Ralph Salloum

Response of Blue Rubber Bleb Nevus Syndrome to Sirolimus Treatment.

Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities include corticosteroids, interferon‐α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports.

The G protein Gαs acts as a tumor suppressor in sonic hedgehog signaling-driven tumorigenesis

ABSTRACT G protein-coupled receptors (GPCRs) are critical players in tumor growth and progression. The redundant roles of GPCRs in tumor development confound effective treatment; therefore, targeting a single common signaling component downstream of these receptors may be efficacious. GPCRs transmit signals through heterotrimeric G proteins composed of Gα and Gβγ subunits. Hyperactive Gαs signaling can mediate tumor progression in some tissues; however, recent work in medulloblastoma and basal cell carcinoma revealed that Gαs can also function as a tumor suppressor in neoplasms derived from ectoderm cells including neural and epidermal stem/progenitor cells. In these stem-cell compartments, signaling through Gαs suppresses self-renewal by inhibiting the Sonic Hedgehog (SHH) and Hippo pathways. The loss of GNAS, which encodes Gαs, leads to activation of these pathways, over-proliferation of progenitor cells, and tumor formation. Gαs activates the cAMP-dependent protein kinase A (PKA) signaling pathway and inhibits activation of SHH effectors Smoothened-Gli. In addition, Gαs-cAMP-PKA activation negatively regulates the Hippo pathway by blocking the NF2-LATS1/2-Yap signaling. In this review, we will address the novel function of the signaling network regulated by Gαs in suppression of SHH-driven tumorigenesis and the therapeutic approaches that can be envisioned to harness this pathway to inhibit tumor growth and progression.

Characterizing temporal genomic heterogeneity in pediatric high-grade gliomas

Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.

Relapsed perinatal neuroblastoma after expectant observation

The Childrens Oncology Group (COG) study ANBL00P2 showed that expectant observation of patients younger than six months of age with perinatal neuroblastoma presenting as a small adrenal mass yields excellent overall survival and spares surgical resection to the majority of patients. We report a 5‐year‐old female who was initially diagnosed with a perinatal neuroblastoma. The patient was observed on COG study ANBL00P2. By nine months of age she had no ultrasonographic or biochemical evidence of disease. She presented four years later with abdominal pain and was found to have high‐risk stage 4 MYCN amplified neuroblastoma. Pediatr Blood Cancer 2015;62:160–162.

Molecular Biology of Pediatric Brain Tumors and Impact on Novel Therapies

Brain tumors are the leading cause of cancer-related death in children. For the past several decades, therapeutic strategies have centered on cytotoxic chemotherapy and radiation therapy due, in part, to limited understanding of genetic events that underlie tumor initiation and maintenance. Significant improvement in high-throughput genomic methods, such as next-generation sequencing, methylation array, and copy number array, in recent years has propelled the knowledge base from which novel therapies are derived. Translation of recent genomic findings into more effective therapies remains the most formidable challenge in improving the outcome for children with brain tumors.