Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity

Manzella, Gabriele; Schreck, Leonie Daria; Breunis, Willemijn B.; Molenaar, Jan J.; Merks, Johannes H. M.; Barr, Frederic G.; Sun, Wenlu; Römmele, Michaela; Zhang, Luduo; Tchinda, Joëlle; Ngo, Quy A.; Bode, P.; Delattre, Olivier; Surdez, Didier; Rekhi, Bharat; Niggli, Felix; Schäfer, Beat W.; Wachtel, Marco

doi:10.1038/s41467-020-18388-7

Cited by 40 publications

(48 citation statements)

References 46 publications

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“…Primary rhabdomyosarcoma cell cultures were maintained in neurobasal medium (Gibco, 21103049, Waltham, MA, USA) supplemented with 1% penicillin/streptomycin (Gibco, 15140-122), 1X Glutamax (Gibco, 35050) and 2X B27 (Life Technologies, 17504044, Carlsbad, CA, USA). For RMS-ZH003_XC and IC-pPDX-29_XC cells, 20 ng/ml basic fibroblast growth factor (bFGF) (Peprotech, AF-100-18B, Rocky Hill, NJ, USA) and 20 ng/mL epidermal growth factor (EGF) (Peprotech, AF-100-15) were added [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells

Bauer

Quante

Breunis

et al. 2021

Cancers

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Amino acids are integral components of cancer metabolism. The non-essential amino acid asparagine supports the growth and survival of various cancer cell types. Here, different mass spectrometry approaches were employed to identify lower aspartate levels, higher aspartate/glutamine ratios and lower tricarboxylic acid (TCA) cycle metabolite levels in asparagine-deprived sarcoma cells. Reduced nicotinamide adenine dinucleotide (NAD+)/nicotinamide adenine dinucleotide hydride (NADH) ratios were consistent with redirection of TCA cycle flux and relative electron acceptor deficiency. Elevated lactate/pyruvate ratios may be due to compensatory NAD+ regeneration through increased pyruvate to lactate conversion by lactate dehydrogenase. Supplementation with exogenous pyruvate, which serves as an electron acceptor, restored aspartate levels, NAD+/NADH ratios, lactate/pyruvate ratios and cell growth in asparagine-deprived cells. Chemicals disrupting NAD+ regeneration in the electron transport chain further enhanced the anti-proliferative and pro-apoptotic effects of asparagine depletion. We speculate that reductive stress may be a major contributor to the growth arrest observed in asparagine-starved cells.

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Section: Methodsmentioning

confidence: 99%

Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells

Bauer

Quante

Breunis

et al. 2021

Cancers

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“…Our PPCs have been molecularly characterized to resemble primary tumors more closely than established cell lines [9] . Hence, expression of BCL-2 family members is also expected to play an important role in human patient tumors.…”

Section: Discussionmentioning

confidence: 99%

“…PDX tumors were transplanted as described previously [9] . For tumor amplification, pieces with a size of ~10 to 30 mm 3 from fresh human tumor biopsies or established PDX tumors were transplanted subcutaneously into the flank of 6 to 10 wk old, sex-matched NOD scid gamma (NSG) mice.…”

Section: Methodsmentioning

confidence: 99%

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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

et al. 2021

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First-line therapy for most pediatric sarcoma is based on chemotherapy in combination with radiotherapy and surgery. A significant number of patients experience drug resistance and development of relapsed tumors. Drugs that have the potential to re-sensitize relapsed tumor cells toward chemotherapy treatment are therefore of great clinical interest. Here, we used a drug profiling platform with PDX-derived primary rhabdomyosarcoma cells to screen a large drug library for compounds re-sensitizing relapse tumor cells toward standard chemotherapeutics used in rhabdomyosarcoma therapy. We identified ABT-263 (navitoclax) as most potent compound enhancing general chemosensitivity and used different pharmacologic and genetic approaches in vitro and in vivo to detect the NOXA-BCL-XL/MCL-1 balance to be involved in modulating drug response. Our data therefore suggests that players of the intrinsic mitochondrial apoptotic cascade are major targets for stimulation of response toward first-line therapies in rhabdomyosarcoma.

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“…Furthermore, there is limited availability of data that can be extrapolated from databases to circumvent this issue. Yet, several studies have established proof-of-concept that patient-derived in vitro models can represent patient tumors in co-clinical trials in colorectal cancer [ 64 ], rhabdomyosarcoma [ 65 ], and rectal cancer [ 66 ]. While, the efforts for developing a dedicated CCA model capable for predictive pre-clinical testing is ongoing, there are numerous experimental models currently available for CCA research [ 63 ].…”

Section: Potential Use Of Non-animal Models As Pre-clinical Modelsmentioning

confidence: 99%

Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

et al. 2021

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Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

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Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity

Cited by 40 publications

References 46 publications

Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells

Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells

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

Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

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