In Search of Targeted Therapies for Childhood Cancer

Mackall, Crystal L.

doi:10.3389/fonc.2011.00018

Cited by 11 publications

(7 citation statements)

References 42 publications

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“…Rationally designed drugs have benefited adults, but with the exception of BCR-ABL-positive leukemias, targeted therapies have so far done little to improve pediatric outcomes. 1 Recently, research into the mechanistic basis for pediatric cancer has begun to uncover defined molecular targets, raising the possibility of treatment by specifically designed drugs.…”

Section: Introductionmentioning

confidence: 99%

Development of a High-Throughput Screening–Compatible Assay for the Discovery of Inhibitors of the AF4-AF9 Interaction Using AlphaScreen Technology

Watson¹,

Drake²,

Peng³

et al. 2013

ASSAY and Drug Development Technologies

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Rearrangements of the mixed-lineage leukemia (MLL) gene occur predominately in pediatric leukemia cases and are generally predictors of a poor prognosis. These chromosomal rearrangements result in fusion of the protein MLL to one of more than 60 protein partners. MLL fusions are potent inducers of leukemia through activation of oncogene expression; therefore, targeting this transcriptional activation function may arrest MLL-rearranged (MLL-R) leukemia. Leukemic cell lines harboring the most common fusion protein, MLL-AF4, require the direct interaction of AF4 with the transcription factor AF9 to survive and self-renew; disrupting this interaction with a cell-penetrating AF4-derived peptide results in cell death, suggesting that the AF4-AF9 interaction could be a viable target for a novel MLL-R leukemia therapy. Here we describe the use of AlphaScreen technology to develop a high-throughput screening (HTS) assay to detect nonpeptidic inhibitors of AF4-AF9 binding. The assay is economical, requiring only low nanomolar concentrations of biotinylated AF4-derived peptide and FLAG-tagged AF9 in low-volume 384-well plates. A Z'-factor of 0.71 and a signal-to-background ratio of 21.3 showed the assay to be robust, and sensitivity to inhibition was demonstrated with competing AF4-derived peptides. Two pilot screens comprising 5,680 compounds served as validation for HTS at Nemours and the Broad Institute. Assay artifacts were excluded using a counterscreen comprising a biotinylated FLAG peptide. This is the first reported HTS-compatible assay to identify compounds that inhibit a key binding interaction of an MLL fusion partner, and the results presented here demonstrate suitability for screening large chemical libraries in high-density, low-volume plate formats.

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Section: Introductionmentioning

confidence: 99%

Development of a High-Throughput Screening–Compatible Assay for the Discovery of Inhibitors of the AF4-AF9 Interaction Using AlphaScreen Technology

Watson¹,

Drake²,

Peng³

et al. 2013

ASSAY and Drug Development Technologies

View full text Add to dashboard Cite

show abstract

“…Targeted therapies research is rapidly revolutionizing how treatments for the most complex diseases can be developed, which has the potential to facilitate innovation targeted directly at pediatric diseases [13]. As precision medicine and tissue agnostic development approaches continue to emerge as key pipeline drivers, and with increase in disease pathophysiology knowledge, more opportunities may emerge in early phase development for investment in innovation for rare or ultra-rare pediatric diseases.…”

Section: Analysis Of Pipeline Opportunitymentioning

confidence: 99%

How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement

Severin¹,

Corriol‐Rohou²,

Bucci‐Rechtweg³

et al. 2020

Ther Innov Regul Sci

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Background Pediatric regulations enacted in both Europe and the USA have disrupted the pharmaceutical industry, challenging business and drug development processes, and organizational structures. Over the last decade, with science and innovation evolving, industry has moved from a reactive to a proactive mode, investing in building appropriate structures and capabilities as part of their business strategy to better tackle the challenges and opportunities of pediatric drug development. Methods The EFGCP Children's Medicines Working Party and the IQ Pediatric working group have joined their efforts to survey their member company representatives to understand how pharmaceutical companies are organized to fulfill their regulatory obligations and optimize their pediatric drug development programs. Results Key success factors and recommendations for a fit-for-purpose Pediatric Expert Group (PEG) were identified. Conclusion Pediatric structures and expert groups were shown to be important to support optimization of the development of pediatric medicines.

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“…Identifying appropriate therapies for each patient may require detailed molecular and cellular analysis of tumor tissues ( 20 ). At present, drugs which target the signaling pathways behind MB, such as the AKT pathway, SHH pathway and NOTCH pathway are already in clinical trials ( 21 ). Some of these targeted drugs have been proven to be ineffective in the clinical trials, while others have presented a significant influence on the prognosis, even within the same molecular subtype of MB ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Production of a SCID mouse model of medulloblastoma to explore the therapeutic value of targeting tumor driver genes

2020

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Tumor driver genes are genes where structural or sequence mutations confer a selective advantage for cancer cells. The individualized targeting of tumor driver genes has become a topic of interest for tumor treatment. The prognosis for medulloblastoma (MB), a common type of malignant intracranial tumor found in children, is poor. The tumor driver genes and the corresponding targeted drugs remain to be studied. The present study analyzed tumor driver genes from tumor tissue and peripheral blood from one patient with nodular desmoplastic MB with Sonic Hedgehog activation and screened targeted drugs for the tumor driver genes. Additionally, MB tissue was successfully implanted into the SCID mouse which were then used for subsequent drug screening. The present study explored novel treatments for MB from the perspective of tumor driver genes, and may provide new ideas for choosing individualized targeted therapies for patients with MB.

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In Search of Targeted Therapies for Childhood Cancer

Cited by 11 publications

References 42 publications

Development of a High-Throughput Screening–Compatible Assay for the Discovery of Inhibitors of the AF4-AF9 Interaction Using AlphaScreen Technology

Development of a High-Throughput Screening–Compatible Assay for the Discovery of Inhibitors of the AF4-AF9 Interaction Using AlphaScreen Technology

How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement

Production of a SCID mouse model of medulloblastoma to explore the therapeutic value of targeting tumor driver genes

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