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In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma
Ziyan Y Pessetto1, Bin Chen2, Hani Alturkmani1
1Departments of Pathology and Laboratory Medicine, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Abstract:
The long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery. To identify new therapeutic options, we employed a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs. Twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches. Among these drugs, 30 were extensively validated as mono-therapeutic agents and 9 in 14 various combinations in vitro. Two drugs, auranofin, a thioredoxin reductase inhibitor, and ganetespib, an HSP90 inhibitor, were predicted to have anti-cancer activities in silico and were confirmed active across a panel of genetically diverse EWS cells. When given in combination, the survival rate in vivo was superior compared to auranofin or ganetespib alone. Importantly, extensive formulations, dose tolerance, and pharmacokinetics studies demonstrated that auranofin requires alternative delivery routes to achieve therapeutically effective levels of the gold compound. These combined screening approaches provide a rapid means to identify new treatment options for patients with a rare and often-fatal disease.
Insights
Researchers identified new potential treatments for Ewing sarcoma (EWS) by combining computational predictions with drug screening. Auranofin and ganetespib showed promise, especially in combination, offering hope for this rare cancer.
Area of Science:
- Oncology
- Pharmacology
- Bioinformatics
Background:
- Ewing sarcoma (EWS) has a poor long-term survival rate, especially for metastatic or recurrent cases, with less than 30% survival despite aggressive treatments.
- Existing therapies including chemotherapy, radiation, and surgery are insufficient for advanced EWS.
Purpose of the Study:
- To discover novel therapeutic strategies for Ewing sarcoma by integrating in silico drug activity predictions with in vitro screening of FDA-approved drugs.
- To identify effective single agents and combinations for EWS treatment.
Main Methods:
- Utilized an integrated bioinformatics approach for in silico drug activity prediction.
- Conducted in vitro screening of FDA-approved drugs against EWS cell lines.
- Validated promising drug candidates as monotherapies and in combinations.
- Performed in vivo studies to assess combination therapy efficacy.
Main Results:
- Identified 27 drugs with anti-proliferative effects via in silico prediction and 46 drugs via in vitro screening.
- Validated 30 drugs as monotherapeutics and 9 drugs in 14 combinations in vitro.
- Auranofin (thioredoxin reductase inhibitor) and ganetespib (HSP90 inhibitor) showed confirmed activity in diverse EWS cells.
- Combination therapy with auranofin and ganetespib demonstrated superior in vivo survival rates compared to monotherapy.
- Auranofin requires alternative delivery methods for effective gold compound levels.
Conclusions:
- Combined in silico and in vitro screening rapidly identifies potential new treatments for rare and fatal diseases like EWS.
- Auranofin and ganetespib represent promising therapeutic candidates for Ewing sarcoma, particularly in combination.
- Further pharmacokinetic and formulation studies are needed for optimal drug delivery, especially for auranofin.
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