Diagnostic and Therapeutic Implications of a FUS::TFCP2 Fusion and ALK Activation in a Metastatic Rhabdomyosarcoma.

The identification of gene fusions in rare sarcoma subtypes can have diagnostic, prognostic, and therapeutic impacts for advanced cancer patients. Here, we present a case of a 31-year-old male with a lytic lesion of the left mandible initially diagnosed as an osteosarcoma but found to have a TFCP2 fusion and ALK alteration, redefining the diagnosis and providing rationale for a novel treatment strategy. Histologically, the tumor displayed hypercellular, spindled to epithelioid neoplasm and nuclear pleomorphism, while immunohistochemistry showed diffuse SATB2 and focal desmin staining. Whole genome and transcriptome analysis revealed a FUS::TFCP2 fusion, the defining alteration of a rare molecularly characterized subtype of soft tissue sarcoma termed intraosseous rhabdomyosarcoma. An internal ALK deletion and extremely high ALK RNA expression were also identified, suggesting potential benefit of an ALK inhibitor. This patient displayed a rapid and dramatic clinical and radiographic response to an ALK inhibitor, alectinib. Unfortunately, the response was short-lived, likely due to the advanced stage and aggressiveness of the disease. This report describes genome and transcriptome characterization of an intraosseous rhabdomyosarcoma, few of which exist in the literature, as well as providing evidence that inhibition of ALK may be a rational treatment strategy for patients with this exceedingly rare soft tissue sarcoma subtype characterized by TFCP2 fusions and ALK activation.

Heterozygosity for CMT Type 4 Predicts a Severe Vincristine-induced Polyneuropathy Phenotype: A Case Report and Review of Literature.

Vincristine (VCR) is a common chemotherapeutic agent used in the treatment of multiple types of pediatric tumors. VCR's adverse effects are well documented and commonly involve peripheral neuropathy via axonal degeneration. Neuropathic severity is dose-dependent, with sensory deficits occurring with as little as 4 mg cumulative dose. Severe peripheral neuropathy is generally rare, but its effects become additive when given to patients with undiagnosed hereditary peripheral neuropathy such as Charcot-Marie-Tooth. We report a case of an effect of VCR administration given to a patient who developed grade 4 neuropathy and was found to be a carrier of Charcot-Marie-Tooth disease type 4.

Radical Surgery for Head and Neck Rhabdomyosarcoma Failed Primary Chemotherapy.

OBJECTIVE: The aim of the study was to explore an optimal surgery way for head and neck rhabdomyosarcoma (HNRMS) children who have failed primary chemotherapy. METHODS: A total of 51 HNRMS children who have failed primary chemotherapy were retrospectively analyzed from April 2005 to May 2017. Surgery was performed in 2 ways, widely radical resection (22 patients) and conservative resection (29 patients). Multivariate analysis was performed to identify the various variables related to overall survival (OS). RESULTS: The estimated 5-year OS was 53%. Embryonic RMS enjoyed a favorable outcome than those nonembryonic RMS (P = 0.03). Head and neck rhabdomyosarcoma children who received partial remission (PR) after primary chemotherapy enjoyed a better outcome than those only achieved stable disease (SD) (P = 0.006). A total of 22 children accepted widely radical resection, whereas 29 patients got conservative resection. Interestingly, the 2 groups did not have a statistical significance (P = 0.86). However, the latter group children have conserved more important organs, such as eyeball, facial nerves, and enough mandible or maxilla bones, and have enjoyed a better life quality. CONCLUSION: Primary chemotherapy is most important for HNRMS children, which influences the prognosis of HNRMS widely. Conservative resection is an optimal surgery way for HNRMS, bringing a better life quality for these children.

Rapid liposomal formulation for nucleolin targeting to rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. More effective and less toxic therapies are urgently needed for high-risk patients. Peptide-guided targeted drug delivery can increase the therapeutic index of encapsulated drugs and improve patients' well-being. To apply this strategy to RMS, we identified the peptide F3 in a screening for peptides binding to RMS cells surface. F3 binds to nucleolin, which is present on the surface of RMS cells and is abundantly expressed at the mRNA level in RMS patients' biopsies compared to healthy tissues. We developed a rapid microfluidic formulation of F3-decorated PEGylated liposomes and remote loading of the chemotherapeutic drug vincristine. Size, surface charge, drug loading and retention of targeted and control liposomes were studied. Enhanced cellular binding and uptake were observed in three different nucleolin-positive RMS cell lines. Importantly, F3-functionalized liposomes loaded with vincristine were up to 11 times more cytotoxic than non-targeted liposomes for RMS cell lines. These results demonstrate that F3-functionalized liposomes are promising for targeted drug delivery to RMS and warrant further in vivo investigations.

Evaluation of Dose-Response Relationship in Novel Extended Release of Targeted Nucleic Acid Nanocarriers to Treat Secondary Cataracts.

Purpose: The present study aimed to determine the dose-response relationship between targeted nanocarriers released from a novel, sustained release formulation and their ability to specifically deplete cells responsible for the development of posterior capsular opacification (PCO) in month-long, dynamic cell cultures. Methods: Injectable, thermosensitive poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic-co-glycolic acid) triblock copolymer hydrogels were loaded with either a low or a high dose of doxorubicin-loaded antibody-targeted nanocarriers (G8:3DNA:Dox). Human rhabdomyosarcoma cells, selected for their expression of PCO marker brain-specific angiogenesis inhibitor 1 (BAI1), were kept under dynamic media flow and received either a low or high dose of nanocarriers. Cells were fixed and stained at predetermined time points to evaluate targeted depletion of BAI1+ cells. Results: A lower dose of nanocarriers in hydrogel depleted BAI1+ cells at a slower rate than the higher dose, whereas both reached over 90% BAI1+ cellular nonviability at 28 days. Both treatment groups also significantly lowered the relative abundance of BAI1+ cells in the population compared with the control group. Conclusions: Controlled release of a lower dose of nanocarriers can still achieve therapeutically relevant effects in the prevention of PCO, while avoiding potential secondary effects associated with the administration of a higher dose.

Intraosseous Spindle Cell/Epithelioid Rhabdomyosarcoma with TFCP2 Rearrangement: A Recent Recognized Subtype with Partial Response to Alectinib.

Rhabdomyosarcoma affects mainly pediatric patients and is currently classified into four categories: embryonal, alveolar, pleomorphic, and spindle cell/sclerosing. Recently, a molecular group of spindle cell/sclerosing rhabdomyosarcoma demonstrated new fusion transcripts involving FET-family genes with TFCP2. In this report, we describe a rare case of spindle cell/sclerosing rhabdomyosarcoma in a 19-year-old woman, presenting as a destructive lesion involving the condyle of mandible. Next generation sequencing was performed, revealing a FUS::TFCP2 fusion and deletion of ALK gene. Alectinib therapy was initiated, which resulted in a favorable response for 4 months. However, the patient died due progression of the tumor. To make an accurate diagnosis and ensure appropriate patient management, it is necessary to be aware of this variant and use proper immunohistochemical stains when facing malignant mesenchymal bone lesions, expanding its differential diagnosis.

Developmental dental defects linked with chemoradiotherapy: a case report.

Developmental orofacial dentoalveolar complications associated with chemoradiotherapy in an 8 year old child with a history of rhabdomyosarcoma are reported. This report details, clinically and radiographically, these effects in a child diagnosed at 3 years of age with a lesion primary to the left buccinator. Early evaluation is vital to determine potential dentoalveolar complications and long-term consequences.

The mannose 6-phosphate receptor targeted with porphyrin-based periodic mesoporous organosilica nanoparticles for rhabdomyosarcoma theranostics.

Porphyrin-based periodic mesoporous organosilica nanoparticles (PMO) synthesized from a large functional octatriethoxysilylated porphyrin precursor and allowing two-photon excitation photodynamic therapy (TPE-PDT) and NIR imaging were synthesized. These PMO were grafted with polyethylene glycol (PEG) moieties and an analogue of mannose 6-phosphate functionalized at the anomeric position (AMFA). AMFAs are known to efficiently target mannose 6-phosphate receptors (M6PRs) which are over-expressed in various cancers. Here, we demonstrated for the first time that M6PRs were over-expressed in rhabdomyosarcoma (RMS) cells and could be efficiently targeted with PMO-AMFA allowing TPE imaging and TPE-PDT of RMS cells. The comparison with healthy myoblasts demonstrated an absence of biological effects, suggesting a cancer cell specificity in the biomedical action observed.

Prolonged circulation and increased tumor accumulation of liposomal vincristine in a mouse model of rhabdomyosarcoma.

AIM: Our goal was to improve vincristine (VCR) based rhabdomyosarcoma (RMS) therapy by encapsulating the drug into liposomes. A targeting strategy was attempted to enhance tumor accumulation. MATERIALS & METHODS: VCR was loaded in control and peptide-decorated liposomes via an active method. The interaction of an RMS-specific peptide with the presumed target furin and the cellular uptake of both liposomal groups were studied in vitro. Pharmacokinetics and biodistribution of VCR-containing liposomes were assessed in an RMS xenograft mouse model. RESULTS: Liposomes ensured high VCR concentration in plasma and in the tumor. Peptide-decorated liposomes showed modest uptake in RMS cells. CONCLUSION: The investigated peptide-modified liposomal formulation may not be optimal for furin-mediated RMS targeting. Nevertheless, VCR-loaded liposomes could serve as a delivery platform for experimental RMS.

A pharmacokinetic study of lipegfilgrastim in children with Ewing family of tumors or rhabdomyosarcoma.

PURPOSE: Neutropenia is a common complication from chemotherapy, limiting optimal dosing and treatment. Lipegfilgrastim is a long-acting granulocyte colony-stimulating factor developed for the management of chemotherapy-induced neutropenia. The objectives of this phase 1, multinational, open-label, single-arm study were to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a single body weight-adjusted dose of lipegfilgrastim and to evaluate the efficacy, safety, and tolerability of the drug in children with Ewing family of tumors or rhabdomyosarcoma treated with myelosuppressive chemotherapy. METHODS: Enrolled patients received lipegfilgrastim (100 µg/kg) 24 h after the last chemotherapy treatment in week 1. Patients were stratified into three age groups: 2 to <6, 6 to <12, and 12 to <18 years. Blood samples for PK analyses were obtained at baseline and at 3, 8, 24, 30, 48, 72, 96, 144, and 240 h postdose for the two oldest groups and up to 144 h in the youngest group. RESULTS: Twenty-one patients were enrolled and received lipegfilgrastim, seven in each age group. Lipegfilgrastim exposure levels were comparable across age groups, with concentrations maintained over a prolonged period after a single injection. Differences in PD were mainly associated with chemotherapy type. Most investigator-reported adverse events were attributed to chemotherapy and not to lipegfilgrastim. Severe adverse events were noted in 57% of patients; febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia were more frequent among the oldest patients. CONCLUSIONS: Results support the use of a body weight-adjusted dose to achieve equivalent initial peak exposure levels of lipegfilgrastim in children of various ages.

Hyperthermia enhances tumor uptake and antitumor efficacy of thermostable liposomal daunorubicin in a rat solid tumor.

The combination of local hyperthermia (HT) with thermostable liposomal daunorubicin (DaunoXome, DX) was investigated to assess targeted drug delivery to experimental tumors. Female Wag/Rij rats bearing solid R-1 rhabdomyosarcomas received i.v. injections of 10 or 15 mg/kg of DX or free-Daunorubicin (f-Dau). After a 1-h interval, HT (60 min at 43 degrees C) was applied. Pharmacokinetics were studied in relation to tumor growth time (TGT), i.e., the time for tumors to reach their original volumes. Pharmacokinetic studies revealed that DX accumulation in tumor tissue was similar to f-Dau. A 5.4-fold increase (P = 0.0084) in tumor drug delivery was observed when DX was combined with HT, whereas liposomes remained stable. For f-Dau, HT had an additional effect on TGT at both drug doses tested (9.6 and 6.2 days, respectively, for 10 mg/kg, P = 0.0092; 17.7 and 13.7, respectively, for 15 mg/kg, P = 0.0431). For DX, HT significantly enhanced TGT of DX in the lower dose (17.1 and 6.4 days, respectively, P = 0.0005), whereas tumors did not regrow at day 25 after DX + HT in the higher dose. Unfortunately, after this time interval, the animals died of late toxicity, probably not related to HT. These results indicate that HT promotes extravasation of DX into tumor tissue and enhances its effectiveness. The finding that HT-induced drug release from the liposomes was not responsible for enhanced antitumor activity provides a rationale for further investigation of thermostable liposomes in conjunction with HT.

Dental root agenesis following radiation and antineoplastic therapy: A Case Report.

The survival rates of patients suffering from various childhood neoplasms have improved dramatically with the advent of chemo-radiation therapy. The harmful effects of chemo-radiation therapy in the oro-facial region such as root agenesis, short roots, impaired amelogenesis, dentinogenesis, radiation caries, and other soft tissue pathologies are well recognized. In spite of these documented risks, the antineoplastic treatment modalities continue to serve the patient for overall improvement in survival and quality of life. However, a thorough understanding of the growth and development process and its relation with the complex antineoplastic treatment is very important for all clinicians. Such awareness could significantly improve the status of patients in the posttreatment period with the implementation of proper preventive and interceptive measures. This article intends to document a case of root agenesis that developed secondary to chemo-radiation therapy in a 12-year-old girl.

Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study.

PURPOSE: To determine the maximum tolerated dose and pharmacokinetics of Doxil in children with recurrent or refractory solid tumors. Doxil is pegylated doxorubicin. EXPERIMENTAL DESIGN: Eligible patients were children with refractory tumors who had received cumulative anthracycline doses <300 mg/m(2). Cohorts of at least three patients each received escalating doses of Doxil starting at 40 mg/m(2) at 4-week intervals. If no dose-limiting toxicity occurred, dosages were escalated by increments of 10 mg/m(2) in subsequent cohorts. Originally, Doxil was administered over 60 min, but significant infusion reactions prompted longer infusion times of 4 h. Patients also received premedication with dexamethasone, ranitidine, and diphenhydramine 24 h before infusion, with ranitidine continued 24 h after infusion. Periodic blood samples were collected and plasma doxorubicin concentrations were quantified to characterize the pharmacokinetics of Doxil. RESULTS: Between January 1997 and June 2000, 22 children ages 4-21 years with refractory tumors were treated with Doxil. Most patients had received one to five prior chemotherapy regimens, and all but five had prior radiotherapy (two had no prior therapy). Doxil was escalated to a dosage of 70 mg/m(2). At that level, dose-limiting mucositis was seen during the first cycle in two of six patients, thus defining dose-limiting toxicity, and in one additional patient during a subsequent cycle. Grade 4 neutropenia lasting less than 7 days was documented in two of six patients. The dose-limiting toxicity among two of six patients at 70 mg/m(2) was grade 3 mucositis during the first cycle of therapy. Painful desquamating dermatitis of the hands and feet, palmar-plantar erythrodysesthesia, occurred in six patients. In two of those patients, palmar-plantar erythrodysesthesia started as grade 1 and progressed to grade 2 during subsequent courses. Mean estimates of central volume of distribution, clearance, and elimination half-life were 1.45 liters/m(2), 0.03 liter/h/m(2), and 36.4 h, respectively. CONCLUSION: The maximum tolerated dose of Doxil administered every 4 weeks to pediatric patients was 60 mg/m(2). The effect of Doxil on pediatric patients with malignancies remains to be determined and should be studied in pediatric Phase II trials.

Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma.

PURPOSE: To examine the long-term effects of treatment in children receiving radiotherapy for head and neck rhabdomyosarcoma. METHODS: From 1967 to 1994, a total of 30 children with head and neck rhabdomyosarcoma received megavoltage radiotherapy at one institution. Seventeen patients (57%) have survived and have at least a 5-year follow-up. There were 11 males and 6 females, with a median age of 5.7 years (range 2.2-11.6) at the time of radiotherapy. Tumor location was orbit in 6 patients, infratemporal fossa in 4, paranasal sinuses in 2, and supraglottic larynx in 2; the nasopharynx, pterygopalatine fossa, and parotid gland were sites for the remaining children. All but 2 patients had tumors of embryonal histology. The Intergroup Rhabdomyosarcoma Study (IRS) Group was I in 2, II in 3, and III in 11 children; 1 patient had a recurrent tumor after surgery alone. Radiotherapy volume was the primary tumor or tumor bed in 13, tumor and whole brain in 3, and tumor and craniospinal axis in 1. Median radiotherapy dose to the primary site was 5,040 cGy (range 4,140-6,500) and to the whole brain was 3,000 cGy. All but 1 were treated with 150-200-cGy fractions; 1 patient received 250-cGy fractions for a tumor in the larynx. Chemotherapy was vincristine (V), actinomycin-D (A), and cyclophosphamide (C) in 10 patients, VAC + adriamycin in 2, VA in 1, VA + ifosfamide in 1, VC + adriamycin in 1, and none in 2. One patient had salvage chemotherapy consisting of cisplatin and etoposide. Median follow-up time was 20 years (range 7.5-33). RESULTS: Late effects of treatment were seen in all patients and included facial growth retardation in 11, neuroendocrine dysfunction in 9, visual/orbital problems in 9, dental abnormalities in 7, hearing loss in 6, and hypothyroidism in 3. Intellectual and academic delays were documented in 3 patients who had received whole brain radiotherapy. While neuroendocrine, thyroid, dental, and cognitive sequelae were primarily attributed to radiotherapy, hearing loss was thought to be a direct result of tumor destruction and, in 1 case, cisplatin chemotherapy. Late effects at or beyond 10 years from radiotherapy were few, but severe, and included chondronecrosis, esophageal stenosis, second malignancy, and brain hemorrhage. CONCLUSION: Late effects of treatment in children receiving radiotherapy for head and neck rhabdomyosarcoma are frequent. Although radiotherapy is a significant contributor of neuroendocrine, dental, thyroid, and cognitive toxicity, it is not usually implicated with hearing loss. Late toxicity of treatment beyond 10 years is not as frequent as those occurring within 10 years of therapy.

Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: effects of treatment with chemotherapy and radiation to the head and neck.

Sixty-eight long-term survivors of childhood cancer were evaluated for dental and maxillofacial abnormalities. Forty-five patients had received maxillofacial radiation for lymphoma, leukemia, rhabdomyosarcoma, and miscellaneous tumors. Forty-three of the 45 patients and the remaining 23 who had not received maxillofacial radiation also received chemotherapy. Dental and maxillofacial abnormalities were detected in 37 of the 45 (82%) radiated patients. Dental abnormalities comprised foreshortening and blunting of roots, incomplete calcification, premature closure of apices, delayed or arrested tooth development, and caries. Maxillofacial abnormalities comprised trismus, abnormal occlusal relationships, and facial deformities. The abnormalities were more severe in those patients who received radiation at an earlier age and at higher dosages. Possible chemotherapeutic effects in five of 23 patients who received treatment for tumors located outside the head and neck region comprised acquired amelogenesis imperfecta, microdontia of bicuspid teeth, and a tendency toward thinning of roots with an enlarged pulp chamber. Dental and maxillofacial abnormalities should be recognized as a major consequence of maxillofacial radiation in long-term survivors of childhood cancer, and attempts to minimize or eliminate such sequelae should involve an effective interaction between radiation therapists, and medical and dental oncologists.

Modified polyvinyl alcohol-benzoporphyrin derivative conjugates as phototoxic agents.

Photosensitizing and biodistribution characteristics of a photosensitizer (benzoporphyrin derivative, monoacid ring A; BPD) conjugated to a macromolecule (modified polyvinyl alcohol; M-PVA, molecular weight = 10,000) were tested in vitro and in vivo. Modified PVA was loaded with BPD at molar ratios 1:12, 1:25, 1:50, 1:75 and 1:100. Most of the work was carried out with a conjugate having a 1:25 molar ratio. In vitro photosensitization was tested using A549 (human lung carcinoma), A432 (human epidermoid carcinoma) and P815 (mastocytoma of DBA/2 mice) cell lines. Photosensitization of M1 (rhabdomyosarcoma of DBA/2 mice) tumors was tested in an in vivo/in vitro assay, in which tumor-bearing mice were injected intravenously with free or conjugated 3H-BPD and 3 h later light activation of tumor cells was carried out in vitro. Biodistribution studies were carried out using M1 tumor-bearing DBA/2 mice and 3H-BPD either free or conjugated to M-PVA. The results of these studies showed that the conjugation of BPD to M-PVA resulted in the formation of a macromolecular photosensitizer that retained full photosensitizing activity of the photosensitizer molecules and at the same time gained new characteristics, advantageous for photodynamic treatment, especially in vivo. In vitro M-PVA-BPD conjugates were at least as efficient in photosensitization of tumor cells as an equivalent number of free BPD molecules, both in the presence and in the absence of serum. Although the biodistribution was in general comparable to free BPD, the conjugate (1:25) reached slightly higher levels in the blood, kidney, lung and spleen, and lower levels in the liver, brain, skin and muscle in comparison with free BPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacokinetic and photodynamic studies with zinc(II) phthalocyanine in hamsters bearing an induced or transplanted rhabdomyosarcoma.

Comparative pharmacokinetic studies in hamsters bearing an induced or first-generation transplanted rhabdomyosarcoma that were injected with liposome-incorporated zinc(II) phthalocyanine (ZnPc) show a higher drug concentration in the induced tumour. The selectivity of tumour targeting is underlined by the fact that, 24 h after injection, larger amounts of ZnPc are found in the tumour than in the liver. Photodynamic therapy investigations were carried out using 673 nm light from an argon-dye laser. On the basis of different assessment criteria (changes in mean tumour diameter with time, tumour mass regression, survival time of the treated groups of animals, and histological determination of the necrotic tissue) the photosensitizing effect of ZnPc appears to be comparable for both kinds of tumour in spite of the higher uptake of photosensitizer by the induced tumour.

Dento-maxillofacial sequelae in a child treated for a rhabdomyosarcoma in the head and neck. A case report.

This case report describes severe dento-maxillofacial defects after chemoradiation therapy in a child aged 9 years 6 months with a parameningeal rhabdomyosarcoma. A clinical and radiologic (apical dental radiographs, orthopantograph, lateral skull roentgenogram) dental follow-up over 4 years showed such dental abnormalities as root blunting, mild to severe root shortening, premature closure of the root apices, and severe radiation caries. Craniofacial morphology evaluated by cephalometric analysis and dental models showed deficiency with mandibular and maxillary hypoplasia.

Chemoradiation therapy: effect on dental development.

Chemoradiation therapy used on pediatric oncology patients often causes dental developmental anomalies that affect future dental care. Defects noted include tooth and root agenesis, root thinning and shortening, and localized enamel defects. Histologically, these defects appear as osteoid-like niches in the developing dentin which alter the overlying enamel. Odontogenic cell sensitivity is dependent upon the position on the cell cycle and the mitotic activity at the time of chemoradiation therapy. Knowledge of the stage of dental development at the time of oncology treatment and the type of therapy allows the clinician to predict dental effects of the chemoradiation. Representative cases illustrate the clinical manifestations of chemoradiation on the developing dentition.

Treatment of neuroblastoma and rhabdomyosarcoma using RGD-modified liposomal formulations of patupilone (EPO906).

BACKGROUND: Patupilone (EPO906) is a microtubule stabilizer with a potent antitumor effect. Integrin αVß3-binding (RGD) liposomes were loaded with EPO906, and their antitumor efficacy was evaluated in two pediatric tumor models, ie, neuroblastoma and rhabdomyosarcoma. METHODS: Integrin αVß3 gene expression, RGD-liposome cellular association, and the effect of EPO906 and liposomal formulations of EPO906 on cell viability were assessed in vitro in human umbilical vein endothelial cells (HUVEC), in the RH-30 rhabdomyosarcoma cell line, and in the Kelly neuroblastoma cell line. In vivo, mice bearing neuroblastoma or rhabdomyosarcoma tumors were treated with EPO906, EPO906-liposomes, or EPO906-RGD-liposomes. Tumor growth, cumulative survival, and toxicity were monitored. RESULTS: Integrin αVß3 was highly expressed in HUVEC and RH-30, but not in Kelly cells. Accordingly, RGD-liposomes were highly associated with HUVEC and RH-30 cells in vitro, but not with the Kelly cells. EPO906 and its liposomal formulations inhibited HUVEC, RH-30, and Kelly cell viability to the same extent. In vivo, EPO906 1.5 mg/kg and liposomal EPO906 potently inhibited tumor growth in both xenograft models without triggering major toxicity. At this dose, liposomal EPO906 did not enhance the antitumor effect of EPO906 in neuroblastoma, but tended to have an increased antitumor effect in rhabdomyosarcoma. Using a lower dose of EPO906-RGD-liposomes significantly enhanced cumulative survival in rhabdomyosarcoma compared with EPO906 alone. CONCLUSION: EPO906 shows a strong antitumor effect in neuroblastoma and rhabdomyosarcoma, without triggering major side effects. Its liposomal encapsulation does not alter its activity, and enhances cumulative survival when EPO906-RGD-liposomes are used at low dose in rhabdomyosarcoma.