G Floris

High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model

Purpose: Histone deacetylase inhibitors have emerged as potent anticancer compounds. Using a nude-mouse xenograft model, for the first time we evaluated the response of human gastrointestinal stromal tumors (GIST) carrying different oncogenic KIT mutations to panobinostat (LBH589), administered single or in combination with imatinib. Experimental Design: We grafted the human GIST882 cell line with KIT exon 13 mutation and two biopsies from patients radiologically progressing under imatinib showing KIT exon11 and KIT exon9 mutations, respectively. Our study included 4 groups: A (n = 9; control), B (n = 10; panobinostat 10 mg/kg daily, i.p.), C (n = 9; imatinib 150 mg/kg bidaily, p.o), and D (n = 8; combination panobinostat-imatinib, same dose/schedule as above). Treatment lasted 12 days. Tumor size was measured regularly using standard variables. Histopathological assessment was by H&E, and immunohistochemically with KIT, cleaved caspase-3, Ki-67, and histone acetylation staining. Results: Overall, GIST xenografts responded rapidly to panobinostat as indicated by tumor regression, necrosis, hemorrhages, fibrosis, and/or myxoid degeneration, remarkable apoptosis, and substantial decline of cell proliferation. H3 and H4 acetylation increased significantly from control level in all treated groups. The combination of panobinostat and imatinib further enhanced most of the assessed parameters. Conclusions: We show for the first time potential therapeutic activity of panobinostat in human GISTs, in vivo. Our results warrant further exploration of histone deacetylase inhibitors for the treatment of advanced GISTs. Our study is also the first one on human GIST mouse xenografts established using patient biopsies.

Coactivated Platelet-Derived Growth Factor Receptor α and Epidermal Growth Factor Receptor Are Potential Therapeutic Targets in Intimal Sarcoma

Intimal sarcoma (IS) is a rare, malignant, and aggressive tumor that shows a relentless course with a concomitant low survival rate and for which no effective treatment is available. In this study, 21 cases of large arterial blood vessel IS were analyzed by immunohistochemistry and fluorescence in situ hybridization and selectively by karyotyping, array comparative genomic hybridization, sequencing, phospho-kinase antibody arrays, and Western immunoblotting in search for novel diagnostic markers and potential molecular therapeutic targets. Ex vivo immunoassays were applied to test the sensitivity of IS primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib. We showed that amplification of platelet-derived growth factor receptor α (PDGFRA) is a common finding in IS, which should be considered as a molecular hallmark of this entity. This amplification is consistently associated with PDGFRA activation. Furthermore, the tumors reveal persistent activation of the epidermal growth factor receptor (EGFR), concurrent to PDGFRA activation. Activated PDGFRA and EGFR frequently coexist with amplification and overexpression of the MDM2 oncogene. Ex vivo immunoassays on primary IS cells from one case showed the potency of dasatinib to inhibit PDGFRA and downstream signaling pathways. Our findings provide a rationale for investigating therapies that target PDGFRA, EGFR, or MDM2 in IS. Given the clonal heterogeneity of this tumor type and the potential cross-talk between the PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve the therapeutic outcome for patients with this disease.

Epithelioid Hemangioma of Bone: A Potentially Metastasizing Tumor?

The case of a 15-year-old boy with a severe swelling of the 2nd toe in the left foot and a large swelling of the left inguinofemoral region is described. Histologic examination of the foot lesion showed a typical epithelioid hemangioma of bone that extended into the soft tissues, with a secondary location in the groin, suggestive of lymph node involvement. Subsequently, imaging also revealed swelling of iliac and para-aortic lymph nodes, which probably indicates further lymph node spread.. Besides the fact that epithelioid hemangioma of the toe has not been reported yet, our case showed a noncontinuous localization, most likely in draining lymph nodes. This finding suggests metastatic disease, an event that is extremely rare for epithelioid hemangioma. As such, epithelioid hemangioma might be comparable to another benign vascular tumor, the retiform hemangioendothelioma, which occasionally metastasizes to the lymph nodes without systemic spread.

Implications of Mutational Analysis for the Management of Patients With Gastrointestinal Stromal Tumors and the Application of Targeted Therapies

ABSTRACT The receptor tyrosine kinase inhibitors, imatinib and sunitinib, have significantly improved the prognosis for patients with advanced gastrointestinal stromal tumors (GISTs). Most GISTs exhibit mutations in the genes encoding the stem cell factor receptor (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Imatinib is more effective in patients with KIT exon 11 mutations compared with KIT exon 9 mutations and wild-type genotype, while sunitinib confers greater in vitro efficacy in patients with KIT exon 9 mutants and wild-type genotype than in KIT exon 11 mutants. This review examines the potential role of mutational analysis to optimize therapy with imatinib and sunitinib for GIST.

Malignant ectomesenchymoma: genetic profile reflects rhabdomyosarcomatous differentiation.

Malignant ectomesenchymoma (MEM) represents a heterogeneous group of tumors, most likely originating from pluripotent primitive neural crest cells. In this report, we present an 8-month-old infant boy with an MEM on the left scrotum. Retrospective review of the incision biopsy showed the presence of a few ganglion cells in an otherwise classic embryonal rhabdomyosarcoma (RMS), whereas in the resection specimen after chemotherapy the combined RMS and ganglioneuroma components were very obvious. Cytogenetic analysis of the residual lesion showed an abnormal karyotype, 49, XY, +2, –6, +11, +20, +mar, with a hyperploidy in a subset of cells. By fluorescence in situ hybridization analysis, the marker chromosome was identified as originating from chromosome 6, and the tumor cells were negative for PAX3/PAX7 disrupting translocations specific for alveolar RMS. Gains of chromosomes 2, 11, and 20, found in the current case, are a common finding in embryonal RMS. These gains probably reflect the myogenic differentiation of MEM and support the genetic link between these 2 neoplasms. In addition to the conventional cytogenetics, array comparative genomic hybridization analysis was performed on the primary and residual tumors. The genomic profiles of both specimens were basically the same including the presence of 2 distinctive chromosome 6p21.32-p21.2 and 6p11.2 amplification regions in the primary tumor, which vanished in the postchemotherapy specimen. The pretreatment biopsy exhibited strong expression of HMGA1 and HMGA2 proteins in immunohistochemistry, with the shift toward the loss of expression of both genes in the posttreatment tumoral tissue. This finding supports the oncogenic properties of the HMGA family of proteins and their role in the process of malignant transformation.