View source for Beta-blockers (especially propranolol) and the role of the sympathetic



{{TreatmentInfo
|drug_name=Beta-blockers (especially propranolol) and the role of the sympathetic
|treatment_category=Hormones and Cancer Therapy
|book_text=nervous system

Recenty the role of the sympathetic nervous system in cancer progression, and the
potential role of beta-adrenergic antagonists (beta-blockers) have come into focus in
some corners of the cancer research community. Early studies linking stress to increased
rates of cancer progression led to epidemiological studies showing lower rates of cancer in
subjects taking beta-blockers. Beta-blockers such as propranolol have more recently
entered controlled clinical cancer trials.

The sympathetic nervous system is a division of the autonomic nervous system, most
often associated with “fight or flight” responses. The sympathetic nervous system
depends upon catecholamines, mainly epinephrine (adrenaline) and norepinephrine
(noradrenaline), which activate two classes of adrenergic receptors in target tissues
throughout the body: alpha and beta adrenergic receptors (which are further subdivided
into alpha-1, alpha-2, beta-1, beta-2 and beta-3 receptors).

The research and evidence concerning the link between the sympathetic nervous system
and cancer progression has narrowed in more specifically on beta-adrenergic receptors
and signaling. Animal studies in various cancer models demonstrated that stress
contributed to tumor progression, and these effects could be blocked with beta-blockers
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(333). Investigated mechanisms are manifold, and include the following downstream
effects of beta-adrenergic signaling: stimulation of pro-inflammatory cytokines such as
interleukin 6 and 8; increased recruitment of macrophages into tumors and increased
macrophage expression of genes such as TGFB, VEGF, IL6, MMP9, and PTGS2 (encoding
the COX-2 enzyme), which together promote angiogenesis, invasion, and
immunosuppression; inhibition of type 1 and 2 interferons, dampening down
cell-mediated anti-cancer immunity, and decreased function of T-lymphocytes and
natural killer cells; activation of transcription factors that promote
epithelial-mesenchymal transition, leading to tumor metastasis and invasion; and
increased production of pro-angiogenic growth factors and cytokines, such as IL-6 and
VEGF. A 2015 review summarizes the current evidence for the sympathetic immune
system’s influence on cancer progression and the tumor microenvironment (334).

Clinical evidence supports the importance of beta blockers in cancer treatment. An
epidemiological study in Taiwan (335) reported that the incidence of cancer was greatly
reduced (30-50%) in subjects using propranolol for at least six months, including
incidence of head and neck cancer and cancers of the esophagus, stomach, colon, and
prostate. Incidence of brain cancer was too low in both the propranolol and
no-propranolol groups to achieve a statistically significant reduction, although the risk of
brain cancer was also lower in the propranolol group. Confirming these findings is a
recent clinical study in the USA of ovarian cancer in which patients were divided into
those who used no beta blockers, those that used older non-specific beta blockers (such as
propranolol), and those that used the newer selective beta blockers specific to beta-1
adrenergic receptors. Ovarian cancer patients not using beta blockers had median
survival of 42 months, those using the beta-1 selective agents had a median survival of 38
months, and those using non-selective beta blockers (eg propranolol) had a superior
median survival of 95 months (336).

Vicus Therapeutics, headquartered in Morristown New Jersey, is a company developing a
combination treatment they call VT-122, which consists of a “chrono-modulated”
formulation of propranolol (a beta-blocker first approved by the FDA in 1967) and
etodolac (a non-steroidal anti-inflammatory first approved by the FDA in 1991). Both
drugs are off-patent and available as generics. Vicus has three clinical trials listed at
clinicaltrials.gov: one, starting in 2007, tested VT-122 as a treatment for cachexia in
non-small cell lung cancer patients (NCT00527319); another, starting in 2010, is testing
VT-122 in combination with sorafenib for hepatocellular carcinoma (NCT01265576); a
third, starting in 2013, is testing VT-122 for progressive prostate cancer (NCT01857817).

Not listed on clinicaltrials.gov is a trial presented in abstract form for the 2015 ASCO
meeting, comparing low dose daily temozolomide (20 mg twice daily) with or without
VT-122 for recurrent glioblastoma. 20 patients were assigned to low-dose temozolomide
alone, and another 21 patients were assigned low-dose temozolomide plus VT-122.
Patient characteristics are not given in the abstract apart from Karnofsky score, which
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was over 60 (median) in both groups. The most remarkable outcome was a median
overall survival of 17.6 months in the low-dose TMZ + VT-122 group versus only 9.2
months in the low-dose TMZ alone group. In the VT-122 group there were 5 complete
responses (24%) and 12 responses altogether (57%), compared to the corresponding
figures of 5% and 35% in the group receiving TMZ alone. One-year survival rate was 67%
in the VT-122 group, and 30% with TMZ alone. Rates of thrombocytopenia, neutropenia,
and anemia were higher in the VT-122 group. Statistical tests for significance were not
reported in the abstract. Although this abstract leaves out vital information (enrollment
criteria, patient characteristics, progression-free survival data, statistical significance,
etc), a median survival of 17.6 months for recurrent glioblastoma is intriguing, while the
9.2 months median survival in the low-dose TMZ alone group is closer to the average for
recurrent glioblastoma trials.
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