Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma

Neal, Molly Heft; Michmerhuizen, Nicole L.; Prince, Mark; Kovatch, Kevin J.; Owen, Jennifer C.; Zhai, Jingyi; Jiang, Hui; McKean, Erin L.; Brenner, J. Chad

doi:10.1055/s-0040-1716694

Cited by 3 publications

(1 citation statement)

References 52 publications

(88 reference statements)

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“…PDOs. Large scale screenings of chordomas have been few and limited to immortalized cell lines so far [39][40][41] . To validate that our PDO mini-ring platform 28,34 is suitable for high-throughput screening of chordomas, we performed proof-of-principle single concentration drug discovery screenings of up to 230 compounds on organoids established from CHORD001-5.…”

Section: High-throughput Drug Screening Of Chordomamentioning

confidence: 99%

Personalized chordoma organoids for drug discovery studies

Davarifar

et al. 2021

Preprint

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Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Primary treatment of chordoma is surgery, however complete resection is not always feasible due to their anatomic location, and recurrence rates remain high. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective regimens. Therefore, there is a need for discovery of novel therapeutic approaches. Drug discovery efforts in chordoma have been mostly limited to cell line models. Patient-derived organoids can accelerate drug discovery studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter- as well as intra-patient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-κB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.

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Section: High-throughput Drug Screening Of Chordomamentioning

confidence: 99%

Personalized chordoma organoids for drug discovery studies

Davarifar

et al. 2021

Preprint

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Unraveling molecular signatures in rare bone tumors and navigating the cancer pathway landscapes for targeted therapeutics

Wani,

Prakash,

Sena

et al. 2024

Critical Reviews in Oncology/Hematology

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Personalized chordoma organoids for drug discovery studies

et al. 2022

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Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective treatments. Therefore, there is a need for discovery of novel therapeutic approaches. Patient-derived organoids can accelerate drug discovery and development studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter- as well as intrapatient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-κB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.

show abstract

Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma

Cited by 3 publications

References 52 publications

Personalized chordoma organoids for drug discovery studies

Personalized chordoma organoids for drug discovery studies

Unraveling molecular signatures in rare bone tumors and navigating the cancer pathway landscapes for targeted therapeutics

Personalized chordoma organoids for drug discovery studies

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