cabazitaxel and Brain-Neoplasms

Brain metastases from prostate cancer (PC) seem to be more frequent than in the past, possibly because advances in the treatment of patients with castration-resistant PC have prolonged their survival. Furthermore, docetaxel (the drug of choice for the first-line treatment of castration-resistant PC) cannot cross the blood-brain barrier and control metastatic foci. However, this problem may be overcome by new active drugs such as cabazitaxel.

Topics: Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Docetaxel; Humans; Male; Prostatic Neoplasms; Taxoids

Glioblastoma (GBM) is the most aggressive brain tumor with poor prognosis and frequent recurrence. The blood-brain barrier (BBB), blood-brain tumor barrier (BBTB) hinder the entry of therapeutics into the glioma region. Vasculogenic mimicry (VM) formed by invasive glioma cells is also related to recurrence of GBM. VAP is a D-peptide ligand of GRP78 protein overexpressed on BBTB, VM, and glioma cells but not on normal tissues. Besides, p-hydroxybenzoic acid (pHA) can effectively traverse the BBB. Herein we developed an all-stage glioma-targeted cabazitaxel (CBZ) nanocrystal loaded liposome modified with a "Y" shaped targeting ligand composed of pHA and VAP (pV-Lip/cNC). The pure drug nanocrystal core provided high drug loading, while lipid membrane promoted the stability and circulation time. pV-Lip/cNC exhibited excellent glioma homing, barriers crossing, and tumor spheroid penetrating capability in vitro. Treatment of pV-Lip/cNC displayed enhanced CBZ accumulation in glioma and anti-glioma effect with a median survival time (53 days) significantly longer than that of cNC loaded liposomes modified with either single ligand (42 days for VAP and 45 days for pHA) in the murine orthotopic GBM model. These results indicated pV-Lip/cNC could traverse the BBB and BBTB, destruct VM, and finally kill glioma cells to realize all-stage glioma therapy.

Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Glioblastoma; Glioma; Ligands; Lipids; Liposomes; Mice; Nanoparticles; Taxoids

Treatment of glioblastoma and other diseases in the brain is especially challenging due to the blood-brain barrier, which effectively protects the brain parenchyma. In this study we show for the first time that cabazitaxel, a semi-synthetic derivative of docetaxel can cross the blood-brain barrier and give a significant therapeutic effect in a patient-derived orthotopic model of glioblastoma. We show that the drug crosses the blood-brain barrier more effectively in the tumor than in the healthy brain due to reduced expression of p-glycoprotein efflux pumps in the vasculature of the tumor. Surprisingly, neither ultrasound-mediated blood-brain barrier opening (sonopermeation) nor drug formulation in polymeric nanoparticles could increase either accumulation of the drug in the brain or therapeutic effect. This indicates that for hydrophobic drugs, sonopermeation of the blood brain barrier might not be sufficient to achieve improved drug delivery. Nonetheless, our study shows that cabazitaxel is a promising drug for the treatment of brain tumors.

Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Docetaxel; Female; Glioblastoma; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasms, Experimental; Taxoids; Xenograft Model Antitumor Assays

Cabazitaxel is a second-generation semisynthetic taxane. The recognized anti-neoplastic effect of Cabazitaxel is cell cycle perturbation by inducing arrest at G2/M. Since glioblastoma tumors have a relatively high expression of P-gp, it is encouraging to find a treatment that is effective against these tumors. This study was conducted to examine the radiosensitizing potential of Cabazitaxel against U87MG cells. In order to evaluate the effect of Cabazitaxel, cells were treated with different concentrations of the drug at different time intervals and then cytotoxicity and cell cycle were assessed using MTT and flow cytometry assays, respectively. Annexin/PI and real-time polymerase chain reaction (PCR) assays were used to evaluate the extent of apoptosis. Cabazitaxel exerted a consistent G2/M arrest and resulted in a concentration- and time-dependent toxicity. Cabazitaxel enhanced the cytotoxicity response of U87MG cells to radiation. Apoptosis increased following Cabazitaxel-IR administration. At the same time, these results were further supported by apoptotic genes regulation. This study provides the first preclinical evidence supporting that Cabazitaxel can render U87MG cells more susceptible to the cytotoxicity of radiation and could potentially be administered in combination modalities as a promising cell cycle-specific radiosensitizer for the future steps of in vivo evaluation.

Topics: Apoptosis; Brain Neoplasms; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Taxoids

Nanoparticles provide a unique opportunity to explore the benefits of selective distribution and release of cancer therapeutics at sites of disease through varying particle sizes and compositions that exploit the enhanced permeability of tumor-associated blood vessels. Though delivery of larger as opposed to smaller and/or actively transported molecules to the brain is prima facie a challenging endeavor, we wondered whether nanoparticles could improve the therapeutic index of existing drugs for use in treating brain tumors via these vascular effects. We therefore selected a family of nanoparticles composed of cabazitaxel-carboxymethyl cellulose amphiphilic polymers to investigate the potential for delivering a brain-penetrant taxane to intracranial brain tumors in mice. Among a small set of nanoparticle formulations, we found evidence for nanoparticle accumulation in the brain, and one such formulation demonstrated activity in an orthotopic model of glioma, suggesting that such nanoparticles could be useful for the treatment of glioma and brain metastases of other tumor types.

Topics: Animals; Antineoplastic Agents; Brain; Brain Neoplasms; Carboxymethylcellulose Sodium; Cell Line, Tumor; Drug Delivery Systems; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Polyethylene Glycols; Taxoids

We describe the case of a 55-year-old man who underwent four cycles of cabazitaxel therapy for castration-resistant prostate cancer (CRPC). After the fourth cycle of cabazitaxel, the patient experienced severe headaches. Brain gadolinium (Gd) contrast-enhanced magnetic resonance imaging (MRI) revealed multiple brain metastases. A few days later, the patient suffered impaired consciousness that progressed rapidly. The patient was treated for the symptoms of increased intracranial pressure and underwent whole-brain radiation. One month later, the patient's consciousness level and headache had improved. Although brain metastases of prostate cancer are rare, the possibility of brain metastases should be considered for prostate cancer patients, especially when a CRPC patient complains of headache. Additionally, even if major conditions such as cerebral hemorrhage are excluded by the use of non-contrast-enhanced computed tomography, brain Gd contrast-enhanced MRI should be performed in consideration of the possibility of brain metastases of prostate cancer.

Topics: Antineoplastic Agents; Brain Neoplasms; Contrast Media; Disease Progression; Gadolinium; Gamma Rays; Headache; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Taxoids

Taxanes target microtubules and are clinically established chemotherapeutic agents with proven efficacy in human cancers. Cabazitaxel (XRP-6258, Jevtana®) is a second generation semisynthetic taxane with high chemotherapeutic potential in prostate cancer. There, cabazitaxel can overcome docetaxel-resistant prostate cancer. Here, we tested the effects of cabazitaxel on glioma cells, and non-transformed cells such as neurons and astrocytes. Cabazitaxel operates highly toxic in various human glioma cells at nanomolar concentrations. In contrast, primary astrocytes and neurons are not affected by this agent. Cabazitaxel disrupts cytoskeletal F-actin fibers and induces apoptotic cell death in gliomas. Moreover, cabazitaxel displayed highest efficacy in inhibiting glioma cell migration and invasion. Here we demonstrate that cabazitaxel inhibited tumor migration already at 1 nM. We also tested cabazitaxel in the ex vivo VOGiM assay. Cabazitaxel stalled glioma growth and at the same time inhibited tumor-induced angiogenesis. In summary, we found that cabazitaxel operates as an apoptosis-inducing gliomatoxic agent with strongest effects on migration and invasive growth. Thus, our report uncovered cabazitaxel actions on gliomas and on the brain tumor microenvironment. These data reveal novel aspects for adjuvant approaches when applied to brain tumor patients.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glioma; Humans; Neovascularization, Pathologic; Rats; Rats, Wistar; Taxoids

There is an unmet need in the treatment of pediatric brain tumors for chemotherapy that is efficacious, avoids damage to the developing brain, and crosses the blood-brain barrier. These experiments evaluated the efficacy of cabazitaxel in mouse models of pediatric brain tumors.. The antitumor activity of cabazitaxel and docetaxel were compared in flank and orthotopic xenograft models of patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, and central nervous system primitive neuroectodermal tumor (CNS-PNET). Efficacy of cabazitaxel and docetaxel were also assessed in the Smo/Smo spontaneous mouse medulloblastoma tumor model.. This study observed significant tumor growth inhibition in pediatric patient-derived flank xenograft tumor models of ATRT, medulloblastoma, and CNS-PNET after treatment with either cabazitaxel or docetaxel. Cabazitaxel, but not docetaxel, treatment resulted in sustained tumor growth inhibition in the ATRT and medulloblastoma flank xenograft models. Patient-derived orthotopic xenograft models of ATRT, medulloblastoma, and CNS-PNET showed significantly improved survival with treatment of cabazitaxel.. These data support further testing of cabazitaxel as a therapy for treating human pediatric brain tumors.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Disease Models, Animal; Docetaxel; Drug Evaluation, Preclinical; Female; Humans; Male; Maximum Tolerated Dose; Medulloblastoma; Mice; Mice, Inbred C57BL; Mice, Nude; Neuroectodermal Tumors; Rhabdoid Tumor; Survival Analysis; Taxoids; Teratoma; Treatment Outcome; Xenograft Model Antitumor Assays

While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed.. Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51.. Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence.. These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain; Brain Neoplasms; Child, Preschool; Cisplatin; Dogs; Drug Synergism; Female; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasm Staging; Neoplasms; Neoplasms, Experimental; Rats; Rats, Sprague-Dawley; Species Specificity; Taxoids; Tissue Distribution; Xenograft Model Antitumor Assays; Young Adult