ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.

Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma.

PURPOSE: Endoglin (ENG; CD105) is a coreceptor of the TGFß family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFß, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease. EXPERIMENTAL DESIGN: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma. RESULTS: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts in a dose-dependent manner. CONCLUSIONS: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.

En face mode of swept-source optical coherence tomography in circumscribed choroidal haemangioma.

PURPOSE: To describe the findings in circumscribed choroidal haemangioma (CCH) using en face swept-source optical coherence tomography (SS-OCT). METHODS: En face images were obtained employing DRI-1 Atlantis OCT (Topcon, Tokyo, Japan), using a three-dimensional volumetric scan of 12×9 mm. Images were obtained from the retinal pigment epithelium to 1000 µm in depth of the tumour. RESULTS: Twenty-two eyes from 22 patients with the clinical diagnosis of CCH were included. In 20 eyes (90.9%), a characteristic pattern was visualised in the en face image across the vascular tumour. A multilobular pattern, similar to a honeycomb, with hyporeflective, confluent, oval or round areas corresponding with the lumen of the tumour vascular spaces, and hyper-reflective zones, which may represent the vessels walls and connective tissue of the tumour. Ten eyes (45.4%) showed a hyper-reflective halo surrounding the tumour. Seventeen tumours (77.2%) showed small diameter vessels at the inner zone and larger vessels in the outer area. Twelve patients (54.5%) had previously received treatment (photodynamic therapy, transpupillary thermotherapy, dexamethasone intravitreal implant or brachytherapy with ruthenium-106). No differences were found between treated and untreated patients in any of the measured parameters. CONCLUSIONS: En face SS-OCT is a rapid, non-invasive, high-resolution, technology, which allows a complementary study to cross-sectional scans in CCH. A characteristic multilobular pattern, with a hyper-reflective halo surrounding the tumour, was found in en face SS-OCT images. No morphological differences were found between naïve patients and patients who received previous treatment.

La familia de tumores del sarcoma de Ewing / No disponible

La familia de tumores del sarcoma de Ewing (SE) es un conjunto de neoplasias primarias del hueso y/o tejidos de soporte, causado por la proliferación de células madre mesenquimales bloqueadas en su maduración fetal y que adquieren posteriormente las características de células malignas. Este conjunto de enfermedades se caracterizan por una firma molecular que las define: la fusión del gen EWS del cromosoma 22q12 con genes implicados en el control de la replicación celular, creando un gen de fusión anómalo. Los genes de fusión o sus productos se detectan mediante la PCR de RNA o RT-PCR. Virtualmente todos los enfermos con SE tienen enfermedad microscópica subclínica, por ello el tratamiento eficaz del SE es por vía sistémica. La probabilidad de supervivencia libre de enfermedad de los pacientes sin metástasis detectables clínicamente es del 70%; para los pacientes con metástasis es inferior al 30%. La quimioterapia es el tratamiento esencial para el control de la enfermedad microscópica sistémica, pero sola no puede erradicar la enfermedad en forma de grandes masas. El control local de la enfermedad visible debe realizarse mediante cirugía y/o radioterapia. El objetivo fundamental de la cirugía es obtener márgenes de resección amplios. El SE es un tumor radiosensible y dada la sinergia entre la quimioterapia y la radioterapia, los tratamientos suelen ser combinados(AU)

The Ewing family of tumors (SE) is a group of neoplasias arising from developing bone or soft tissues. SE is likely derived from the malignant proliferation of mesenchymal stem cells. This group of diseases has a unique molecular signature: the fusion of the EWS gene on chromosome 22q12 to genes involved in the control of cell proliferation, generating an abnormal fusion gene. The fusion genes and their products are detected in the laboratory by the RTPCR method. Virtually all SE patients have subclinical microscopic disease; therefore effective treatment must always include systemic chemotherapy. The event-free survival for patients without clinically detectable disease is 70% at 5 years from diagnosis; for patients with metastasis at diagnosis is less than 30%. Chemotherapy is essential for the treatment of microscopic metastatic disease, but it cannot eradicate the disease in the form of masses. The local control of the disease is made by surgery and/or radiation therapy. The main objective of surgery is to achieve tumor resection with ample margins. The SE is a radiosensitive tumor and because the synergistic effect with chemotherapy, they are used in combination. In summary: SE is a rare, complex and life-threatening group of diseases that should be managed in comprehensive cancer centers(AU)

Axenfeld-Rieger ocular anomaly and retinoblastoma caused by constitutional chromosome 13q deletion.

Axenfeld-Rieger (AR) ocular anomaly might be due to deletions of different chromosomes. No association between AR, mental retardation, and retinoblastoma has been described. We report a 2-month-old female with general development delay and dysmorphic features. AR anomaly was detected, and a retinoblastoma (RB) was diagnosed in a very early stage. De novo 13q deletion was identified. Systemic chemotherapy, focal cryotherapy, transpupillary thermotherapy, brachytherapy, and intra-arterial chemotherapy were needed to control the RB. This is the first report of an association of AR, 13q deletion, and retinoblastoma, to be disclosed in patients born with such ocular and dysmorphic features.