Lea Roth

University Medical Center of the Johannes Gutenberg University Mainz

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Claudia Paret

Johannes Gutenberg University Mainz

Nadine Lehmann

University Medical Center of the Johannes Gutenberg University Mainz

Alexandra Russo

Johannes Gutenberg University Mainz

Arthur Wingerter

University Medical Center of the Johannes Gutenberg University Mainz

Larissa Seidmann

Johannes Gutenberg University Mainz

Khalifa El Malki

Johannes Gutenberg University Mainz

Francesca Alt

University Medical Center of the Johannes Gutenberg University Mainz

Jörg Faber

Johannes Gutenberg University Mainz

Nora Backes

University Medical Center of the Johannes Gutenberg University Mainz

Marie A. Neu

University Medical Center of the Johannes Gutenberg University Mainz

Cooperative Institutions

University Medical Center of the Johannes Gutenberg University Mainz

Johannes Gutenberg University Mainz

German Cancer Research Center

Heidelberg University

Leefmilieu Brussel

Los Alamos Medical Center

Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie

University Hospital Heidelberg

3E (Belgium)

University Medical Center

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49P Targeting IGF1R in osteosarcoma

Annals of Oncology (2020)

Nadine Vewinger Olof Beck Arthur Wingerter Alexandra Russo Larissa Seidmann

Ceritinib

10.1016/j.annonc.2020.08.2208

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Citations (0)

Analysis of RBP expression and binding sites identifies PTBP1 as a regulator of CD19 expression in B-ALL

OncoImmunology (2023)

Nicole Ziegler Mariela Cortés-López Francesca Alt Maximilian Sprang Arsenij Ustjanzew

Despite massive improvements in the treatment of B-ALL through CART-19 immunotherapy, a large number of patients suffer a relapse due to loss of the targeted epitope. Mutations in the CD19 locus and aberrant splicing events are known to account for the absence of surface antigen. However, early molecular determinants suggesting therapy resistance as well as the time point when first signs of epitope loss appear to be detectable are not enlightened so far. By deep sequencing of the CD19 locus, we identified a blast-specific 2-nucleotide deletion in intron 2 that exists in 35% of B-ALL samples at initial diagnosis. This deletion overlaps with the binding site of RNA binding proteins (RBPs) including PTBP1 and might thereby affect CD19 splicing. Moreover, we could identify a number of other RBPs that are predicted to bind to the CD19 locus being deregulated in leukemic blasts, including NONO. Their expression is highly heterogeneous across B-ALL molecular subtypes as shown by analyzing 706 B-ALL samples accessed via the St. Jude Cloud. Mechanistically, we show that downregulation of PTBP1, but not of NONO, in 697 cells reduces CD19 total protein by increasing intron 2 retention. Isoform analysis in patient samples revealed that blasts, at diagnosis, express increased amounts of CD19 intron 2 retention compared to normal B cells. Our data suggest that loss of RBP functionality by mutations altering their binding motifs or by deregulated expression might harbor the potential for the disease-associated accumulation of therapy-resistant CD19 isoforms.

10.1080/2162402x.2023.2184143

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Tumor Lipids of Pediatric Papillary Renal Cell Carcinoma Stimulate Unconventional T Cells

Frontiers in Immunology (2020)

Nadine Lehmann Claudia Paret Khalifa El Malki Alexandra Russo Marie A. Neu

Papillary renal cell carcinoma (PRCC) is a rare entity in children with no established therapy protocols for advanced diseases. Immunotherapy is emerging as an important therapeutic tool for childhood cancer. Tumor cells can be recognized and killed by conventional and unconventional T cells. Unconventional T cells are able to recognize lipid antigens presented via CD1 molecules independently from major histocompatibility complex, which offers new alternatives for cancer immunotherapies. The nature of those lipids is largely unknown and α-galactosylceramide is currently used as a synthetic model antigen. In this work, we analyzed infiltrating lymphocytes of two pediatric PRCCs using flow cytometry, immunohistochemistry and qRT-PCR. Moreover, we analyzed the CD1d expression within both tumors. Tumor lipids of PRCC samples and three normal kidney samples were fractionated and the recognition of tumor own lipid fractions by unconventional T cells was analyzed in an in vitro assay. We identified infiltrating lymphocytes including γδ T cells and iNKT cells, as well as CD1d expression in both samples. One lipid fraction, containing ceramides and monoacylglycerides amongst others, was able to induce the proliferation of iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy donors and of one matched PRCC patient. Furthermore, CD1d tetramer stainings revealed that a subset of iNKT cells is able to bind lipids being present in fraction 2 via CD1d. We conclude that PRCC are infiltrated by conventional and unconventional T cells and express CD1d. Moreover, certain lipids, present in pediatric PRCC, are able to stimulate unconventional T cells. Manipulating these lipids and T cells may open new strategies for therapy of pediatric PRCCs.

CD1D

CD1

10.3389/fimmu.2020.01819

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IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

International Journal of Molecular Sciences (2019)

Nadine Vewinger Sabrina Huprich Larissa Seidmann Alexandra Russo Francesca Alt

(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class “HGNET-BCOR” and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC50 < 10 nM for all drugs), and ceritinib (IC50 = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.

Bromodeoxyuridine

10.3390/ijms20123027

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Citations (19)

Linked Data City - Visualization of Linked Enterprise Data.

LWDA (2016)

Joachim Baumeister Sebastian Furth Lea Roth Volker Belli

Source

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The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

European Journal of Cancer (2016)

Kristina von Heyking Lea Roth Miriam Ertl Oxana Schmidt Julia Calzada‐Wack

Ewing's sarcoma

10.1016/s0959-8049(16)32726-5

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Citations (14)

CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis

Journal of Immunotherapy (2017)

Jeannette Fischer Claudia Paret Khalifa El Malki Francesca Alt Arthur Wingerter

B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer and the prognosis of children with relapsed or therapy refractory disease remains a challenge. Treatment with chimeric antigen receptor-modified T cells targeting the CD19 antigen (CART-19 therapy) has been presented as a promising approach toward improving the outcome of relapsed or refractory disease. However, 10%–20% of the patients suffer another relapse. Epitope-loss under therapy pressure has been suggested as a mechanism of tumor cells to escape the recognition from CART-19 therapy. In this work, we analyzed the expression of CD19 isoforms in a cohort of 14 children with CD19 + B-ALL and 6 nonleukemia donors. We showed that an alternatively spliced CD19 mRNA isoform lacking exon 2, and therefore the CART-19 epitope, but not isoforms lacking the transmembrane and cytosolic domains are expressed in leukemic blasts at diagnosis in children and in the bone marrow of nonleukemia donors. Furthermore, we clarified the sequence of a further isoform lacking the epitope recognized by CART-19 therapy and disclosed the presence of new isoforms. In comparison with the children, we showed that alternatively spliced CD19 mRNA isoforms affecting exon 2 are also expressed in 6 adult patients with CD19 + B-ALL. On top of that, one of the adults expressed an isoform lacking the CD19 transmembrane and cytosolic domains. In conclusion, we proved that some of the CD19 isoforms contributing to CART-19 escape already preexist at diagnosis and could evolve as a dominant clone during CART-19 therapy suggesting the application of combined treatment approaches.

Cart

clone (Java method)

10.1097/cji.0000000000000169

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Citations (201)

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma

Cancers (2020)

Olaf Beck Claudia Paret Alexandra Russo Jürgen Burhenne Margaux Fresnais

Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient’s liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols.

Ceritinib

10.3390/cancers12040793

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EPEN-29. INDIVIDUALIZED THERAPY OF AN ANAPLASTIC EPENDYMOMA PEDIATRIC PATIENT WITH A NOTCH1 GERMLINE MUTATION

Neuro-Oncology (2018)

Alexandra Russo Claudia Paret Nadine Lehmann Hannah Bender Arthur Wingerter

The treatment of relapsed pediatric cancers represents a challenge, also due to possible underlying rare germline mutations. The introduction of next sequencing technologies allows a deeper understanding of molecular mechanisms involved in cancer progression helping in the identification of personalized therapies for these patients. However, most tumors harbor several pathway alterations and it is necessary to prioritize the treatment options. Here we applied the concept of personalized therapy to a pediatric patient with an anaplastic ependymoma and who relapsed three times under standard chemio and radiotherapy. By RNA sequencing we identified in the tumor a Notch1 mutation which was confirmed by Sanger Sequencing and which was also present in the blood DNA. Pathway analysis revealed an activation of the sonic hedgehog (SHH), the WNT, the IGF and the Notch pathway. In an attempt to prioritize possible targeted therapies, we treated the patient-specific tumor cells with relevant inhibitors in vitro. The cells were particularly sensitive to Arsenic Trioxide, an inhibitor of the SHH pathway, and to ceritinib, an off-target inhibitor of IGF-1R. Combination of Arsenic Trioxide with chemotherapy reduced the growth rate of the tumor. However, because we were not able to reach the needed Arsenic concentration in CSF, we switched to ceritinib. The patient is currently receiving the first cycle of ceritinib and chemotherapy. In the era of personalized medicine, the molecular analysis of the tumor and the use of patient-specific tumor cells may represent a powerful tool to identify new therapeutic treatments for patients with underlying rare mutations.

10.1093/neuonc/noy059.229

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Aging — Raum und Wohnen Altersgerechtes Wohnumfeld und Wohnen: Angebot und Bedarf

Fabian Neuhaus Regula Ruetz Lea Roth

10.26041/fhnw-1270

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Citations (1)