Beta-blockers (especially propranolol) and the role of the sympathetic
| Property | Information |
|---|---|
| Drug Name | Beta-blockers (especially propranolol) and the role of the sympathetic |
| FDA Approval | Not specified |
| Used for | Not specified |
| Clinical Trial Phase | Not specified |
| Clinical Trial Explanation | Not specified |
| Common Side Effects | Not specified |
| OS without | Not specified |
| OS with | Not specified |
| PFS without | Not specified |
| PFS with | Not specified |
| Usefulness Rating | Not rated |
| Usefulness Explanation | Not specified |
| Toxicity Level | Not specified |
| Toxicity Explanation | Not specified |
From Ben Williams Book: 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 29
(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 30
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.Property "Has original text" (as page type) with input value "nervous system</br></br>Recenty the role of the sympathetic nervous system in cancer progression, and the</br>potential role of beta-adrenergic antagonists (beta-blockers) have come into focus in</br>some corners of the cancer research community. Early studies linking stress to increased</br>rates of cancer progression led to epidemiological studies showing lower rates of cancer in</br>subjects taking beta-blockers. Beta-blockers such as propranolol have more recently</br>entered controlled clinical cancer trials.</br></br>The sympathetic nervous system is a division of the autonomic nervous system, most</br>often associated with “fight or flight” responses. The sympathetic nervous system</br>depends upon catecholamines, mainly epinephrine (adrenaline) and norepinephrine</br>(noradrenaline), which activate two classes of adrenergic receptors in target tissues</br>throughout the body: alpha and beta adrenergic receptors (which are further subdivided</br>into alpha-1, alpha-2, beta-1, beta-2 and beta-3 receptors).</br></br>The research and evidence concerning the link between the sympathetic nervous system</br>and cancer progression has narrowed in more specifically on beta-adrenergic receptors</br>and signaling. Animal studies in various cancer models demonstrated that stress</br>contributed to tumor progression, and these effects could be blocked with beta-blockers</br>29</br></br>(333). Investigated mechanisms are manifold, and include the following downstream</br>effects of beta-adrenergic signaling: stimulation of pro-inflammatory cytokines such as</br>interleukin 6 and 8; increased recruitment of macrophages into tumors and increased</br>macrophage expression of genes such as TGFB, VEGF, IL6, MMP9, and PTGS2 (encoding</br>the COX-2 enzyme), which together promote angiogenesis, invasion, and</br>immunosuppression; inhibition of type 1 and 2 interferons, dampening down</br>cell-mediated anti-cancer immunity, and decreased function of T-lymphocytes and</br>natural killer cells; activation of transcription factors that promote</br>epithelial-mesenchymal transition, leading to tumor metastasis and invasion; and</br>increased production of pro-angiogenic growth factors and cytokines, such as IL-6 and</br>VEGF. A 2015 review summarizes the current evidence for the sympathetic immune</br>system’s influence on cancer progression and the tumor microenvironment (334).</br></br>Clinical evidence supports the importance of beta blockers in cancer treatment. An</br>epidemiological study in Taiwan (335) reported that the incidence of cancer was greatly</br>reduced (30-50%) in subjects using propranolol for at least six months, including</br>incidence of head and neck cancer and cancers of the esophagus, stomach, colon, and</br>prostate. Incidence of brain cancer was too low in both the propranolol and</br>no-propranolol groups to achieve a statistically significant reduction, although the risk of</br>brain cancer was also lower in the propranolol group. Confirming these findings is a</br>recent clinical study in the USA of ovarian cancer in which patients were divided into</br>those who used no beta blockers, those that used older non-specific beta blockers (such as</br>propranolol), and those that used the newer selective beta blockers specific to beta-1</br>adrenergic receptors. Ovarian cancer patients not using beta blockers had median</br>survival of 42 months, those using the beta-1 selective agents had a median survival of 38</br>months, and those using non-selective beta blockers (eg propranolol) had a superior</br>median survival of 95 months (336).</br></br>Vicus Therapeutics, headquartered in Morristown New Jersey, is a company developing a</br>combination treatment they call VT-122, which consists of a “chrono-modulated”</br>formulation of propranolol (a beta-blocker first approved by the FDA in 1967) and</br>etodolac (a non-steroidal anti-inflammatory first approved by the FDA in 1991). Both</br>drugs are off-patent and available as generics. Vicus has three clinical trials listed at</br>clinicaltrials.gov: one, starting in 2007, tested VT-122 as a treatment for cachexia in</br>non-small cell lung cancer patients (NCT00527319); another, starting in 2010, is testing</br>VT-122 in combination with sorafenib for hepatocellular carcinoma (NCT01265576); a</br>third, starting in 2013, is testing VT-122 for progressive prostate cancer (NCT01857817).</br></br>Not listed on clinicaltrials.gov is a trial presented in abstract form for the 2015 ASCO</br>meeting, comparing low dose daily temozolomide (20 mg twice daily) with or without</br>VT-122 for recurrent glioblastoma. 20 patients were assigned to low-dose temozolomide</br>alone, and another 21 patients were assigned low-dose temozolomide plus VT-122.</br>Patient characteristics are not given in the abstract apart from Karnofsky score, which</br>30</br></br>was over 60 (median) in both groups. The most remarkable outcome was a median</br>overall survival of 17.6 months in the low-dose TMZ + VT-122 group versus only 9.2</br>months in the low-dose TMZ alone group. In the VT-122 group there were 5 complete</br>responses (24%) and 12 responses altogether (57%), compared to the corresponding</br>figures of 5% and 35% in the group receiving TMZ alone. One-year survival rate was 67%</br>in the VT-122 group, and 30% with TMZ alone. Rates of thrombocytopenia, neutropenia,</br>and anemia were higher in the VT-122 group. Statistical tests for significance were not</br>reported in the abstract. Although this abstract leaves out vital information (enrollment</br>criteria, patient characteristics, progression-free survival data, statistical significance,</br>etc), a median survival of 17.6 months for recurrent glioblastoma is intriguing, while the</br>9.2 months median survival in the low-dose TMZ alone group is closer to the average for</br>recurrent glioblastoma trials." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
