Eribulin Induction of Immunogenic Cell Death (ICD): Comparison With Other Cytotoxic Agents and Temporal Relationship of ICD Biomarkers.

Background/aim: Preclinical studies were undertaken to investigate whether eribulin's known cytotoxic antimitotic effects are characterized by immunogenic cell death (ICD) as assessed by three established ICD biomarkers: extracellular released ATP, released HMGB1 and cell surface calreticulin.

Materials And Methods: Using BT-549, Hs578T and MCF-7 breast cancer cell lines, antiproliferative IC's of eribulin, five other microtubule targeting agents (MTAs; ER-076349, vinblastine, vinorelbine, paclitaxel, docetaxel) and three DNA damaging agents (DDAs; doxorubicin, cisplatin, oxaliplatin) were determined.

Results: Treatment of cells with 10×IC concentrations of all drugs in serum-free media resulted in time-dependent induction of cytotoxicity over DMSO controls.

Doublet and Triplet Combinations of Eribulin, Fulvestrant, and Palbociclib in Preclinical Breast Cancer Models.

Background/aim: This study investigated in vivo synergism between eribulin and palbociclib in a breast cancer patient-derived xenograft (PDX) model, with expanded scope to include fulvestrant as a third drug.

Materials And Methods: Eribulin plus palbociclib combinations were tested in vitro in six cell lines each of estrogen receptor positive and triple-negative breast cancer, and in vivo in the OD-BRE-0192 PDX model using weekly eribulin plus 5×/week or 7×/week palbociclib (holiday or no-holiday schedules, respectively). When included as a third drug, fulvestrant was dosed weekly.

Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE).

Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine against 100 human cancer cell lines from the Cancer Cell Line Encyclopedia, and correlated results with publicly available databases to identify genes and pathways associated with eribulin response, either uniquely or shared with paclitaxel or vinorelbine. Mean expression ratios of 11,985 genes between the most and least sensitive cell line quartiles were sorted by -values and drug overlaps, yielding 52, 29 and 80 genes uniquely associated with eribulin, paclitaxel and vinorelbine, respectively.

GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells.

Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after drug treatment. We performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. We showed that the growth differentiation factor 15 (GDF15) is a protein significantly over-secreted upon eribulin treatment.

Molecular Biomarkers of Response to Eribulin in Patients with Leiomyosarcoma.

Purpose: A randomized phase III study evaluated the efficacy of eribulin versus dacarbazine in patients with advanced liposarcoma and leiomyosarcoma. Improved overall survival (OS) led to approval of eribulin for liposarcoma, but not for leiomyosarcoma.

Experimental Design: We explored the molecular profile of 77 archival leiomyosarcoma samples from this trial to identify potential predictive biomarkers, utilizing low-coverage whole-genome and whole-exome sequencing.

Multiple modes of action of eribulin mesylate: Emerging data and clinical implications.

Eribulin mesylate (eribulin) is a synthetic analogue of the marine-sponge natural product halichondrin B. Eribulin exhibits potent antiproliferative activities against a variety of human cancer cell types in vitro and in vivo, and is used for the treatment of certain patients with advanced breast cancer or liposarcoma who are refractory to other treatments. The antiproliferative effects of eribulin have long been attributed to its antimitotic activities.

Broad-spectrum Preclinical Antitumor Activity of Eribulin (Halaven®): Combination with Anticancer Agents of Differing Mechanisms.

Background: Eribulin is used in many countries to treat patients with advanced breast cancer or liposarcoma and exerts in vivo anticancer activity under monotherapy conditions against various human tumor xenograft models. Here, eribulin in combination with mechanistically different anticancer agents was evaluated.

Materials And Methods: Eribulin was combined with cytotoxic agents (capecitabine, carboplatin, cisplatin, doxorubicin, gemcitabine) or targeted agents (bevacizumab, BKM-120, E7449, erlotinib, everolimus, lenvatinib, palbociclib) in tumor xenograft models of breast cancer, melanoma, non-small cell lung cancer (NSCLC), and ovarian cancer.

Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery.

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.

Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment with microtubule-targeted agents (MTAs). The frequency of severe CIPN, which can be dose limiting and even life threatening, varies widely among different MTAs. For example, paclitaxel induces a higher frequency of severe CIPN than does eribulin.

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

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.

Effects of Paclitaxel and Eribulin in Mouse Sciatic Nerve: A Microtubule-Based Rationale for the Differential Induction of Chemotherapy-Induced Peripheral Neuropathy.

Microtubule targeting agents (MTAs) often lead to treatment limiting and life threatening side effects, including chemotherapy-induced peripheral neuropathy (CIPN). The frequency of severe CIPN varies among different MTAs. Since the microtubule binding interactions and mechanisms of action also vary among MTAs, we hypothesized that these distinct mechanisms may underlie the variability in frequency of severe CIPN.

Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.

Patients with non-Hodgkin lymphoma (NHL) are treated today with a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Subsets of patients with NHL of germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical testing of the EZH2 inhibitor EPZ-6438 has recently begun in patients.

Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy.

Eribulin mesylate (E7389, INN:eribulin mesilate Halaven(®)) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone.

Broad spectrum preclinical antitumor activity of eribulin (Halaven(R)): optimal effectiveness under intermittent dosing conditions.

Background: Eribulin is a pharmaceutically and structurally optimized analog of the marine sponge natural product halichondrin B. Its salt form, eribulin mesylate (Halaven®) is clinically used in the United States, the European Union, and Japan for the treatment of heavily pretreated patients with metastatic breast cancer, who previously received an anthracycline and a taxane. Early preclinical studies of this new inhibitor of microtubule dynamics showed high antitumor potency towards several human cancer types in vitro and in vivo.

In vitro and in vivo anticancer activity of (+)-spongistatin 1.

The marine natural product (+)-spongistatin 1 is an extremely potent growth inhibitory agent having activity against a wide variety of cancer cell lines, while exhibiting low cytotoxicity against quiescent human fibroblasts. Consistent with a microtubule-targeting mechanism of action, (+)-spongistatin 1 causes mitotic arrest in DU145 human prostate cancer cells. More importantly, (+)-spongistatin 1 exhibits significant in vivo antitumor activity in the LOX-IMVI human melanoma xenograft model.

Effective antibody therapy induces host-protective antitumor immunity that is augmented by TLR4 agonist treatment.

Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of the adaptive immune response that can be utilized for therapeutic purposes. We tested the hypothesis that combined treatment with a Toll-like receptor agonist and an antitumor monoclonal antibody is effective and induces host-protective antitumor immunity. C57BL/6 human mutated HER2 (hmHER2) transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter were established.

Heavy metal and pesticide content in commonly prescribed individual raw Chinese Herbal Medicines.

Heavy metal and pesticide contamination has previously been reported in Chinese Herbal Medicines (CHMs), in some cases at potentially toxic levels. This study was conducted to determine general patterns and toxicological significance of heavy metal and pesticide contamination in a broad sample of raw CHMs. Three-hundred-thirty-four samples representing 126 species of CHMs were collected throughout China and examined for arsenic, cadmium, chromium, lead, and mercury.

Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice.

Chemotherapy-induced neurotoxicity is a significant problem associated with successful treatment of many cancers. Tubulin is a well-established target of antineoplastic therapy; however, tubulin-targeting agents, such as paclitaxel and the newer epothilones, induce significant neurotoxicity. Eribulin mesylate, a novel microtubule-targeting analogue of the marine natural product halichondrin B, has recently shown antineoplastic activity, with relatively low incidence and severity of neuropathy, in metastatic breast cancer patients.

Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo.

Eribulin mesylate is a newly approved treatment for locally advanced and metastatic breast cancer. We targeted oral bioavailability and efficacy against multidrug resistant (MDR) tumors for further work. The design, synthesis and evaluation of novel amine-containing analogs of eribulin mesylate are described in this part.

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

Novel second generation analogs of eribulin mesylate, a tubulin agent recently approved for the treatment of breast cancer, are reported. Our recent efforts have focused on expanding the target indications for this class of compounds to other tumor types. Herein, we describe the design, synthesis and evaluation of eribulin analogs active against brain tumor cell lines in vitro and corresponding brain tumor models in mice.

Novel second generation analogs of eribulin. Part I: Compounds containing a lipophilic C32 side chain overcome P-glycoprotein susceptibility.

Eribulin mesylate (Halaven™), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux.

Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions.

Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival.

Developing a library of authenticated Traditional Chinese Medicinal (TCM) plants for systematic biological evaluation--rationale, methods and preliminary results from a Sino-American collaboration.

While the popularity of and expenditures for herbal therapies (aka "ethnomedicines") have increased globally in recent years, their efficacy, safety, mechanisms of action, potential as novel therapeutic agents, cost-effectiveness, or lack thereof, remain poorly defined and controversial. Moreover, published clinical trials evaluating the efficacy of herbal therapies have rightfully been criticized, post hoc, for their lack of quality assurance and reproducibility of study materials, as well as a lack of demonstration of plausible mechanisms and dosing effects. In short, clinical botanical investigations have suffered from the lack of a cohesive research strategy which draws on the expertise of all relevant specialties.

Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability.

Eribulin mesylate (E7389), a synthetic analogue of the marine natural product halichondrin B, is in phase III clinical trials for the treatment of cancer. Eribulin targets microtubules, suppressing dynamic instability at microtubule plus ends through an inhibition of microtubule growth with little or no effect on shortening [Jordan, M. A.