-neoplastic actions of
angiogenic inhibitors and cytotoxic agents are
clearly different. Treatment with antiangio-
genic agents could interact in a positive way
with a variety of anti-cancer therapies, and the
anti-metastatic and anti-tumor effects of
combination therapy were stronger than those
of angiogenic inhibitors alone and cytotoxic
agents alone. In the early era of anti-
angiogenic therapy, one focus of research in
pancreatic cancer was the use of matrix-
metalloproteinase inhibitors (MMPIs), such as
marimastat and BAY 12-9566, as an adjunct
to conventional chemotherapy. Most recently,
agents targeting against vascular endothelial
growth factor (VEGF) have been the focus of
The author reviews data on these agents:
I - matrix metalloproteinase inhibitors;
II - VEGF-signaling pathway in pancreatic
III - cyclooxygenase-2 and celecoxib in
pancreatic cancer;
IV - others, including thalidomide, mam-
malian target of rapamycin (mTOR) inhibitors
and epidermal growth factor receptor (EGFR)
I - Matrix Metalloproteinase Inhibitors
Matrix metalloproteinases (MMPs) are a
family of proteolytic enzymes that are
responsible for the breakdown of connective
tissue proteins. These enzymes play an
important role in normal processes of growth,
differentiation and repair. The activity of
MMPs is tightly regulated at several levels
including gene expression and inhibition by
tissue inhibitors known as tissue inhibitors of
metalloproteinases (MMPIs). There is now
considerable evidence however, that aberrant
MMP expression contributes to the invasive
growth and spread of a variety of solid
malignancies, including gastrointestinal
tumors [8]. MMP-2 (gelatinase A), MMP-9
(gelatinase B) [9], MMP-7 (matrilysin) [10]
and MMP-14 (MT1-MMP) [11] are over-
expressed in human gastric cancer. It is
therefore feasible that specific MMP
inhibitors might restore the normal balance of
proteolytic activity and thereby prevent
further tumor growth and metastasis.
Marimastat (BB-2516) is a broad spectrum,
low molecular weight MMP inhibitor with
inhibitory concentrations 50% (IC50s) against
purified enzymes in the low nanomolar range
[12]. The closely related inhibitor batimastat
(BB-94) has been shown to inhibit tumor
growth and spread in a range of cancer
models [13, 14] and marimastat has been
shown to inhibit tumor growth in a xenograft
model of human gastric cancer [15]. MMP
inhibitors have not been shown to cause
tumor regression in cancer model studies and
it was therefore proposed that these agents be
tested in the clinic as oncostatic treatments.
Based on these preclinical data, a randomized
study in pancreatic cancer compared
marimastat in combination with gemcitabine
to gemcitabine alone [16]. Two hundred and
thirty-nine patients with unresectable
pancreatic cancer were randomized to receive
gemcitabine (1,000 mg/m
) in combination
with either marimastat 10 mg bid or placebo.
There was no significant difference in
survival between gemcitabine and marimastat
and gemcitabine and placebo (P=0.95, log-
rank test). Median survival times were 165.5
and 164 days and 1-year survival was 18%
and 17%, respectively. There were no
significant differences in overall response
rates (11% and 16%, respectively),
progression-free survival (P=0.68, log-rank
test) or time to treatment failure (P=0.70, log-
rank test) between the treatment arms. Grade
3 or 4 musculoskeletal toxicities were
reported in only 4% of the marimastat treated

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patients, although 59% of marimastat treated
patients reported some musculoskeletal events.
The results of this study provided no evidence
to support a combination of marimastat with
gemcitabine in patients with advanced
pancreatic cancer [16]. The major criticism on
this study was about the dose of marimastat
selected, that might have been sub-optimal
(10 mg bid).
Another study randomized 414 patients with
unresectable pancreatic cancer to receive
marimastat 5, 10, or 25 mg bid or gemcitabine
1,000 mg/m
[17]. This study also did not
show any significant difference in survival
between 5, 10, or 25 mg of marimastat and
gemcitabine (P=0.19). Median survival times
were 111, 105, 125, and 167 days,
respectively, and 1-year survival rates were
14%, 14%, 20%, and 19%, respectively.
There was a significant difference in survival
rates between patients treated with
gemcitabine and marimastat 5 and 10 mg
(P<0.003). The results of this study provided
evidence of a dose response for marimastat in
patients with advanced pancreatic cancer. The
1-year survival rate for patients receiving
marimastat 25 mg was similar to that of
patients receiving gemcitabine [17].
The prior study [16] was designed and
commenced prior to analysis of the results of
the comparative study between gemcitabine
and marimastat [17]. In this study there was a
dose dependent effect of marimastat with the
dose of 25 mg bid comparing favorably with
gemcitabine in pancreatic cancer [17]. In the
prior study marimastat dosing was 10 mg bid
[16] and could be considered sub-optimal,
however even in sub-group analysis there was
very little indication of synergy between
marimastat and gemcitabine. In conclusion
the combination of gemcitabine and a MMPI
can be safely delivered to patients with
pancreatic cancer but there appears little
evidence to support further study of this
BAY 12-9566
BAY 12-9566 is a specific inhibitor of MMP-
2, MMP-3, MMP-9, and MMP-13 with Ki of
11, 134, 301, and 1,470 nmol/L, respectively
[18]. It also has antiangiogenic properties on
the basis of its ability to inhibit degradation
and invasion of the extracellular matrix by
endothelial cells, a process necessary for
tumor neovascularization [18]. Phase I studies
of BAY 12-9566 have demonstrated that
doses up to 1,600 mg/day given continuously
were well tolerated and gave serum
concentrations greater than 2 to 4 logs higher
than the Ki for MMP-2, MMP-3, and MMP-9.
Absorption was saturable at the higher doses
[19, 20, 21]. Patients on phase I studies have
shown stable diseases, and in few sustaining
greater than 1 year [19, 20, 21].
Therefore, a randomized Phase III study using
a dose of 800 mg bid was chosen from three
phase I studies [19, 20, 21], randomized
chemo-naïve patients with advanced
pancreatic adenocarcinoma to receive BAY
12-9566 800 mg orally bid continuously or
gemcitabine 1,000 mg/m
intravenously on days 1, 8, 15, 22, 29, 36, and
43 for the first 8 weeks, and then days 1, 8,
and 15 of each subsequent 28-day cycle [22].
Two-hundred and 77 patients were enrolled
onto the study: 138 in the BAY 12-9566 arm
and 139 in the gemcitabine arm. The median
survival for the BAY 12-9566 arm and the
gemcitabine arm was 3.74 months and 6.59
months, respectively (P<0.001; stratified log-
rank test). The median progression-free
survival for the BAY 12-9566 and
gemcitabine arms was 1.68 and 3.5 months,
respectively (P<0.001). Quality of life
analysis also favored gemcitabine. The results
of the study concluded that gemcitabine is
significantly superior to BAY 12-9566 in
advanced pancreatic cancer [22].
“When randomized trials failed to show
significant efficacy of MMPIs in this tumor
entity, anti-angiogenic approaches shifted
toward inhibition of the VEGF-signaling
II - VEGF-Signaling Pathway in Pancreatic
The VEGF-system is an attractive therapeutic
target in another gastrointestinal malignancy,
pancreatic cancer [23, 24, 25, 26].

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Both VEGF and VEGF-receptors are
overexpressed in pancreatic cancer;
VEGF promotes pancreatic cancer growth
via a paracrine and autocrine mechanism;
high VEGF - expression correlates with
poor prognosis in patients and animal models.
Seo Y et al. [24] investigated VEGF expres-
sion and microvessel density (MVD) in ductal
pancreatic adenocarcinoma and examined the
correlations among VEGF expression,
clinicopathologic factors, and clinical
outcome, especially the liver metastasis. One-
hundred and 42 paraffin embedded tumor
specimens of surgically resected pancreas
carcinoma were immunohistochemically
stained for VEGF and MVD. One-hundred
and 32 out of 142 (93%) ductal pancreatic
adenocarcinomas were positive for VEGF
protein by immunohistochemistry. A
significant correlation was observed between
VEGF positivity and MVD (P<0.0001).
Multivariate logistic regression analysis
indicated a significant association between
high VEGF expression and liver metastasis
(P=0.010) but no other factors, such as age,
tumor size, histologic type, lymph node
metastasis, venous invasion, neural invasion,
peritoneal metastasis, or local recurrence.
Patients with tumors that showed moderate or
high VEGF expression had significantly
shorter survival than patients with low VEGF
expression or none at all in their tumors
(P<0.05). These results indicated that VEGF
expression is closely correlated with MVD
and seems to be an important predictor for
both liver metastasis and poor prognosis in
ductal pancreatic adenocarcinoma [24].
Another study by Niedergethmann M et al.
[25] analyzed the correlation between VEGF
expression and MVD with early recurrence
and poor prognosis after curative resection,
since only curative resection for pancreatic
adenocarcinoma is related to a favorable
prognosis, but the overall survival after
surgery still remains poor, and early
recurrence is frequently observed. Seventy
patients with ductal adenocarcinoma of the
pancreas were studied after curative resection
with a follow-up of at least 2 years. The
VEGF immunoreactivity was 88.6%, and
positive mRNA signals were obtained in the
cytoplasm of carcinoma and endothelial cells
in 81.4%. Furthermore, we observed tumor-
associated macrophages close to infiltrating
carcinoma cells. All endothelial cells showed
positive immunoreactivity to the anti-CD34
antibody, and a median distribution of 85
vessels/200 field was observed. A significant
correlation (P<0.05) was found between the
MVD and the International Union Against
Cancer (UICC) stage. Statistical analysis
showed a significant correlation between
VEGF expression and the height of MVD
(P<0.05). Kaplan-Meier analyses revealed
that VEGF expression and MVD had a
statistically significant correlation with
survival after curative resection (P<0.05).
Furthermore, multivariate analysis indicated
that VEGF expression is an independent
prognostic marker for cancer recurrence
within 8 months after curative surgery
(P=0.003). In summary, the VEGF expression
and the height of MVD in pancreatic
adenocarcinoma are closely correlated, and
both - rather than UICC stage and TNM
classification (tumor size and nodal
involvement) - are markers of prognostic
relevance after curative resection.
Furthermore, VEGF is a predictor of early
recurrence after curative resection. The
current study indicates that VEGF may
promote the distribution of metastases,
leading to early cancer recurrence and poor
outcome [25].
Bevacizumab (Avastin, Genentech, South San
Francisco, CA, USA) is a recombinant
humanized anti-VEGF monoclonal antibody.
In a phase III randomized trial in patients with
advanced colorectal cancer, the addition of
bevacizumab to standard chemotherapy
resulted in a significant improvement in
response, survival, and progression-free
survival [27]. Inhibitors of VEGF suppress
the growth of pancreatic cancer in preclinical
models. In addition to inhibiting
neovascularization and lymphangiogenesis,

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bevacizumab has shown to decrease the
interstitial pressure in the tumor, increase the
delivery of chemotherapy, and by direct
effects on tumor (by decreasing chemotaxis)
mediated by the neuropilin-1 receptor [28, 29,
Bevacizumab with Gemcitabine
Based on these findings a phase II trial in 52
patients was initiated combining the
chemotherapy standard gemcitabine with
bevacizumab as first-line treatment in
metastatic (stage IV) pancreatic cancer [31].
In view of bleeding concerns patients that
showed obvious involvement of major intra-
abdominal blood vessels were excluded from
the trial. Patients with previously untreated
advanced pancreatic cancer received
gemcitabine 1,000 mg/m
intravenously over
30 minutes on days 1, 8, and 15 every 28 days.
Bevacizumab, 10 mg/kg, was administered
after gemcitabine on days 1 and 15. Tumor
measurements were assessed every two cycles.
Plasma VEGF levels were obtained
Fifty-two patients with metastatic disease
(83% had liver metastases) were enrolled on
to this study. Eleven patients (21%) had
confirmed partial responses, and 24 (46%)
had stable disease. The 6-month survival rate
was 77%. Median survival was 8.8 months;
median progression-free survival was 5.4
months. Pretreatment plasma VEGF levels
did not correlate with outcome. Grade 3 and 4
toxicities included hypertension in 19% of the
patients, thrombosis in 13%, visceral
perforation in 8%, and bleeding in 2%.
Pretreatment plasma VEGF levels did not
correlate with outcome.
The results of this study were comparable to
prior studies of gemcitabine doublets with
cytotoxics, such as gemcitabine plus cisplatin
or oxaliplatin [32, 33], and a potentially lethal
8% perforation rate justifies a more
differentiated assessment of toxicity. In the
pivotal phase III trial of bevacizumab in
colorectal cancer, Hurwitz et al. observed a
1.5% rate of perforation in the treatment
group and none in the placebo control [27].
The 8% rate of visceral perforation in this
study is significantly higher than that in the
colorectal study. Among these patients, one
patient developed a perforation after a colon
stent placement and another after severe
vomiting from a duodenal obstruction. It is
suggestive that it would be appropriate to hold
additional bevacizumab in these situations.
In addition, other toxicities of bevacizumab
includes thromboembolism and gastro-
intestinal bleeding. Patients who had venous
thromboses that required anticoagulation were
excluded from Kindler’s study. Grade 3 or 4
thrombosis occurred in 13% of patients. It is
quite possible that a selection bias by
excluding these patients, was introduced in
the study as cancer patients who have
experienced thromboembolism may have a
worse prognosis [34].
Gastrointestinal bleeding is another potential-
ly lethal complication of pancreatic cancer
especially when the pancreatic tumor invades
the duodenum, as well as a toxicity of
bevacizumab. Fatal bleeding occurred in a
patient, whose tumor eroded into his
duodenum while on bevacizumab, making it
impossible to ascertain whether bevacizumab
exacerbated the ultimately fatal bleeding in
this patient. However, it is recommended to
not to administer bevacizumab in a patient,
who has tumor invasion of an adjacent organ,
especially duodenum.
Because there have been no dose-finding
trials of bevacizumab in pancreatic cancer, the
optimal dose of this agent for this disease
remains unclear. A 10 mg/kg dose was used
in this trial [31]. In contrary, a randomized
phase II trial in colorectal cancer suggested
that a dose of 5 mg/kg every 14 days was
more effective than 10 mg/kg [35] and a
randomized phase III trial in similar patient
population confirmed the efficacy of the 5
mg/kg dose [27]. Another phase III study in
colorectal cancer that used a 10 mg/kg dose in
combination with oxaliplatin-based regimen
revealed significant activity and tolerable
toxicity [36]. In a randomized phase II trial in
non-small-cell lung cancer, a dose of 15
mg/kg every 21 days was found to be more
active than the 7.5 mg dose, associated with

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fewer episodes of significant bleeding at the
higher dose [37]. The efficacy and safety of
the 15 mg/kg bevacizumab dose in lung
cancer has been confirmed in a randomized
phase III trial [38]. However, it is reasonable
to speculate whether fewer toxicities or
alternate efficacy might have been observed
had Kindler et al. [31] arbitrarily chosen a
lower dose than the 10 mg/kg used in this trial,
this cannot be definitively ascertained without
additional study. A randomized phase III trial
of gemcitabine plus bevacizumab versus
gemcitabine plus placebo is ongoing in the
Cancer and Leukemia Group B (CALGB).
Bevacizumab with Radiation
Crane C et al. [39] has investigated
bevacizumab in a phase I study as component
of a multi-modality approach in combination
with capecitabine and radiation for locally
advanced pancreatic cancer. Forty-five
patients were included in the dose-finding
trial for bevacizumab concomitant to 50.4 Gy
radiation and capecitabine (final dose: 825
bid continuously Monday-Friday). The
addition of bevacizumab did not significantly
increase the acute toxicity of the
chemoradiation regimen. At the 5 mg/kg level
for bevacizumab 6 of 12 patients showed a
partial response, overall RR for the whole
study population was 19%. Radiation Therapy
Oncology Group (RTOG) is currently running
a phase II study to further evaluate this tri-
modality therapy in patients with locally
advanced pancreatic cancer. This study
excludes patients with duodenal involvement.
III - Cyclooxygenase-2 and Celecoxib in
Pancreatic Cancer
Overexpression of cyclooxygenase-2 (COX-
2) is detected in 75% of resected pancreatic
cancer and correlates with aggressive tumor
biology [40]. COX-2 promotes tumor growth
by up-regulating angiogenesis and
invasiveness, and inhibiting apoptosis [41].
Celecoxib, a COX-2 specific inhibitor, has
demonstrated anti-tumor activity against a
variety of human cancers in animal models,
including pancreatic cancer xenografts [42].
A phase II study evaluated the role of adding
celecoxib to gemcitabine in patients with
advanced pancreatic cancer [43]. Twenty-
eight patients with pancreatic cancer received
gemcitabine (650 mg/m
over a 65 min
infusion at days 1, 8, and 15 every 4 weeks)
and celecoxib (400 mg per os bid)
continuously. Based on the data presented at
the annual meeting of the American Society
of Clinical Oncology (ASCO), the Kaplan-
Meier median survival duration for 20
patients was 6.2 months, and 3-months
survival rate was 72%. Grade 3 or 4
thrombocytopenia and neutropenia developed
in two patients each. Clinically relevant
treatment related grade 3 or 4 non-
hematological toxicities include nausea or
vomiting, supraventricular arrhythmia,
dyspnea, pleural effusion, and hyponatremia.
Grade 3 or 4 gastrointestinal bleeding
occurred in one patient. In a pre-clinical study
using athymic mice injected with BxPC-3
cells, we also evaluated the efficacy of adding
celecoxib to capecitabine and radiotherapy. In
irradiated xenografts, capecitabine and
external radiation therapy showed synergistic
antitumor efficacy (P=0.008), which was
further improved with the addition of
celecoxib (P<0.001) [44]. Further evaluation
of this agent in pancreatic cancer is halted by
the cardiac toxicity affiliated with the agent
IV - Other Anti-Angiogenic Agents
Thalidomide was first introduced in the 1950s
as a sedative but was quickly removed from
the market after it was linked to cases of
severe birth defects. However, it has since
made a remarkable comeback for the U.S.
Food and Drug Administration (approved use
in the treatment of erythema nodosum
leprosum). Further, it has shown its
effectiveness in many malignancies, in
particular multiple myeloma, renal cell

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carcinoma, prostate cancer and hepatocellular
cancer [46]. Although the exact mechanism of
anti-angiogenesis caused by thalidomide is
not know, it was found in a study by Vacca et
al. that thalidomide markedly down-regulates
the genes in a dose-dependent fashion in
active multiple myeloma endothelial cells and
Kaposi sarcoma cell line [47]. Secretion of
vascular VEGF, basic fibroblast growth factor
(bFGF) and hepatocyte growth factor also
diminishes according to the dose in culture
conditioned media of active these cell lines.
Based on its anti-angiogenic activity, a Phase
I/II study evaluated the safety and efficacy of
the addition of thalidomide to celecoxib and
gemcitabine [48]. Twelve patients with
advanced pancreatic cancer received
gemcitabine (1,000 mg/m
) on days 1 and 8
every 21 days, celecoxib 400 mg per os bid
and thalidomide 200 mg per os one at night
time and titrating to 300 mg per os one at
night time if tolerated after one week.
Celecoxib and thalidomide were started 2
weeks prior to the first dose of gemcitabine
and continued throughout the treatment.
Among 12 patients, 5 achieved a partial
biochemical response and no radiographic
responses were noted. Mean survival of
patients from time of diagnosis was 10
months. Toxicities included 3 patients with a
skin rash and 1 patient with pulmonary
Moreover, thalidomide, which is an inhibitor
of tumor necrosis factor alpha (TNF-alpha)
synthesis [49]. Because proinflammatory
cytokines, especially TNF-alpha, play a
prominent role in the pathogenesis of cancer
cachexia., thalidomide represent a novel and
rational approach to the treatment of cancer
cachexia. To assess the safety and efficacy of
thalidomide in attenuating weight loss in
patients with cachexia secondary to advanced
pancreatic cancer, 50 patients with advanced
pancreatic cancer who had lost at least 10% of
their body weight were randomised to receive
thalidomide 200 mg once a day per os or
placebo for 24 weeks in a single centre,
double blind, randomized controlled trial [50].
Thirty-three patients (16 control, 17
thalidomide) were evaluated at 4 weeks, and
20 patients (8 control, 12 thalidomide) at 8
weeks. At 4 weeks, patients who received
thalidomide had gained on average 0.37 kg in
weight and 1.0 cm
in arm muscle mass
(AMA) compared with a loss of 2.21 kg
(absolute difference: -2.6 kg; 95% confidence
interval (CI): -4.3 to -0.8 kg; P=0.005) and
4.46 cm
(absolute difference: -5.6 cm
; 95%
CI: -8.9 to -2.2 cm
; P=0.002) in the placebo
group. At 8 weeks, patients in the thalidomide
group had lost 0.06 kg in weight and 0.5 cm
in AMA compared with a loss of 3.62 kg
(absolute difference: -3.57 kg; 95% CI: -6.8 to
-0.3 kg; P=0.034) and 8.4 cm
difference: -7.9 cm
; 95% CI: -14.0 to -1.8
; P=0.014) in the placebo group.
Improvement in physical functioning
correlated positively with weight gain (r=0.56,
P=0.001). This study revealed that
thalidomide was effective at attenuating loss
of weight and lean body mass in patients with
cachexia due to advanced pancreatic cancer.
Mammalian Target of Rapamycin (mTOR)
The mTOR is a serine/threonine kinase that
has been increasingly recognized as key to the
regulation of cell growth and proliferation.
mTOR either directly or indirectly regulates
translation initiation, actin organization,
tRNA synthesis, ribosome biogenesis, and
many other key cell maintenance functions,
including protein degradation and
transcription functions. Inhibition of mTOR
blocks traverse of the cell cycle from the G1
to S phase [51]. Preclinical data show
inhibition of tumor growth in a number of cell
lines and xenograft models. Clinical trials are
ongoing, including pancreatic cancer.
Epidermal Growth Factor Receptor (EGFR)
EGFR is a cell surface molecule that mediates
signal transduction from the cell surface to
cytoplasm. Elevated expression of EGFR or
its ligand correlates with worse prognosis in a
variety of human cancers, including
pancreatic cancer [52]. Therefore, blockade of

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