Entrectinib in Two Pediatric Patients With Inflammatory Myofibroblastic Tumors Harboring ROS1 or ALK Gene Fusions.
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ABSTRACT:
SUBMITTER: Ambati SR
PROVIDER: S-EPMC6874363 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC7594679 | biostudies-literature
Project description:Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer.
| S-EPMC4465992 | biostudies-literature
Project description:Abstract The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b study of entrectinib in pediatric patients with cancer, including primary brain tumors, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring NTRK, ROS1, or ALK gene fusions (NCT02650401). Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2?nM (biochemical kinase assay). Overall, gene fusions are rare in the cancer population (<3%); however, they have been seen in over 40 solid tumor histologies, including non-small cell lung cancer, salivary gland cancers, soft tissue sarcomas and glioneuronal tumors. A survey of two pediatric cancer databases, St. Jude pediatric cancer database (PeCan; total n=1,604) and the University of Michigan database (Peds-MiOncoSeq; total n=91), identified malignancies with gene fusions in all three NTRK genes, including infantile fibrosarcoma, juvenile breast cancer, mesoblastic nephroma, intrinsic pontine gliomas, acute leukemias and anaplastic lymphoma. Previously, we reported an objective response rate of 79% was seen in 24 tyrosine kinase inhibitor-naïve patients with solid tumors harboring NTRK, ROS1, or ALK gene fusions, who were treated at doses consistent with the RP2D (Drilon et al, AACR 2016). The most common (>10% incidence) treatment-related adverse events have been fatigue/asthenia, dysgeusia, paresthesia, nausea, myalgia, diarrhea, dizziness, arthralgia, vomiting, and constipation; importantly, there has been no evidence of cumulative toxicity. In addition, we have treated a 20-month-old boy presenting with infantile fibrosarcoma metastatic to the brain, which harbored an ETV6-NTRK3 fusion. Tumor restaging following 1 month of therapy showed a significant tumor regression of CNS metastases accompanied by significant clinical improvement. Together, these data provide compelling evidence to identify pediatric patients harboring NTRK, ROS1, or ALK fusions for enrollment in the STARTRK-NG trial.
| S-EPMC5475194 | biostudies-literature
Project description:ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC5337428 | biostudies-literature
Project description:Inflammatory myofibroblastic tumors (IMTs) are neoplastic mesenchymal proliferations featuring an inflammatory infiltrate composed primarily of lymphocytes and plasma cells. The myofibroblastic cells in some IMTs contain chromosomal rearrangements involving the ALK receptor tyrosine-kinase locus region (chromosome band 2p23). ALK-which is normally restricted in its expression to neural tissues-is expressed strikingly in the IMT cells with 2p23 rearrangements. We now report a recurrent oncogenic mechanism, in IMTs, in which tropomyosin (TPM) N-terminal coiled-coil domains are fused to the ALK C-terminal kinase domain. We have cloned two ALK fusion genes, TPM4-ALK and TPM3-ALK, which encode approximately 95-kd fusion oncoproteins characterized by constitutive kinase activity and tyrosylphosphorylation. Immunohistochemical and molecular correlations, in other IMTs, implicate non-TPM ALK oncoproteins that are predominantly cytoplasmic or pre- dominantly nuclear, presumably depending on the subcellular localization of the ALK fusion partner. Notably, a TPM3-ALK oncogene was reported recently in anaplastic lymphoma, and TPM3-ALK is thereby the first known fusion oncogene that transforms, in vivo, both mesenchymal and lymphoid human cell lineages.
| S-EPMC1850130 | biostudies-literature
Project description:Inflammatory myofibroblastic tumor (IMT) is a neoplasm that typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase (ALK) rearrangements, no therapeutic targets have been identified in ALK-negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFR? fusions. We detail the case of an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evaluated harbored kinase fusions involving ALK, ROS1, or PDGFR?. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.Our study describes the most comprehensive genomics-based evaluation of IMT to date. Because there is no "standard-of-care" therapy for IMT, the identification of actionable genomic alterations, in addition to ALK, is expected to redefine management strategies for patients with this disease.
| S-EPMC4125481 | biostudies-literature
Project description:The fusions of receptor tyrosine kinase (RTK) involving anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and neurotrophic receptor tyrosine kinase (NTRK) represent the potential targets of therapeutic intervention for various types of solid tumors. Here, the genomic features of 180 Chinese solid tumor patients with ALK, ROS1, and NTRK fusions by next generation sequencing (NGS) were comprehensively characterized, and the data from 121 patients in Memorial Sloan Kettering Cancer Center (MSKCC) database were used to compare. We found that ALK, ROS1, and NTRK fusions were more common in younger female patients (p<0.001) and showed a higher expression of programmed death ligand 1 (PD-L1). The gene-intergenic fusion and the fusion with rare formation directions accounted for a certain proportion in all samples and 62 novel fusions were discovered. Alterations in TP53 and MUC16 were common in patients with RTK fusions. The mutational signatures of patients were mainly distributed in COSMIC signature 1, 2, 3, 15 and 30, while had a higher frequency in copy number variations (CNVs) of individual genes, such as IL-7R. In the MSKCC cohort, patients with fusions and CNVs showed shorter overall survival than those with only fusions. Furthermore, the differentially mutated genes between fusion-positive and -negative patients mainly concentrated on MAPK signaling and FOXO signaling pathways. These results may provide genomic information for the personalized clinical management of solid tumor patients with ALK, ROS1, and NTRK fusions in the era of precision medicine.
| S-EPMC9243239 | biostudies-literature
Project description:Gene expression imbalances were measured for tyrosine kinase (TK) genes using Nanostring in 19 samples of inflammatory myofibroblastic tumor (IMT). All cases were immunohistochemically stained with anaplastic lymphoma kinase (ALK) and pan-tropomyosin-related-kinase (pan-Trk) antibodies. Five cases with imbalanced ALK expression, reported with Nanostring, were tested using fluorescence in situ hybridization (FISH); two cases with imbalanced neurotrophic tyrosine receptor kinase 3 (NTRK3) expression were tested using reverse transcription-polymerase chain reaction (RT-PCR). One case with imbalanced expression for ROS proto-oncogene 1 (ROS1) was tested using RNA sequencing and RT-PCR. TK fusions were detected in all cases with imbalanced TK expression. RNA sequencing detected a FN1-ROS1 fusion gene in an adult IMT case. IMT with ALK rearrangement showed myofibroblast-dominant features. IMT with ETV6-NTRK3 fusion showed prominent lymphoplasmacytic infiltration with scattered myofibroblasts. Pan-Trk IHC revealed only scattered positively stained cells in IMT with ETV6-NTRK3 fusion gene. ROS1-positive IMT showed myofibroblast-dominant features.
| S-EPMC7603320 | biostudies-literature
Project description:With the advent of precision medicine, medical oncology is undergoing a transcendental change. These molecular studies have allowed us to learn about potential targeted therapies for patients with advanced cancers. Perhaps the best-known example of success in precision medicine is chronic myeloid leukemia and its response to tyrosine kinase inhibitors targeting the BCR-ABL kinase. Since that original discovery, the role of molecular therapeutics has expanded, and it now presents us with treatment options for common malignancies and rare atypical tumors. In this article, we present a case of a 61-year-old female with a recurrent pulmonary inflammatory myofibroblastic tumor. Subsequent molecular studies revealed an ALK rearrangement. The significance of this alteration in this tumor type and its therapeutic implications are discussed herein. KEY POINTS:This case exemplifies the heterogeneous behavior of inflammatory myofibroblastic tumors (IMTs) and the current role of targeted therapy in the therapeutic armamentarium of neoplastic processes.As evidenced by the different mutations found in IMTs, it is of great importance to perform next-generation sequencing in uncommon neoplasms.These studies can find different potential targets and therapeutic options for patients devoid of standard effective therapies.
| S-EPMC6263129 | biostudies-literature
Project description:The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.
| S-EPMC6172052 | biostudies-literature