A combinatorial drug screen in PDX-derived primary rhabdomyosarcoma cells identifies the NOXA - BCL-XL/MCL-1 balance as target for re-sensitization to first-line therapy in recurrent tumors

Manzella, Gabriele; Moonamale, Devmini C.; Römmele, Michaela; Bode, P.; Wachtel, Marco; Schäfer, Beat W.

doi:10.1016/j.neo.2021.07.001

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…It is crucial to conduct studies using PDX before conducting clinical studies in humans, since PDX models closely mimic the essential features of patients' tumors. Although limited research has been carried out on PDX in RMS, a study by Manzella et al found that a subgroup of RMS was highly sensitive to AKT inhibitors and that NOXA-BCL-XL/MCL-1, which are crucial molecules in the mitochondrial apoptotic cascade, could be targeted therapeutically to modulate the drug response in RMS using the PDX model (21,22). However, the current study is the first to use PDX to evaluate redox regulation in RMS.…”

Section: Discussionmentioning

confidence: 81%

Thioredoxin Reductase Inhibitor Suppresses the Local Progression of Rhabdomyosarcoma With PDX Models

KINOSHITA,

KAMODA

et al. 2024

Cancer Genomics Proteomics

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Background/Aim: Chemoresistance in rhabdomyosarcoma (RMS) is associated with poor survival, necessitating the development of novel anticancer drugs. Auranofin (AUR), an anti-rheumatic drug, is a thioredoxin reductase (TXNRD) inhibitor with anticancer properties. Although patient-derived xenograft (PDX) models are essential for studying cancer biology, reports on sarcomas using the PDX model are scarce because of their rarity. This study aimed to investigate the effectiveness of AUR treatment in RMS using a PDX model to evaluate its impact on local progression. Materials and Methods: A 20-year-old woman who was diagnosed with alveolar RMS was used to generate the PDX model. RMS PDX tumors were implanted in nude mice and divided into non-treated (vehicle) and treated (AUR) groups. Tumor volume and weight were evaluated, and immunohistochemical staining was performed to evaluate local progression of the sarcoma. The relationship between the TXNRD-1 expression and survival probability of patients with RMS was evaluated using publicly available expression cohorts. Results: AUR significantly suppressed RMS tumor progression over time. It also significantly suppressed the tumor size and weight at the time of excision. Histological evaluation showed that AUR induced oxidative stress in the PDX mouse models and inhibited the local progression of RMS by inducing apoptosis. High TXNRD-1 expression was found to be a negative prognostic factor for overall survival in patients with RMS. Conclusion: AURinduced inhibition of TXNRDs can significantly impede the local progression of RMS through the oxidative stressapoptosis pathway as demonstrated in PDX models. Thus, targeting TXNRD inhibition may be a promising therapeutic strategy for the treatment of RMS.

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Section: Discussionmentioning

confidence: 81%

Thioredoxin Reductase Inhibitor Suppresses the Local Progression of Rhabdomyosarcoma With PDX Models

KINOSHITA,

KAMODA

et al. 2024

Cancer Genomics Proteomics

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“…A previous study demonstrated the survival of a cell subpopulation expressing MYOD1 in an RMS cell line following treatment with the standard-of-care chemotherapeutic agents vincristine and doxorubicin [7]. Other studies have shown high levels of antiapoptotic proteins are present in treatment-refractory RMS tumors [8,9] and upregulation of selective signaling pathways (e.g., GP130/STAT and Hedgehog) in chemotherapy-resistant RMS cells [10,11]. Recently, a study by Patel et al demonstrated that chemotherapy eliminates proliferative myoblast-like cells in the FN embryonal subtype of RMS (ERMS), leaving behind an immature cell population that recapitulates paraxial mesodermal cells in development [12].…”

Section: Introductionmentioning

confidence: 98%

The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma

Fritzke

Chen

Tang

et al. 2023

Cancers

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Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that causes significant devastation, with no effective therapy for relapsed disease. The mechanisms behind treatment failures are poorly understood. Our study showed that treatment of RMS cells with vincristine led to an increase in CD133-positive stem-like resistant cells. Single cell RNAseq analysis revealed that MYC and YBX1 were among the top-scoring transcription factors in CD133-high expressing cells. Targeting MYC and YBX1 using CRISPR/Cas9 reduced stem-like characteristics and viability of the vincristine-resistant cells. MYC and YBX1 showed mutual regulation, with MYC binding to the YBX1 promoter and YBX1 binding to MYC mRNA. The MYC inhibitor MYC361i synergized with vincristine to reduce tumor growth and stem-like cells in a zebrafish model of RMS. MYC and YBX expression showed a positive correlation in RMS patients, and high MYC expression correlated with poor survival. Targeting the MYC-YBX1 axis holds promise for improving survival in RMS patients.

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“…High expression of anti-apoptotic BCL-2 family protein members has also been reported for RMS [93][94][95] and preclinical testing of BH3-mimetics as singleagents or in combination with other drugs has shown efficacy in RMS [96][97][98] .…”

Section: Programmed Cell Death Mechanisms In Rmsmentioning

confidence: 99%

En route to better treatment of rhabdomyosarcoma

Meister¹

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Rhabdomyosarcomas (RMS) are the most common tumors of the soft tissues (sarcomas) in children and adolescents. RMS grow aggressively and show a propensity to spread in the body (metastasize). Treatment is harsh and consists of chemotherapy and local therapy which can be radiotherapy and/or surgical removal. Depending on the localization in the body, children with localized disease can be cured in 50-70% of cases, often at the cost of severe long-term effects. Children with metastases, however, face poor survival with 40% survival at best. Thus, new therapies are needed for patients with RMS. The development of such new therapies has been hampered by several factors of which a number are addressed in this thesis. First, we explore the relationship between aberrant so-called Hedgehog signaling pathway activity and programmed cell death (PCD) in RMS cell lines. We propose mechanisms by which RMS cells evade PCD induction and thereby acquire a growth advantage. Furthermore, we study how to overcome this mechanism by using combination treatments. Cell lines are in vitro models derived from primary tumor material which have been altered to allow for indefinite growth. However, due to these alterations, cell lines reflect patient tumors to a lesser degree, thereby limiting their applicability. Thus, we sought to generate novel preclinical models of RMS which more closely resemble patient tumors. To this end, we established so-called tumor organoid models of RMS. Extensive characterization experiments indicate that RMS tumor organoid models indeed reflect patient tumors to a high degree. We could establish such models from most RMS subtypes, thereby expanding the arsenal of preclinical RMS models. A key characteristic of tumors is their cellular heterogeneity, i.e., the variation between tumor cells within one or between tumors. Furthermore, it is important to understand what other cell types are present in a tumor as their presence and activation state (such as it is the case for immune cells) can be crucial for the survival of tumor cells. To address these two aspects, we performed single-cell RNA-sequencing of primary RMS tumors. With this novel technique, the gene expression of individual cells within a tumor sample can be measured. Using this information, we show that the relative contribution of tumor cells within a tumor exhibiting certain so-called transcriptional meta-programs is predictive for the survival of a patient. Furthermore, we propose a direct cell-cell interaction between tumor and immune cells by which the tumor cells inactivate the immune cells, thereby facilitating their own survival. In conclusion, this thesis provides novel insights into the biology of RMS and proposes avenues for development of new treatment options.

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A combinatorial drug screen in PDX-derived primary rhabdomyosarcoma cells identifies the NOXA - BCL-XL/MCL-1 balance as target for re-sensitization to first-line therapy in recurrent tumors

Cited by 4 publications

References 36 publications

Thioredoxin Reductase Inhibitor Suppresses the Local Progression of Rhabdomyosarcoma With PDX Models

Thioredoxin Reductase Inhibitor Suppresses the Local Progression of Rhabdomyosarcoma With PDX Models

The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma

En route to better treatment of rhabdomyosarcoma

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