RIST: A potent new combination therapy for glioblastoma

Abstract

Glioblastoma is a highly aggressive, common brain tumor with poor prognosis. Therefore, this study examines a new therapeutic approach targeting oncogenic and survival pathways combined with common chemotherapeutics. The RIST (rapamycin, irinotecan, sunitinib, temozolomide) and the variant aRIST (alternative to rapamycin, GDC-0941) therapy delineate growth inhibiting effects in established glioblastoma cell lines and primary cultured patient material. These combinations significantly decreased cell numbers and viability compared to inhibitors and chemotherapeutics alone with aRIST being superior to RIST. Notably, RIST/aRIST appeared to be apoptogenic evoked by reduction of anti-apoptotic protein levels of XIAP and BCL-2, with concomitant up-regulation of pro-apoptotic protein levels of p53 and BAX. The treatment success of RIST therapy was confirmed in an orthotopic mouse model. This combination treatment revealed significantly prolonged survival time and drastically reduced the tumor burden by acting anti-proliferative and pro-apoptotic. Surprisingly, in vivo, aRIST only marginally extended survival time with tumor volumes comparable to controls. We found that aRIST down-regulates the microvessel density suggesting an insufficient distribution of chemotherapy. Further, alterations in different molecular modes of action in vivo than in vitro suggest, that in vivo RIST therapy may mimic the superior aRIST protocol's pro-apoptotic inhibition of pAKT in vitro. Of note, all substances were administered in therapeutically relevant low doses with no adverse side effects observed. We also provide evidence of the potential benefits of the RIST therapy in a clinical setting. Our data indicates RIST therapy as a novel treatment strategy for glioblastoma achieving significant anti-tumorigenic activity avoiding high-dose chemotherapy.Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a mean overall patient survival time of 12 months. 1 Despite intensive research into new treatment strategies, the overall survival rate has not improved substantially over the last two decades. The most recent major alteration to the standard therapeutic protocol, then consisting of surgery followed by radiotherapy, was the addition of temozolomide, an alkylating agent, which increased the mean survival time by approximately four months. 2

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

“…This result suggests that it may be difficult for GDC-0941 to reach the distant part of GBM, thus being insufficient to treat GBM with intact BBB. An in-vivo study also shows that combination of GDC-0941, irinotecan, sunitinib and temozolomide doesn’t significantly prolong the survival of mice with GBM xenograft, possibly due to the poor BBB permeability of GDC-0941 [67]. Nevertheless, a phase IIb clinical trial in patients with recurrent GBM is ongoing to evaluate the anti-tumor activity of pembrolizumab (MK-3475, a PD-1 monoclonal antibody) alone or in combination of PI3K/Akt inhibitors including GDC-0941, NVP-BEZ235 and GDC-0068 (NCT02430363).…”

Molecularly targeted therapies for recurrent glioblastoma: current and future targets

“…71 There are several clinical trials that evaluated the use of combination therapy in the treatment of recurrent glioblastoma, and in general, outcomes for combination therapy tend to be superior to monotherapy. 4,28,30,41,84,85,87,106,108 A case example demonstrating the efficacy of combination therapy can be seen in Fig.…”

“…58,71 More recently, a group proposed supplementing 9 additional agents (aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, and sertraline) to continuous low-dose temozolomide in the treatment of recurrent glioblastoma. 58 The authors had a rationale for the addition of each agent; each drug targeted a mechanism or pathway involved with either glioblastoma growth or compensatory mechanisms against temozolomide.…”

Darwinian Principles in Cancer Therapy

“…31 In our clinic we have introduced the rapamycin, irinotecan, sunitinib, temozolomide (RIST) protocol, which is a complex combination therapy consisting of combinations of chemotherapeutic agents and small molecule inhibitors and by metronomic dosage we could achieve a reduction of tumour burden with relatively few side effects. 32 While patients are not cured and tumour recurrence occurs upon cessation of treatment, quality and quantity of life are greatly improved. 32 Protocols that are aimed at the chronification of a malignancy should take ease of administration into account, ideally in the form of orally available medication, which eliminates the need for lengthy or regular clinic stays and improves patient compliance.…”

“…32 While patients are not cured and tumour recurrence occurs upon cessation of treatment, quality and quantity of life are greatly improved. 32 Protocols that are aimed at the chronification of a malignancy should take ease of administration into account, ideally in the form of orally available medication, which eliminates the need for lengthy or regular clinic stays and improves patient compliance. However, it needs to be pointed out that the management of one of the diseases successfully controlled by chronification, 33 type 1 diabetes, is based on regular subcutaneous injections of insulin.…”