Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial

Abstract

Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1-25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and costeffective therapeutic option for patients with glioblastoma.

Role of Turmeric and Curcumin in Prevention and Treatment of Chronic Diseases: Lessons Learned from Clinical Trials

“…Despite advancements in multimodal treatment modalities, glioblastoma remains a devastating disease with poor prognosis and rare long-term survival. , Studies have shown promising results with curcumin in treating glioblastoma. For example, in a phase I dose escalation study, after the administration of renin-angiotensin system blockers, i.e., curcumin, propranolol, aliskiren cilazapril, celecoxib, piperine, aspirin, and metformin (piperine was ingested to enhance the absorption of curcumin), an increase in median survival (not statistically significant) was observed in patients with advanced-stage relapsed glioblastoma with a Karnofsky performance score of at least 60 ( n = 10) . In another study, Esposito et al demonstrated that dietary supplementation with 1200 mg/day curcumin reduced the number and volume of cutaneous neurofibromas in patients with neurofibromatosis I, which is an autosomal dominant disorder associated with a predisposition to tumor development, including glioma ( n = 11) …”

“…For example, in a phase I dose escalation study, after the administration of renin-angiotensin system blockers, i.e., curcumin, propranolol, aliskiren cilazapril, celecoxib, piperine, aspirin, and metformin (piperine was ingested to enhance the absorption of curcumin), an increase in median survival (not statistically significant) was observed in patients with advanced-stage relapsed glioblastoma with a Karnofsky performance score of at least 60 (n = 10). 270 In another study, Esposito et al demonstrated that dietary supplementation with 1200 mg/day curcumin reduced the number and volume of cutaneous neurofibromas in patients with neurofibromatosis I, which is an autosomal dominant disorder associated with a predisposition to tumor development, including glioma (n = 11). 271 Head and neck squamous cell carcinoma is the sixth most frequently occurring cancer and belongs to the challenge-totreat category of malignancies.…”

Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment

“…We have recently presented results of a phase I clinical trial on recurrent glioblastoma by targeting CSCs in by influencing the TME to modulate the RAS using multiple medications (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin) [ 254 ]. The treatment was well tolerated with low side-effects, and the quality of life and performance status of the participants were preserved during treatment with an overall median survival 19.9 months [ 254 ]. The increased survival of 5.3 months, although not statistically significant, was encouraging, and warrants further investigation.…”

Insights Into Vascular Anomalies, Cancer, and Fibroproliferative Conditions: The Role of Stem Cells and the Renin-Angiotensin System

“…Targeting the RAS, its bypass loops and converging signaling pathways to achieve optimal blockade of the RAS to regulate CSCs has been proposed ( 3 – 5 ). This “hollistic” approach of blocking the RAS at multiple points simultaneously, forms the basis of a phase I clinical trial for recurrent glioblastoma ( 187 ) resulting in a trend toward increased survival by 5.3 months. The encouraging results of this trial warrant further clinical trials on this novel, well-tolerated and cost-effective potential therapeutic option for patients with glioblastoma, and potentially other cancer types.…”

“…This offers an exciting opportunity in developing novel therapeutic approaches to achieve optimal modulation of the crucial and complex system by further investigations. This novel approach of blocking the RAS at multiple points simultaneously forms the basis of a phase I clinical trial for glioblastoma ( 187 ). The encouraging results of this trial warrant further clinical trials on this potential novel, well-tolerated and cost-effective therapeutic option for patients with glioblastoma, and potentially other cancer types.…”