Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study

Brenner, Andrew; Zuniga, Richard; Sun, Jessica; Floyd, John R.; Hart, Charles P.; Kroll, Stew; Fichtel, Lisa; Cavazos, David; Caflisch, Laura; Gruslova, Aleksandra; Huang, Shi‐Liang; Liu, Yichu; Lodi, Alessia; Tiziani, Stefano

doi:10.1093/neuonc/noy015

Cited by 29 publications

(33 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considering the critical roles of HIF1α and HIF2α in cancer biology, many strategies have been considered to target HIFα signaling in solid tumors including GBMs. Targeting hypoxia/HIFα signaling is thought to be a viable strategy to sensitize GSCs to radiation and chemotherapy as well as to inhibit the pro-tumorigenic biology induced when blood vessel collapse occurs with anti-angiogenics 44 , 204 . Inhibition could be mediated by therapies that promote oxygenation, decrease HIFα stability, prevent HIFα DNA binding, or inhibit the downstream mediators of pro-tumorigenic hypoxia/HIF effects.…”

Section: Interactions Of the Immune System And Gscs In The Hypoxic Nimentioning

confidence: 99%

Glioma stem cells and their roles within the hypoxic tumor microenvironment

et al. 2021

View full text Add to dashboard Cite

Tumor microenvironments are the result of cellular alterations in cancer that support unrestricted growth and proliferation and result in further modifications in cell behavior, which are critical for tumor progression. Angiogenesis and therapeutic resistance are known to be modulated by hypoxia and other tumor microenvironments, such as acidic stress, both of which are core features of the glioblastoma microenvironment. Hypoxia has also been shown to promote a stem-like state in both non-neoplastic and tumor cells. In glial tumors, glioma stem cells (GSCs) are central in tumor growth, angiogenesis, and therapeutic resistance, and further investigation of the interplay between tumor microenvironments and GSCs is critical to the search for better treatment options for glioblastoma. Accordingly, we summarize the impact of hypoxia and acidic stress on GSC signaling and biologic phenotypes, and potential methods to inhibit these pathways.

show abstract

Section: Interactions Of the Immune System And Gscs In The Hypoxic Nimentioning

confidence: 99%

Glioma stem cells and their roles within the hypoxic tumor microenvironment

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Hypoxia-activated prodrugs (HAPs) are selectively activated by enzymatic reduction in hypoxic cells, and may provide a means to test this hypothesis. One of the most clinically advanced HAPs, evofosfamide, has successfully demonstrated efficacy towards glioblastoma in a preclinical rodent model [32] and in human patients [33] but has yet to be combined with SOC. HAP administration prior to SOC therapy could potentially remove both the TMZ-resistant and radio-resistant hypoxic cells, providing additional benefit to both components of SOC.…”

Section: Discussionmentioning

confidence: 99%

Use of a Luciferase-Expressing Orthotopic Rat Brain Tumor Model to Optimize a Targeted Irradiation Strategy for Efficacy Testing with Temozolomide

Mowday

Lieuwes

Biemans

et al. 2020

Cancers

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is a common and aggressive malignant brain cancer with a mean survival time of approximately 15 months after initial diagnosis. Currently, the standard-of-care (SOC) treatment for this disease consists of radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ). We sought to develop an orthotopic preclinical model of GBM and to optimize a protocol for non-invasive monitoring of tumor growth, allowing for determination of the efficacy of SOC therapy using a targeted RT strategy combined with TMZ. A strong correlation (r = 0.80) was observed between contrast-enhanced (CE)-CT-based volume quantification and bioluminescent (BLI)-integrated image intensity when monitoring tumor growth, allowing for BLI imaging as a substitute for CE-CT. An optimized parallel-opposed single-angle RT beam plan delivered on average 96% of the expected RT dose (20, 30 or 60 Gy) to the tumor. Normal tissue on the ipsilateral and contralateral sides of the brain were spared 84% and 99% of the expected dose, respectively. An increase in median survival time was demonstrated for all SOC regimens compared to untreated controls (average 5.2 days, p < 0.05), but treatment was not curative, suggesting the need for novel treatment options to increase therapeutic efficacy.

show abstract

“…Nevertheless, to date, no treatment has shown survival benefit in GBM patients who progress on bevacizumab. Evofosfamide plus bevacizumab, dianhydrogalactitol (VAL‐083), and salvage re‐irradiation have shown modest preliminary activity, although further studies are required to confirm their potential benefit.…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of ponatinib in patients with bevacizumab‐refractory glioblastoma

et al. 2019

View full text Add to dashboard Cite

Background Responses to bevacizumab in glioblastoma (GBM) are not durable. Plasma levels of basic fibroblast growth factor (bFGF) increase at the time of tumor progression. By targeting vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor, Src, and FGF receptor pathways, ponatinib may potentially help to overcome some of the putative mechanisms of adaptive resistance. Methods We performed a phase II trial of ponatinib in patients with bevacizumab‐refractory GBM and variants. Adult patients with Karnofsky performance score (KPS) ≥60, measurable disease, and normal organ and marrow function received 45 mg ponatinib daily. No limit on the number of prior therapies but only one prior bevacizumab‐containing regimen was allowed. Primary endpoint was 3‐month progression‐free survival. Plasma biomarkers of angiogenesis and inflammation were evaluated before and after treatment. Results The study closed after the first stage. Fifteen patients enrolled: median age 61 [27‐74]; median KPS 80 [70‐90]; median number of prior relapses 2 [2‐4]. Three‐month progression‐free survival rate was 0, median overall survival was 98 days [95% CI 56, 257], and median PFS was 28 days [95% CI 27, 30]. No responses were seen. The most common grade ≥3 adverse events included fatigue (n = 3), hypertension (2), and lipase elevation (2). Ponatinib treatment significantly increased plasma VEGF, soluble (s)VEGFR1, sVEGFR2, sTIE2, interferon gamma (IFNγ), tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐6, IL‐8, and IL‐10 and decreased sVEGFR2. Conclusions Ponatinib was associated with minimal activity in bevacizumab‐refractory GBM patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines.

show abstract

Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study

Abstract: Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.

Cited by 29 publications

References 37 publications

Glioma stem cells and their roles within the hypoxic tumor microenvironment

Glioma stem cells and their roles within the hypoxic tumor microenvironment

Use of a Luciferase-Expressing Orthotopic Rat Brain Tumor Model to Optimize a Targeted Irradiation Strategy for Efficacy Testing with Temozolomide

Phase II trial of ponatinib in patients with bevacizumab‐refractory glioblastoma

Contact Info

Product

Resources

About