Novel second generation analogs of eribulin. Part III: Blood–brain barrier permeability and in vivo activity in a brain tumor model

Nimmagadda, Sridhar; Carlson, Eric M.; Cheng, Hongsheng; Condon, Krista; Du, Hong; Eckley, Sean; Hu, Yongbo; Jiang, Yimin; Kumar, Vipul; Lewis, Bryan M.; Saxton, Philip L.; Schuck, Edgar; Seletsky, Boris M.; Tendyke, Karen; Zhang, Huiming; Zheng, Wanjun; Littlefield, Bruce A.; Towle, Murray J.; Yu, Melvin J.

doi:10.1016/j.bmcl.2011.01.096

Cited by 22 publications

(11 citation statements)

References 17 publications

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Section: Discussionmentioning

confidence: 99%

“…In a previous preclinical study, glioblastoma was among the several cancer types that showed sensitivity to eribulin . However, glioblastoma was not considered a target for eribulin because the drug could not penetrate the blood‐brain barrier (BBB) . This was most likely because eribulin is a substrate of P‐glycoprotein (P‐gp), an efflux transporter that plays an important role in elimination of drugs at the BBB .…”

Section: Discussionmentioning

confidence: 99%

“…27,31 However, glioblastoma was not considered a target for eribulin because the drug could not penetrate the blood-brain barrier (BBB). 31 This was most likely because eribulin is a substrate of Pglycoprotein (P-gp), an efflux transporter that plays an important role in elimination of drugs at the BBB. 32,33 To explain the unexpectedly high efficacy of eribulin against intracerebral tumor, we hypothesized that although eribulin could not penetrate the BBB of normal brain, it may penetrate the brain tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

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Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts

Takahashi¹,

Miki²,

Fujimoto³

et al. 2019

Cancer Science

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Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre–clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)‐RNA‐dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation‐harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix‐assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA‐approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator‐initiated registration‐directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts

Takahashi¹,

Miki²,

Fujimoto³

et al. 2019

Cancer Science

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“…While extensive work has been completed to understand how efflux through P-glycoproteins affects exposure of chemotherapeutics in solid tumors (36,37) little is known regarding efflux mechanisms in peripheral nervous system tissue. It is known that paclitaxel and ixabepilone do not achieve high levels of exposures in the brain in patients (19,38) but this is presumed due to active efflux by P-glycoproteins across the blood brain barrier, not lack of CNS distribution (14,39,40). While the efflux transporters found in the blood-brain barrier have been found in blood vessels in peripheral nerve (41,42), the DRG appear to exist outside the blood brain barrier, and thus are exposed to greater plasma components (43), possibly leading to the observed rapid accumulation and retention.…”

Section: Discussionmentioning

confidence: 99%

Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity

Wozniak

Vornov

et al. 2016

Cancer Research

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Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities of certain drugs are unclear. At their maximal tolerated doses (MTD), the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a two week MTD-dosing regimen followed by a determination of drug pharmacokinetics, tissue distribution and multiple functional measures of peripheral nerve toxicity for four weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity produced biologically was consistently more severe with paclitaxel. Overall, our results argued that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity.

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“…In contrast, few data exist about prognostic and predictive factors of response with eribulin in everyday clinical practice [12,13]. Efficacy in elderly patients, obese patients, or in patients with central nervous system (CNS)disease has not been well reported either [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Real-world data of eribulin in advanced and pretreated HER2-negative breast cancer in a Spanish comprehensive cancer center

Sirvén

Fernández-Ortega

Stradella

et al. 2019

Preprint

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Background Eribulin improves survival in pre-treated HER2-negative advanced breast cancer (ABC). However, limited data exist on co-morbidities and central nervous system (CNS) efficacy. The purpose of this study was to review eribulin’s efficacy and safety in everyday clinical practice with special focus on age, body mass index (BMI) and central nervous system (CNS) activity.Methods An observational study was conducted in a series of HER2-negative ABC patients treated from January’14-December’17 outside a clinical trial. Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS), and association of clinical and pathological variables with outcome were evaluated.Results Ninety-five women were treated with at least one cycle of eribulin. Median age was 57 (33-83), and 18% were obese. Median number of prior chemotherapies for ABC was 3 (2-5) and 76% of patients had visceral metastases, including 21% with CNS involvement. Most tumors were estrogen receptor-positive (79%). ORR and stable disease (SD) at 6 months were 26.2% and 37.5%, respectively. Remarkably, relevant CNS efficacy was observed with eribulin: 20% of patients obtained partial response and 25% SD. Treatment was generally well tolerated and manageable, with 29% grade 3 and 10.9% grade 4 toxicities. Median PFS and OS were 4.1 months (CI95% 3.2-4.9) and 11.1 months (CI95% 9.5-14.7), respectively. Triple-negative disease, >2organs involved and being younger than 70 years old were independent prognosis factors for worse OS in multivariate analysis. Most patients (75%) progressed in pre-existing metastases sites.Conclusions In everyday clinical practice, eribulin’s efficacy seems similar to pivotal trials. CNS-efficacy was observed. TNBC, >2 organs involved and being younger than 70 years old were independent prognosis factors for worse OS. Remarkably, less incidence of grade 4-toxicity compared to previous studies was found.

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Novel second generation analogs of eribulin. Part III: Blood–brain barrier permeability and in vivo activity in a brain tumor model

Cited by 22 publications

References 17 publications

Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts

Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts

Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity

Real-world data of eribulin in advanced and pretreated HER2-negative breast cancer in a Spanish comprehensive cancer center

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