Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments.
View Article and Find Full Text PDFBackground RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by cancer cells over-expressing uridine cytidine kinase 2 (UCK2). Single agent RX-3117 demonstrated efficacy in a phase I trial in patients with metastatic (met) pancreatic adenocarcinoma (PC). RX-3117 plus nab-paclitaxel (nab-Pac) was evaluated as a first line treatment in met-PC cancer.
View Article and Find Full Text PDFPurpose: Chemotherapy-induced alopecia (CIA) negatively affects psychosocial health and quality of life (QoL). Currently, there are no approved pharmacologic agents to prevent CIA. Here, we evaluated the safety, tolerability, and potential signal of efficacy of topical calcitriol (BPM31543) on CIA prevention.
View Article and Find Full Text PDFBackground: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.
View Article and Find Full Text PDFRX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed.
View Article and Find Full Text PDFRX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells.
View Article and Find Full Text PDFPurpose: Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies.
View Article and Find Full Text PDFThe main obstacles to successful haploidentical haematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections and severe graft-versus-host disease (GvHD). We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin in order to expedite immune reconstitution after a CD3-depleted haploidentical stem cell transplant. This protocol was used to treat 22 paediatric patients with refractory haematological malignancies.
View Article and Find Full Text PDFBackground: Adenovirus (ADV) infections are associated with significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The virus is endemic in the general pediatric population and frequently causes severe disease in immunocompromised patients, especially children. We report our experience with cidofovir (CDV) for treatment of ADV infection in 57 HSCT patients, median age 8 years (range 0.
View Article and Find Full Text PDFThe extent and rapidity with which T cells are regenerated from graft-derived precursor cells directly influences the incidence of infection and the T-cell-based graft-versus-tumor effect. Measurement of T-cell receptor excision circles (TRECs) in peripheral blood is a means of quantifying recent thymic T-cell production and has been used after transplantation in many studies to estimate thymus-dependent T-cell reconstitution. We hypothesized that the quality of thymic function before transplantation affects thymus-dependent T-cell reconstitution after transplantation.
View Article and Find Full Text PDFPurpose: To determine the incidence, etiology and outcome of graft failure in pediatric allogeneic bone marrow transplant (BMT) recipients.
Patients And Methods: Patients with primary or secondary graft failure were identified by database review. A retrospective chart review was performed.
Natural killer (NK) cell alloreactivity resulting from killer immunoglobulin-like receptor (KIR) ligand incompatibility improves outcomes in patients receiving extensively T-cell-depleted bone marrow (BM) grafts. Patients with KIR ligand incompatibility are at risk for donor T-cell alloreactivity. We investigated the relative significance of NK-cell and T-cell alloreactivity in 105 paediatric patients who received a minimally T-cell-depleted human leucocyte antigen-non-identical BM transplantation.
View Article and Find Full Text PDFPurpose: The aim of this study was to evaluate the clinical benefits of open lung biopsy in the diagnosis and treatment of pulmonary infiltrates in children who have undergone bone marrow transplantation.
Methods: The authors retrospectively reviewed the medical records of all patients in whom pulmonary infiltrates developed within 6 months after bone marrow transplantation. Of 528 patients who received bone marrow transplants (313 allogeneic, 215 autologous) at St Jude Children's Research Hospital between June 1991 and December 1998, 83 (16%) had radiographic evidence of pulmonary infiltrates after the procedure.