A Pilot Phase II Study of Valproic Acid for Treatment of Low-Grade
TABRAIZ A. MOHAMMED,a,dKYLE D. HOLEN,b,dRENATA JASKULA-SZTUL,cDANIEL MULKERIN,b,d
SAM J. LUBNER,b,dWILLIAM R. SCHELMAN,b, dJENS EICKHOFF,eHERBERT CHEN,b,c
NOELLE K. LOCONTEb,d
aUniversity of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA;bUniversity of Wisconsin Carbone
Cancer Center, Madison, Wisconsin, USA; Departments ofcSurgery,dMedicine, andeBiostatistics and
Medical Informatics, University of Wisconsin, Madison, Wisconsin, USA
Key Words. Neuroendocrine tumors • Valproic acid • Histone deacetylase inhibitor • Pancreatic carcinoid • Notch signaling
Disclosures: Tabraiz A. Mohammed: None; Kyle D. Holen: Employment/leadership position: Abbott Laboratories; Ownership
interest: Abbott Laboratories; Renata Jaskula-Sztul: None; Daniel Mulkerin: None; Sam J. Lubner: None; William R.
Schelman: None; Jens Eickhoff: None; Herbert Chen: None; Noelle K. LoConte: 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 independent peer
Introduction. Notch1 has been shown to be a tumor sup-
pressor in neuroendocrine tumors (NETs). Previous in
vitro studies in NET cell lines have also suggested that
induce Notch1 and that Notch1 activation correlates
with a decrease in tumor markers for NETs. Thus, this
study aimed to evaluate the role of VPA in treating
signaling pathway signaling in vivo.
Patients and Methods. Eight patients with low-grade
goal VPA level between 50 and 100 ?g/mL. All patients
were followed for 12 months or until disease progression.
Results. Notch1 signaling was absent in all tumors
prior to treatment and was upregulated with VPA. One
patient had an unconfirmed partial response and was
Four patients had stable disease as best response. Tu-
mor markers improved in 5 out of 7 patients. Overall,
treatment with VPA was well tolerated.
Conclusion. VPA activates Notch1 signaling in vivo
and may have a role in treating low-grade NETs. The
Neuroendocrine tumors (NETs) include a range of rare and
NETs include low-grade, indolent tumors like carcinoid tu-
mors, gastroenteropancreatic endocrine tumors, medullary
carcinomas of the thyroid, and high-grade, aggressive tu-
mors like catecholamine secreting tumors, Merkel cell car-
cinoma, and other rare tumors [1, 2]. These tumors are
Correspondence: Tabraiz Mohammed, D.O., M.S., University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison,
Wisconsin 53792, USA. Telephone 608-262-2122; e-mail: firstname.lastname@example.org or Noelle K. LoConte, M.D., K4/548 CSC, 600
Highland Avenue, Madison Wisconsin 53792, USA. Telephone 608-263-5883.
April 7, 2011; first published online in The Oncologist Express on May 31, 2011. ©AlphaMed Press 1083-7159/2011/$30.00/0 doi:
Received February 1, 2011; accepted for publication
characterized histologically by the presence of neurosecre-
tory granules. The tumors react positively to silver stains
and to markers of neuroendocrine tissue including neuron-
specific enolase, synaptophysin, and chromogranin that re-
flect tumor activity in vivo [3–5]. NETs represent 0.5% of
all malignancies; however, their incidence has risen from
1.09 out of 100,000 in 1973 to 5.25 out of 100,000 in 2004
[6, 7]. The gastroenteropancreatic NETs include pancreatic
mon of the NETs [1, 8]. Despite being the most common
gastrointestinal malignant neoplasms [9, 10].
For low-grade NETs, the definitive management for lo-
calized disease is surgical resection ; however, the di-
agnosis of these tumors is often delayed and many patients
are, therefore, diagnosed with metastatic or inoperable tu-
mors. For these patients, observation is usually sufficient
management until the patient either develops symptoms
secondary to hormone production or tumor bulk or shows
Patients who become symptomatic from hormonal hy-
persecretion can be treated effectively with somatostatin
the PROMID study also suggest that treatment with oc-
. ?-Interferon has also been shown to improve symp-
toms of hormonal hypersecretion in patients with both car-
with somatostatin analogs . Although both somatosta-
tin analogs and ?-interferon can result in tumor stabiliza-
tion, neither agent is considered effective in controlling
tumor growth [12, 14]. Tumor response has been reported
in ?10%–15% of patients treated with interferon, but tu-
mor regression has been reported to occur only in ?5% of
patients treated with somatostatin analogs [12, 14, 15].
Cytotoxic chemotherapy is also a therapeutic consider-
ation in patients who are symptomatic secondary to tumor
bulk or who have rapidly progressive disease. In general,
tients with gastroenteropancreatic NETs. Multiple chemo-
therapeutic agents have been assessed alone or in
combination for patients with advanced carcinoid and pan-
creatic islet cell NETs. The response rate to chemotherapy
in metastatic carcinoid tumors has been reported to be no
higher than ?20%–30% . In endocrine pancreatic tu-
ported to generate responses in 69% of patients ;
however, the determination of response in this trial con-
tained methods unacceptable to today’s standards. Re-
searchers at the Memorial Sloan-Kettering Cancer Center
(MSKCC) reported a patient series treated with this regi-
men with a response rate of only 6% as determined by stan-
dard common toxicity criteria (CTC) . Further studies
topotecan, bortezomib, and gemcitabine, all of which re-
ported a 0% response rate [19–21]. Recent data from a
phase III trial involving the use of sunitinib in patients with
advanced pancreatic NETs, however, suggest improved
treatment outcomes (PFS and possibly overall survival
all low response rates, however, the chemotherapeutic reg-
imens recommended in NETs are also associated with
significant toxicities . Clearly, in patients with a poten-
tially indolent disease, reducing the toxicities associated
with treatment is of utmost importance. Less toxic, effec-
tive therapies for this population of patients are urgently
Recent studies have shown that Notch1 signaling has a
role in tumor suppression . It has also been found that
Notch1 signaling is very minimal or nonexistent in NETs
 and that the activation of Notch1 signaling in NET cell
lines results in a significant decrease in protein secretion of
both chromogranin A and synaptophysin levels, serotonin
secretion, and tumor growth in BON (human gastrointesti-
cell lines [26–29]. The search for compounds that activate
in the treatment of seizure disorders and bipolar disorder
. A study conducted with the BON and H727 cell lines
sequently decrease tumor biomarkers and hormone secre-
tion. The study also confirmed VPA-associated reduction
in tumor growth in nude mice that were transfected with
both (BON and H727) human tumor xenografts . The
precise mechanism through which VPA increases Notch1
signaling remains unclear but may be related to its property
as a histone deacetylase inhibitor [32, 33].
in NET hormone production and tumor proliferation, as
well as the effects of VPA on Notch1 in vivo and in vitro,
tumor marker production, tumor response, survival, and
MATERIALS AND METHODS
To be eligible for the trial, patients had to have histologi-
cally confirmed metastatic low-grade NETs. All tumor
VPA Use in Treatment of Neuroendocrine Tumors
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