Search

Editorial on this Article from A Phase I Study of Eribulin Mesylate (E7389), a Mechanistically Novel Inhibitor of Microtubule Dynamics, in Patients with Advanced Solid Malignancies

File contains description of supplementary methods used for sciatic nerve immunofluorescence data generation and quantification with Supplementary Fig 1 showing how raw fluorescence intensity values were normalized in order to compare levels of acetylated alpha tubulin from samples across treatment groups. Supplementary Figs 2 thru 4 show DRG and sciatic nerve morphology/morphometrics for chemotherapies other than PACLI. Supplementary Table 1 adds perspective to how MTD used to compare the chemotherapies in this study relates to their pharmacokinetic and IC50 properties.

Purpose: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies.Experimental Design: Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m2 with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized.Results: Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m2). Neutropenia was the principal DLT: At 1.4 mg/m2, two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m2. Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease.Conclusions: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m2 with further dose escalation limited by neutropenia and fatigue.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817–29. ©2017 AACR.

Objective: Test whether the efficacy of Project Health, an obesity/eating disorder prevention program, is improved by delivering it in single-sex groups and adding food response inhibition and attention training. Method: High-risk young adults (N = 261; M age = 19.3, 74% female) were randomized to (1) single-sex or (2) mixed-sex groups that completed food response inhibition and attention training or (3) single-sex or (4) mixed-sex groups that completed sham training with nonfood images in a 2 × 2 factorial design. Results: There was a significant sex-composition by training-type by time interaction; participants who completed single- or mixed-sex Project Health groups plus food response and attention training showed significant reductions in body fat over a 2-year follow-up, though this effect was more rapid and persistent in single-sex groups, whereas those who completed single- or mixed-sex Project Health groups plus sham training did not show body fat change. However, there were no differences in overweight/obesity onset over the follow-up. The manipulated factors did not affect eating disorder symptoms or eating disorder onset, but there was a significant reduction in symptoms across the conditions (within-condition d = −0.58), converging with prior evidence that Project Health produced larger reductions in symptoms (within-condition d = −0.48) than educational control participants. Average eating disorder onset over the 2-year follow-up (6.4%) was similar to that observed in Project Health in a past trial (4.5%). Conclusions: Given that Project Health significantly reduced future onset of overweight/obesity in a prior trial and the present trial found that body fat loss effects were significantly greater when implemented in single-sex groups and paired with food response and attention training, there might be value in broadly implementing this combined intervention.

Purpose Eribulin, a synthetic analog of the natural product halichondrin B, is a microtubule dynamics inhibitor. In this study, we report the pharmacokinetic profiles of eribulin in mice, rats, and dogs following intravenous administrations with optimized and validated bio-analytical methods. Methods Eribulin was administered at 0.5 and 2 mg/kg in mice, 0.5 and 1 mg/kg in rats, and 0.08 mg/kg in dogs. Tumor and brain penetration of eribulin was also evaluated in LOX human melanoma xenograft models. Concentrations in plasma, tumor, and brain were measured by the LC–MS/MS method. Results The profiles of eribulin were characterized by extensive distribution, moderate clearance, and slow elimination in the three species. The pharmacokinetics are linear in mice and rats. In xenograft mice, the penetration into the brain was low, as expected, since eribulin is a P-glycoprotein substrate. In contrast to disposition in brain, the exposure of eribulin was approximately 20–30 times higher in tumor than that in plasma and half-lives were 17.8–35.9 h after both single and multiple dose regimens. Conclusions Eribulin was distributed rapidly and eliminated slowly in mice, rats, and dogs. The exposure of eribulin was approximately 20–30 times higher in tumor than in plasma in xenograft mice. These results might be caused by eribulin’s mechanism of action including increased perfusion in tumor by vascular remodeling effect.

Chemotherapy-induced peripheral neuropathy is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities are unclear. At their MTDs, 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 2-week MTD-dosing regimen, followed by a determination of drug pharmacokinetics, tissue distribution, and multiple functional measures of peripheral nerve toxicity for 4 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 observed functionally was consistently more severe with paclitaxel. Overall, our results argue that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity. Cancer Res; 76(11); 3332–9. ©2016 AACR.

The human gut microbiota forms a diverse, dynamic, and complex ecosystem that modulates numerous host processes including metabolism, inflammation, and cellular and humoral immune responses. Emerging data suggest that the gut microbiota of cancer patients may predict tumor response to immune checkpoint inhibitors (ICI). To better understand how the microbiome may impact response to ICI, we have developed and validated robust tumor models using either conventional mice treated with antibiotics or germ-free (GF) mice. We have confirmed in both models that mice lacking a diverse microbiome fail to mount an efficient antitumor immune response after treatment with anti-PD-1, primarily due to T-cell dysfunction. This response to anti-PD-1 can be restored by introduction of a microbiome using fecal microbial transplant (FMT) prepared from stool from healthy donors in GF mice and is driven by increased tumor-infiltrating lymphocytes (TILs), specifically CD8+ T cells. Importantly, for the first time we show that the bacterial spore fraction from healthy donor stool can also restore response to anti-PD-1 and increase CD8+ TILs in both conventional mice treated with antibiotics and GF mice. We have also tested cancer patient-derived microbiome samples that are efficacious or nonefficacious in GF mouse models. We have sequenced the input material as well as the engrafted gut microbiota in these mice via 16S rDNA sequencing. Comparison of these sequences has enabled us to develop a “microbiome signature” of response that is being used in the development of a microbiome-based therapy for combination with ICI. Based on these encouraging animal model data, we plan to initiate a randomized, placebo-controlled clinical study at MD Anderson Cancer Center in 2018, sponsored by the Parker Institute for Cancer Immunotherapy, in patients with advanced metastatic melanoma. The clinical trial will evaluate the impact of an anti-PD-1 checkpoint inhibitor with adjunctive microbiome therapy on patient outcomes. Seres is developing SER-401, a preclinical-stage oral microbiome therapy to improve the efficacy and safety of immunotherapy. Our drug-discovery strategy combines computational analyses and empirical in vitro, in vivo, and ex vivo screening of strains and consortia to inform selection and drive microbiome drug design. Data from such a comprehensive approach are invaluable for designing compositions of bacteria that form “functional ecological networks” that can impact response to ICI therapy. We believe these data will provide insight into how microbiome drugs can be developed in the setting of immunotherapy to augment the efficacy of ICIs by altering the cancer-immune set point. This abstract is also being presented as Poster A65. Citation Format: Jaclyn Sceneay, Srimathi Srinivasan, Keith Halley, Meghna Bist, Kathleen Cieciuch, George Marnellos, Christopher Desjardins, Jennifer Wortman, Matthew Henn, David Cook, Lata Jayaraman. Leveraging gut microbiota networks to impact tumor immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR01.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice. Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817–29. ©2017 AACR.

Hyaluronan (hyaluronic acid, HA), a glycosaminoglycan found in tissue throughout the body, overaccumulates in the tumor microenvironment (TME) of many non-hematologic malignancies, including breast cancer. HA overaccumulation in breast cancer patients correlates with tumor progression and decreased survival (Tammi 2008). Pegylated recombinant human hyaluronidase PH20 (PEGPH20), an investigational therapeutic agent entering Phase 3 clinical development in pancreatic cancer, enzymatically removes HA from the TME. In preclinical animal models, PEGPH20-mediated HA degradation is associated with remodeling of the tumor stroma, reduction of tumor pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy (Thompson 2010, Provenzano 2012, Jacobetz 2013). Accordingly, preclinical studies investigated the combination of PEGPH20 with eribulin mesylate (ERI, HALAVEN®), a microtubule dynamics inhibitor with a novel mechanism of action (Towle 2001, Jordan 2005), currently approved for treatment of certain patients with advanced breast cancer. NCr nu/nu mice were inoculated subcutaneously with human triple-negative breast cancer (TNBC) HCC1806 or HCC1806/HAS3 cells; the latter subline was engineered to accumulate high HA levels, confirmed by immunohistochemistry, via overexpression of hyaluronan synthase 3 (HAS3). When tumors reached ∼350 mm3, animals were randomly assigned to four treatments groups: vehicle, ERI (0.7 mg/kg, IV, QW), PEGPH20 (37.5 µg/kg, IV, BIW), or ERI plus PEGPH20. In the parental HCC1806 model, addition of PEGPH20 did not significantly change the antitumor effects of ERI. In contrast, combining PEGPH20 with ERI in the HCC1806/HAS3 model increased the antitumor effects of ERI by 27% (94.5% vs. 119.7% TGI, ERI alone vs. ERI+PEGPH20, respectively; p=0.05) and resulted in 6 of 7 complete tumor regressions. In a complementary study in HCC1806/HAS3 tumors evaluating ERI pharmacokinetics with and without PEGPH20, mice were assigned to three treatments groups: ERI (0.5 mg/kg, IV), simultaneous ERI plus PEGPH20 (37.5 µg/kg, IV); or ERI plus PEGPH20 predosed 24 h prior to ERI. Animals were sacrificed at 0.5, 1, 4, 24, 48, 72 and 96 h post ERI dose, and ERI levels in tumor, muscle, plasma and liver were subsequently analyzed by liquid/liquid extraction and LC-MS/MS chromatography. Simultaneous administration of ERI and PEGPH20 increased ERI maximum tumor concentration (Cmax) slightly and approximately doubled ERI tumor exposure (AUC); whereas the 24 h pretreatment with PEGPH20 approximately doubled ERI Cmax and increased ERI AUC more than two-fold. No significant differences in plasma ERI levels were observed between groups, and no significant differences in ERI levels in liver or muscle tissue were observed between groups. Taken together, these data suggest that PEGPH20-mediated HA removal significantly increases both ERI tumor concentrations and antitumor effectiveness in an HA-high TNBC model. A clinical phase 1b/2 clinical trial is planned to evaluate PEGPH20 plus ERI in first-line HER2-negative metastatic breast cancer. Citation Format: Bahn JD, DesJardins C, Condon KB, Fathallah A, Zimmerman S, Maneval DC, Littlefield BA, Thompson CB. Pegylated recombinant human hyaluronidase PH20 (PEGPH20) enhances efficacy of eribulin mesylate (HALAVEN®) in triple negative breast cancer xenografts. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-09.

BAL101553 is a highly water soluble prodrug of {"type":"entrez-protein","attrs":{"text":"BAL27862","term_id":"359270343","term_text":"BAL27862"}}BAL27862 that arrests tumor cell proliferation and induces cell death in cancer cells through disruption of the microtubule network. In vitro {"type":"entrez-protein","attrs":{"text":"BAL27862","term_id":"359270343","term_text":"BAL27862"}}BAL27862 demonstrated potent activity, with the median relative IC50 (rIC50) of 13.8 nM (range 5.4 to 25.2 nM). The in vitro activity of {"type":"entrez-protein","attrs":{"text":"BAL27862","term_id":"359270343","term_text":"BAL27862"}}BAL27862 against the PPTP cell lines is distinctive from that previously described for vincristine. BAL101553 induced significant differences in EFS distribution compared to control in 16 of 30 (53%) solid tumor xenografts and in 2 of 4 (67%) of the evaluable ALL xenografts. No objective responses were observed.

Eribulin mesylate (E7389), a tubulin and microtubule inhibitor, has been approved to treat metastatic breast cancer in certain patient populations. A liposomal formulation of E7389, E7389-LF, aims to increase the therapeutic profile of E7389. As determining the free drug concentration is crucial for the assessment of efficacy and toxicity of liposomal drug, in this study, an ultracentrifugation method coupled with LC–MS/MS was developed to separate the free E7389 from liposomal and protein bound E7389. The pharmacokinetics of the free E7389 after dosing either E7389 or E7389-LF was characterized. The concentration ratio of E7389 in ultracentrifuged mice plasma (UCM) vs E7389 in plasma after a 2 mg/kg i.v. of E7389 ranged from 54.19% to 65.41%, which was similar to the free fraction in the mouse plasma. The respective concentration ratio of E7389 in UCM vs E7389 in plasma after a 2 mg/kg i.v. of E7389-LF ranged from 0.07% to 0.59%, and the exposure, expressed as AUC, of UCM/plasma ratio was determined to be 0.2%. Pharmacokinetic modeling was performed to estimate the release kinetics of E7389 from E7389-LF, and the release was best described by a first order rate constant krel 0.078 h−1. Sensitivity analysis demonstrated that further decrease the release rate constant by adjusting liposome formulation would lead to decreased Cmax and much longer half-life of UCM E7389, which might result in better efficacy and lower toxicity.

Purpose: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies. Experimental Design: Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m2 with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized. Results: Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m2). Neutropenia was the principal DLT: At 1.4 mg/m2, two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m2. Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease. Conclusions: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m2 with further dose escalation limited by neutropenia and fatigue.

Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range0.1-14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR.The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine.

Eribulin is a new anticancer agent currently in Phase III clinical trials for the treatment of metastatic breast cancer. In the current studies, we have investigated the effects of P-glycoprotein (P-gp) on the in vivo disposition of eribulin using CF-1 abcb1a-deficient mice, and the influence of eribulin on P-gp-mediated efflux of digoxin in Caco-2 cells. Eribulin was administered intravenously and orally in both CF-1 wild-type and CF-1 abcb1a-deficient mice. P-gp-mediated efflux of digoxin in Caco-2 cell monolayers was measured in the presence of eribulin. The plasma exposure to eribulin was higher in CF-1 abcb1a-deficient mice than that in CF-1 wild-type mice after intravenous (IV) and oral (PO) administrations. The oral bioavailability of eribulin was 62.3% in CF-1 abcb1a-deficient mice compared with 7.6% in wild-type mice. The brain penetration of eribulin in CF-1 abcb1a-deficient mice was 30-fold greater than that in wild-type mice. Eribulin decreased the efflux ratio of digoxin in a concentration-dependent manner, with the result of IC(50) greater than 10 µM. The [I]/IC(50) of eribulin was estimated to be

An LC/MS/MS method was developed to quantify carboplatin and eribulin mesylate (E7389) in human plasma and urine. For carboplatin, sample clean-up by protein precipitation and supernatant injection into a Waters Spherisorb((R)) S5 SCX column was used. Liquid-phase extraction and reverse-phase chromatography on a Polaris C18 column were used for eribulin. Quantitation involved LC/MS/MS with positive electrospray ionization. Accuracy, precision, linearity, range, specificity, recovery and stability were also evaluated. Both compounds were stable in human plasma (or=80 days at -80 degrees C), at room temperature (or=4h), following three freeze-thaw cycles and in 50/50 methanol/H(2)O (4 degrees C foror=252 days).

Neuropathy arising from chemotherapy (CIPN) is a major clinical problem representing the dose-limiting side effect of many antineoplastic drugs. At their respective MTDs, we previously reported paclitaxel and ixabepilone produced more severe deficits in nerve conduction velocity, amplitude and degenerative changes in dorsal root ganglia (DRG) and sciatic nerve (SN) versus eribulin mesylate (Wozniak et al 2011). Similar trends for eribulin to cause less neuropathy have also been reported in the clinic (Cigler and Vadhat 2010, Jain and Cigler 2012, Vadhat et al 2013). The underlying reason for this differential effect remains elusive. Differences in tubulin binding may, in part, explain the differential effect (Perez et al 2009, Jordan et al 2005). Another potential explanation could reside in different pharmacokinetic (PK) and nervous tissue distribution of these agents. Toward this latter point, we conducted tissue distribution and pharmacokinetic studies following acute dosing of eribulin mesylate, paclitaxel and ixabepilone. We reported that while all three drugs rapidly cleared from plasma, they distributed into and cleared slowly (>3 days) from peripheral nervous system tissues (Wozniak et al 2014). We have now extended these studies to look out to 42 days following both acute and 2 week MTD-dosing paradigms evaluating drug pharmacokinetics in plasma, DRG and SN as well as pharmacodynamic measurements of nerve conduction and amplitude. We found plasma levels of eribulin mesylate and paclitaxel rapidly declined over 24h after infusion. In contrast, the levels of eribulin mesylate and paclitaxel persisted at above quantification levels (ranging from 5-10 ng/g) for 7 to 14 days post cessation of 2 week MTD dosing. Eribulin mesylate consistently showed greater distribution into DRG and SN over paclitaxel. When comparing the induced nerve conduction deficits, we found paclitaxel and eribulin mesylate caused reduction of nerve conduction parameters similar to our previous studies, most notably in caudal nerve amplitude (by 80.5% and 54.9% respectively). However these deficits, which were sustained for up to several weeks after cessation of dosing, were more severe with paclitaxel. The findings demonstrate that despite eribulin mesylate showing higher nervous tissue distribution than paclitaxel, eribulin mesylate caused less neurotoxicity as evidenced by milder reductions in nerve conduction and amplitude. This work was financially supported by Eisai. Citation Format: Krystyna Wozniak, Ying Wu, Bruce A. Littlefield, Kenichi Nomoto, Christopher DesJardins, Yanke Yu, George Lai, Larisa Reyderman, Barbara S. Slusher. Pharmacokinetics and pharmacodynamic analysis of eribulin mesylate and paclitaxel in mouse. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4503. doi:10.1158/1538-7445.AM2015-4503

The sequences of two giant viral genomes, Mimivirus and a polydnavirus, have revealed unusual features that challenge the way we view the evolution and definition of viruses., The sequences of two giant viral genomes, Mimivirus and a polydnavirus, have recently been published. Mimivirus has the largest known viral genome and encodes an unprecedented number of proteins, whereas the polydnavirus genome has an extremely low coding density and does not encode DNA-replication proteins. These and other unusual features challenge the way we view the evolution and definition of viruses.

Chemotherapy-induced peripheral neurotoxicity is a major clinical problem representing the dose-limiting side effect of many antineoplastic drugs. The degree and type of neuropathy incurred is dependent on the chemotherapeutic drug, dose intensity, and cumulative dose. In an earlier study by our group, we found that paclitaxel and ixabepilone, administered to mice at their respective MTDs, produced dose dependent deficits in caudal nerve conduction velocity, caudal amplitude and digital nerve amplitudes, as well as moderate to severe degenerative pathologic changes in dorsal root ganglia (DRG) and sciatic nerve (SN). In contrast, eribulin mesylate produced no significant deleterious effects on any nerve conduction parameter measured and caused milder, less frequent effects on morphology. Similar trends for eribulin to cause less neuropathy (including later onset and resolution) in the clinic have also been reported (Cigler and Vadhat, 2010; Jain and Cigler 2012, Vadhat et al., 2013). Differences in tubulin binding may, in part, potentially explain the differential effect (Perez et al 2009; Jordan et al 2005). Another potential explanation may reside in different pharmacokinetic (PK) and peripheral nerve distribution of these agents. To elucidate this, mice received a single dose of paclitaxel, ixabepilone or eribulin mesylate (30, 3 and 1.75mg/kg respectively, based on an MTD regimen), administered IV into the caudal vein. Plasma, DRG and SN samples were obtained at 0.25, 1, 3, 6, 8, 24, 48, and 72 h post dose. Tissues were homogenized and after extraction, concentrations of eribulin mesylate, ixabepilone and paclitaxel were determined in each matrix using LC/MS/MS. PK parameters were calculated using noncompartmental analysis in WinNonLin v 5.0.3. We report that all 3 chemotherapies rapidly penetrated both SN and DRG with maximal concentrations seen at, or within 15 mins after administration. Concentrations of all 3 agents in DRG and SN then declined by 30-50% over the first 1-3h and thereafter remained relatively stable in the tissue for up to 72 h, despite clearing rapidly from plasma to reach levels below quantification, ( This work was financially supported by Eisai. Citation Format: Krystyna Wozniak, Ying Wu, Kenichi Nomoto, Bruce A. Littlefield, Christopher DesJardins, Edgar Schuck, Phil Saxton, Nancy Wong, Barbara S. Slusher. Pharmacokinetics and biodistribution of eribulin mesylate, paclitaxel, and ixabepilone in mouse. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4653. doi:10.1158/1538-7445.AM2014-4653