Amy-Lee Bredlau

Oral Ketamine for Children with Chronic Pain: A Pilot Phase 1 Study

OBJECTIVE To assess whether oral ketamine is safe at higher dosages for sedating children and whether it may be an option for the control of chronic pain in children. STUDY DESIGN A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.25-1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment. RESULTS Two participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, 2 with complete resolution of pain, lasting >4 weeks off ketamine treatment. CONCLUSION Oral ketamine at dosages of 0.25-1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain.

Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma

Background Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment. Results Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%). Conclusions Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

Thermal Therapy Approaches for Treatment of Brain Tumors in Animals and Humans

Primary brain tumors are often aggressive, with short survival from time of diagnosis even with standard of care therapies such as surgery, chemotherapy, and radiation therapy. Thermal therapies have been extensively investigated as both primary and adjuvant therapy. Although thermal therapies are not yet widely used clinically, there have been several promising approaches demonstrated in both animals and humans. This review presents thermal therapy approaches in animal and human studies, including both hyperthermia (temperatures ~42°C-45°C) and thermal ablation (temperatures > 50°C). Hyperthermia is primarily used as adjuvant to chemotherapy and radiotherapy, and is the most widely studied radiation sensitizer where enhanced efficacy has been shown in human patients with brain cancer. Hyperthermia has additional beneficial effects such as immunogenic effects, and opening of the bloodbrain barrier to potentially enhance drug delivery, for example in combination with nanoparticle drug delivery systems. Thermal ablation uses high temperatures for direct local tumor destruction, and it found its way into clinical use as laser interstitial thermal therapy (LITT). This review presents various hyperthermia and ablation approaches, including a review of different devices and methods that have been used for thermal therapies, such as radiofrequency/microwaves, laser, high-intensity focused ultrasound, and magnetic nanoparticles. Current research efforts include the combination of advanced thermal therapy devices, such as focused ultrasound with radiation, as well as the use of thermal therapies to enhance chemotherapy delivery across the blood-brain barrier.

Abstract 4467: Treating brain tumors with targeted-micelles containing rapamycin

The development of selectively targeted nanoparticles that can act as drug delivery vehicles is critical for improving the treatment and monitoring of glioblastoma, a life threatening disease. Rapamycin (Sirolimus, rapa), a large, lipophilic carboxylic lactone-lactam macrolide antibiotic, is recognized for its potent anti-proliferative and immunosuppressive effects in vitro and in vivo. These properties make rapa a potential chemotherapeutic agent against several tumors. Despite its promising properties, clinical applications of rapa have been limited due to its hydrophobicity, limiting its utility as an intravenously administered drug. Presently, the commercially available formulations of rapa include tablet or oral forms. Nevertheless, the low oral bioavailability of rapa limits the effectiveness of both of these forms. In addition, the lipophilicity makes the drug susceptible to attachment to the lipid membranes of normal as well as cancer cells. A selectively targeted carrier for rapa will enhance its delivery to malignant cells, avoid non-specific interactions, and reduce non-tumor toxicity. In order to design an efficient and effective drug carrier, we created a multifunctional nanocarrier that contains a tailored surface on the carrier to attach biomolecules for targeted drug delivery; a biocompatible coating which can efficiently encapsulate the hydrophobic drug thereby reducing cytotoxicity; and the capability for stimuli-induced (pH) disruption of the carrier agent for slow and controlled drug release to the desired environment, Micelles are the preferred choice of carrier as they fulfill these requirements based on their composition. Micelles containing rapamycin drug are synthesized using PEG-PE-Amine and N-palmitoyl homocysteine (PHC, pH sensitive lipid breaks in endosome pH 5.5). Specific targeting of the micelles to glioblastoma cells is achieved by PDGF (platelet derived growth factor) or EGF (epidermal growth factor) coupled to the amine moeity of the DSPE-PEG. In addition these micelles have been labeled with a NIR fluorphore to track them for cellular uptake. These micelles have an advantage of small size ( Note: This abstract was not presented at the meeting. Citation Format: Ann-Marie Broome, Suraj K. Dixit, Kayla Miller, Alfred Moore, Amy-Lee Bredlau. Treating brain tumors with targeted-micelles containing rapamycin. [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 4467. doi:10.1158/1538-7445.AM2014-4467

Abstract 3981: Targeted delivery of temozolomide to pediatric brain tumors using micelle-based theranostic nanocarriers

Diffuse intrinsic pontine glioma (DIPG) is the single most devastating pediatric brain tumor. Surgical excision of these tumors, due to the exquisite location of the pons, is dangerous and is not curative. No chemotherapy has been identified that can control these tumors. One theory for this failure is that the pons is a unique location into which delivery of medications at therapeutic concentrations is singularly challenging. Current standard of care utilizes temozolomide (TMZ), a pro-drug that releases a DNA alkylating agent that is used to kill glial cells. TMZ is very toxic when delivered systemically and therapeutic dosages are limited by severe side effects. These factors necessitate a selectively targeted carrier for TMZ to deliver the drug efficiently to malignant cells avoiding nonspecific interaction and reducing offsite toxicity. In order to design an efficient and effective drug carrier, we addressed several issues: a tailored surface on the carrier to attach biomolecules for targeted drug delivery; a biocompatible coating which can efficiently encapsulate the hydrophobic drug thereby reducing cytotoxicity; and stimuli-induced (pH) disruption of the carrier agent for slow and controlled drug release to the desired environment. Micelles are the preferred choice of carrier as they fulfill these requirements based on their composition. Micelles containing drug are synthesized using PEG-PE-Amine and N-palmitoyl homocysteine (pH sensitive lipid breaks in endosome pH 5.5). Specific targeting of the micelles to glioblastoma cells is achieved by coupling a short 12 a.a. PDGF (platelet derived growth factor) peptide to the amine moeity of the DSPE-PEG. In addition, these micelles have been labeled with a NIR fluorophore to track them for cellular uptake and can be used to image tumor internalization in vivo. These micelles have an advantage of small size ( Citation Format: Kayla Miller, Suraj K. Dixit, Amy-Lee Bredlau, Ann-Marie Broome. Targeted delivery of temozolomide to pediatric brain tumors using micelle-based theranostic nanocarriers. [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 3981. doi:10.1158/1538-7445.AM2014-3981