Two clinically distinct cases of infant hemispheric glioma carrying <i>ZCCHC8:ROS1</i> fusion and responding to entrectinib

Papusha, Ludmila; Zaytseva, Margarita; Panferova, Agnesa; Druy, Alexander; Valiakhmetova, Andge; Артемов, А. В.; Salnikova, Ekaterina; Kislyakov, A. N.; Imyanitov, Evgeny N.; Карачунский, А. И.; Maschan, Alexei; Hwang, Eui-Hyoung; Novichkova, Galina; Packer, Roger J.

doi:10.1093/neuonc/noac026

Cited by 8 publications

(5 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, in infant hemispheric glioma, only the patients with preserved open reading frame for a ZCCHC8-ROS1 fusion were responding to entrectinib. 107 Note also the published outstanding case of heavily pretreated glioblastoma which expressed transcripts for four clinically relevant fusion transcripts: with ALK, FGFR2, NTRK2 , and NTRK3 genes. Due to tumor heterogeneity, these were, however, expressed each by only a minor fraction of tumor cells, and the prescription of the corresponding targeted therapies would be most likely unsuccessful.…”

Section: Novel Fusion Genes In Cancermentioning

confidence: 99%

Clinically relevant fusion oncogenes: detection and practical implications

et al. 2022

View full text Add to dashboard Cite

Mechanistically, chimeric genes result from DNA rearrangements and include parts of preexisting normal genes combined at the genomic junction site. Some rearranged genes encode pathological proteins with altered molecular functions. Those which can aberrantly promote carcinogenesis are called fusion oncogenes. Their formation is not a rare event in human cancers, and many of them were documented in numerous study reports and in specific databases. They may have various molecular peculiarities like increased stability of an oncogenic part, self-activation of tyrosine kinase receptor moiety, and altered transcriptional regulation activities. Currently, tens of low molecular mass inhibitors are approved in cancers as the drugs targeting receptor tyrosine kinase (RTK) oncogenic fusion proteins, that is, including ALK, ABL, EGFR, FGFR1-3, NTRK1-3, MET, RET, ROS1 moieties. Therein, the presence of the respective RTK fusion in the cancer genome is the diagnostic biomarker for drug prescription. However, identification of such fusion oncogenes is challenging as the breakpoint may arise in multiple sites within the gene, and the exact fusion partner is generally unknown. There is no gold standard method for RTK fusion detection, and many alternative experimental techniques are employed nowadays to solve this issue. Among them, RNA-seq-based methods offer an advantage of unbiased high-throughput analysis of only transcribed RTK fusion genes, and of simultaneous finding both fusion partners in a single RNA-seq read. Here we focus on current knowledge of biology and clinical aspects of RTK fusion genes, related databases, and laboratory detection methods.

show abstract

Section: Novel Fusion Genes In Cancermentioning

confidence: 99%

Clinically relevant fusion oncogenes: detection and practical implications

et al. 2022

View full text Add to dashboard Cite

show abstract

“…123 Cases on the use of entrectinib for ER+/HER2-breast cancer, ARCN1-ROS1 and ZCCHC8-ROS1 fusion pediatric glioma, GOPC-ROS1 fusion limbal melanoma, and SLC4A4-ROS1 fusion metastatic pancreatic cancer have also been reported. 28,[124][125][126][127] Among the next-generation TKIs, lorlatinib has been suggested to be potentially effective in ROS1 p.L1950F point-mutated pancreatic cancer and TFG-ROS1 fusion IMT of the chest wall, 128,129 with no relevant case reports for other TKIs. 6 | CHALLENGES OF ROS1-TARGETED THERAPY 6.1 | Adverse effects related to ROS1 inhibitors Adverse events (AEs) are a major challenge in ROS1targeted therapy.…”

Section: Non-nsclc Tumorsmentioning

confidence: 99%

“…For example, crizotinib has shown good or partial remission in YWHAE1‐ROS1 fusion inflammatory myofibroblastoma (IMT), 120 GOPC‐ROS1 fusion Spitz naevi, high‐grade serous ovarian cancer, 67,121 RDX‐ROS1 fusion intrahepatic cholangiocarcinoma, 122 and TJP1‐ROS1 fusion malignant peripheral nerve sheath tumors(MPNST) 123 . Cases on the use of entrectinib for ER+/HER2‐breast cancer, ARCN1‐ROS1 and ZCCHC8‐ROS1 fusion pediatric glioma, GOPC‐ROS1 fusion limbal melanoma, and SLC4A4‐ROS1 fusion metastatic pancreatic cancer have also been reported 28,124–127 . Among the next‐generation TKIs, lorlatinib has been suggested to be potentially effective in ROS1 p.L1950F point‐mutated pancreatic cancer and TFG‐ROS1 fusion IMT of the chest wall, 128,129 with no relevant case reports for other TKIs.…”

Section: Treatment Of Ros1‐mutant Tumorsmentioning

confidence: 99%

Current treatment and novel insights regarding ROS1‐targeted therapy in malignant tumors

Li,

Zhang,

Chen

et al. 2024

Cancer Medicine

View full text Add to dashboard Cite

BackgroundThe proto‐oncogene ROS1 encodes an intrinsic type I membrane protein of the tyrosine kinase/insulin receptor family. ROS1 facilitates the progression of various malignancies via self‐mutations or rearrangements. Studies on ROS1‐directed tyrosine kinase inhibitors have been conducted, and some have been approved by the FDA for clinical use. However, the adverse effects and mechanisms of resistance associated with ROS1 inhibitors remain unknown. In addition, next‐generation ROS1 inhibitors, which have the advantage of treating central nervous system metastases and alleviating endogenous drug resistance, are still in the clinical trial stage.MethodIn this study, we searched relevant articles reporting the mechanism and clinical application of ROS1 in recent years; systematically reviewed the biological mechanisms, diagnostic methods, and research progress on ROS1 inhibitors; and provided perspectives for the future of ROS1‐targeted therapy.ResultsROS1 is most expressed in malignant tumours. Only a few ROS1 kinase inhibitors are currently approved for use in NSCLC, the efficacy of other TKIs for NSCLC and other malignancies has not been ascertained. There is no effective standard treatment for adverse events or resistance to ROS1‐targeted therapy. Next‐generation TKIs appear capable of overcoming resistance and delaying central nervous system metastasis, but with a greater incidence of adverse effects.ConclusionsFurther research on next‐generation TKIs regarding the localization of ROS1 and its fusion partners, binding sites for targeted drugs, and coadministration with other drugs is required. The correlation between TKIs and chemotherapy or immunotherapy in clinical practice requires further study.

show abstract

“…The agnostic use of ROS1 inhibitors was considered in the NCI-MATCH investigation; however, only one out of four recruited patients experienced an objective tumor response [80]. Still, several case reports have convincingly demonstrated the utility of ROS1 inhibitors in non-lung cancer types [83][84][85][86][87][88][89][90]. Although case reports are understandably biased towards "positive" findings, they apparently provide a correct picture while justifying a histology-independent use of ALK-and ROS1-targeted drugs.…”

Section: Other Mutated Oncogenes As Potential Agnostic Targetsmentioning

confidence: 99%

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Aleksakhina,

Ivantsov,

Imyanitov

2024

IJMS

Self Cite

View full text Add to dashboard Cite

Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

show abstract

Two clinically distinct cases of infant hemispheric glioma carrying ZCCHC8:ROS1 fusion and responding to entrectinib

Cited by 8 publications

References 10 publications

Clinically relevant fusion oncogenes: detection and practical implications

Clinically relevant fusion oncogenes: detection and practical implications

Current treatment and novel insights regarding ROS1‐targeted therapy in malignant tumors

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Contact Info

Product

Resources

About