Back to Search Start Over

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP).

Authors :
Rashid, Masturah Bte Mohd Abdul
Rashid, Masturah Bte Mohd Abdul
Toh, Tan Boon
Hooi, Lissa
Silva, Aleidy
Zhang, Yanzhou
Tan, Pei Fang
Teh, Ai Ling
Karnani, Neerja
Jha, Sudhakar
Ho, Chih-Ming
Chng, Wee Joo
Ho, Dean
Chow, Edward Kai-Hua
Rashid, Masturah Bte Mohd Abdul
Rashid, Masturah Bte Mohd Abdul
Toh, Tan Boon
Hooi, Lissa
Silva, Aleidy
Zhang, Yanzhou
Tan, Pei Fang
Teh, Ai Ling
Karnani, Neerja
Jha, Sudhakar
Ho, Chih-Ming
Chng, Wee Joo
Ho, Dean
Chow, Edward Kai-Hua
Source :
Science translational medicine; vol 10, iss 453, eaan0941; 1946-6234
Publication Year :
2018

Abstract

Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. We developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. We found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Details

Database :
OAIster
Journal :
Science translational medicine; vol 10, iss 453, eaan0941; 1946-6234
Notes :
Science translational medicine vol 10, iss 453, eaan0941 1946-6234
Publication Type :
Electronic Resource
Accession number :
edsoai.on1287298379
Document Type :
Electronic Resource