Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR(FOXO1) subtype and provide targeted therapeutic options

Brown, Robert E.; Buryanek, Jamie; Katz, Amanda; Paz, Keren; Wolff, Johannes

doi:10.18632/oncotarget.10089

Cited by 9 publications

(8 citation statements)

References 48 publications

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“…Although the majority of patients with rhabdomyosarcoma have a low mutational burden, a recent report did reveal a number of activating mutations and epigenetic alterations that could have an effect on pathway activity (28). Also a phosphoproteomics screen in rhabdomyosarcoma cell lines, and a combined genomic and morphoproteomic screening of an ARMS sample identified and validated adequate treatment strategies (7,81). This exemplifies that molecular genomics, epigenomics, and (phospho)proteomics might have a place in rhabdomyosarcoma diagnosis to provide patients with the best, most personalized treatment available.…”

Section: Discussionmentioning

confidence: 99%

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Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Erp¹,

Graaf

Fleuren

2018

Molecular Cancer Therapeutics

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Targeted therapies have revolutionized cancer treatment; however, progress lags behind in alveolar (ARMS) and embryonal rhabdomyosarcoma (ERMS), a soft-tissue sarcoma mainly occurring at pediatric and young adult age. Insulin-like growth factor 1 receptor (IGF1R)-directed targeted therapy is one of the few single-agent treatments with clinical activity in these diseases. However, clinical effects only occur in a small subset of patients and are often of short duration due to treatment resistance. Rational selection of combination treatments of either multiple targeted therapies or targeted therapies with chemotherapy could hypothetically circumvent treatment resistance mechanisms and enhance clinical efficacy. Simultaneous targeting of distinct mechanisms might be of particular interest in this regard, as this affects multiple hallmarks of cancer at once. To determine the most promising and clinically relevant targeted therapy-based combination treatments for ARMS and ERMS, we provide an extensive overview of preclinical and (early) clinical data concerning a variety of targeted therapy-based combination treatments. We concentrated on the most common classes of targeted therapies investigated in rhabdomyosarcoma to date, including those directed against receptor tyrosine kinases and associated downstream signaling pathways, the Hedgehog signaling pathway, apoptosis pathway, DNA damage response, cell-cycle regulators, oncogenic fusion proteins, and epigenetic modifiers. .

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Section: Discussionmentioning

confidence: 99%

“…In vivo combination treatments were designed and the combination of the HDAC inhibitor entinostat and the chemotherapeutic docetaxel was most effective, with 65% tumor regression. Monotherapy entinostat led to a 43% tumor regression (81).…”

Section: Epigenomementioning

confidence: 96%

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Erp¹,

Graaf

Fleuren

2018

Molecular Cancer Therapeutics

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“…Accordingly, the tumor-targeting properties of the preparations with the most favorable biodistribution, K237/FA-PEG-PLGA (LA/GA = 80/20) NPs was studied in mice xenografted with SKOV-3 cells. For inoculation, SKOV-3 cells (1 × 10 6 ) were implanted in the right hind leg of immunodeficient mice [50–52]. Additionally, 3.7 MBq of 99m Tc-labeled K237/FA-PEG-PLGA (LA/GA = 80/20) NPs in 150 μL of normal saline were administered into the mice tail vein.…”

Section: Methodsmentioning

confidence: 99%

Immune activity and biodistribution of polypeptide K237 and folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles radiolabeled with 99mTc

Zhang

Huang

et al. 2016

Oncotarget

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In a previous study, amphiphilic copolymer, polypeptide K237 (HTMYYHHYQHHL) and folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (K237/FA-PEG-PLGA) nanoparticles were developed and studied as a drug carrier. To further promote the clinical application of K237/FA-PEG-PLGA nanoparticles and provide guidance for future research, we need to examine their specific biodistribution in vivo. In this study, K237/FA-PEG-PLGA nanoparticles were effectively labeled by a direct method with Technetium-99m (99mTc) using stannous chloride as a reducing agent. The optimal stability of the labeled nanoparticles was determined by evaluating their radiochemical purity in serum, physiological saline, diethylenetriaminepentaacetic acid (DTPA) and cysteine solutions. The affinity of ligands and receptors was elicited by cell binding and blocking experiments in KDR/folate receptor high expressing SKOV-3 ovarian cancer cells. The nanoparticles biodistribution was studied after intravenous administration in healthy mice xenografted with SKOV-3 cells. A higher percent injected dose per gram of tissue (% ID/g) was observed in liver, kidney, spleen, blood and tumor at 3 and 9 h post-injection. Scintigraphic images revealed that the radioactivity was mainly concentrated in tumor, liver, kidney and bladder; and in the heart, lung, and muscle was significantly lower at 3 h. The radioactivity distribution in the images is consistent with the in vivo biodistribution data. Our works demonstrated that K237/FA-PEG-PLGA nanoparticles have great potential as biodegradable drug carriers, especially for tumors expressing the folate and KDr receptor.

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“…Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive soft tissue sarcoma associated with translocations involving PAX3‐FOXO1 [t(2;13)(q35;q14)] or PAX7‐FOXO1 [t(1;13)(p36;q14)] reportedly accounting for 55–80% and 15–22% of ARMS, respectively . These translocations generate fusion proteins that function as transcriptional activators with oncogenic effects.…”

Section: Chromosomal Translocations Mainly Associated With Sarcomasmentioning

confidence: 99%

Fluorescence in situ hybridization in surgical pathology: principles and applications

Cheng

Zhang

Wang

et al. 2017

The Journal of Pathology CR

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Identification of recurrent tumour‐specific chromosomal translocations and novel fusion oncogenes has important diagnostic, therapeutic and prognostic implications. Over the past decade, fluorescence in situ hybridization (FISH) analysis of tumour samples has been one of the most rapidly growing areas in genomic medicine and surgical pathology practice. Unlike traditional cytogenetics, FISH affords a rapid analysis of formalin‐fixed, paraffin‐embedded cells within a routine pathology practice workflow. As more diagnostic and treatment decisions are based on results of FISH, demand for the technology will become more widespread. Common FISH‐detected alterations are chromosome deletions, gains, translocations, amplifications and polysomy. These chromosome alterations may have diagnostic and therapeutic implications for many tumour types. Integrating genomic testing into cancer treatment decisions poses many technical challenges, but rapid progress is being made to overcome these challenges in precision medicine. FISH assessment of chromosomal changes relevant to differential diagnosis and cancer treatment decisions has become an important tool for the surgical pathologist. The aim of this review is to provide a theoretical and practical survey of FISH detected translocations with a focus on strategies for clinical application in surgical pathology practice.

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Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR(FOXO1) subtype and provide targeted therapeutic options

Cited by 9 publications

References 48 publications

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Immune activity and biodistribution of polypeptide K237 and folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles radiolabeled with 99mTc

Fluorescence in situ hybridization in surgical pathology: principles and applications

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