Identification of clinically achievable combination therapies in childhood rhabdomyosarcoma.
OBJECTIVE
Systemic therapy has improved rhabdomyosarcoma event-free and overall survival; however, approximately 40 % of patients will have progressive or recurrent disease which is difficult to cure and remains a considerable challenge. Minimal progress has been made in improving outcomes for metastatic or relapsed RMS due to a lack of effective therapeutic agents. Targeted therapies are likely to be incorporated into regimens which rely on conventional cytotoxic chemotherapy. A system to evaluate novel combinations of interest is needed.


METHODS
In this study, we explored 8 agents, 5 that are routinely used or similar to agents used in the clinical management of RMS and 3 biologically targeted agents with novel mechanisms of action, the Wee1 inhibitor AZD1775, the tyrosine kinase inhibitor cabozantinib, and the proteasome inhibitor bortezomib. All were tested individually at clinically achievable concentrations for activity in 4 RMS cell lines and then for potential synergy in two-drug combinations.


RESULTS
We found single-agent activity in five of the agents (or their active metabolites) that constitute the standard of care in RMS and for AZD1775 with mean IC50 values of 207 ng/ml, well below clinically achievable levels. In addition, the combination of individual cytotoxic chemotherapeutics currently used for RMS demonstrated largely synergistic activity with higher, but clinically achievable concentrations of AZD1775 in our assays.


CONCLUSIONS
Prioritization of chemotherapeutics in RMS is possible using an in vitro system that can define novel drug combinations worthy of future investigation. AZD1775 exhibits single-agent activity, as well as synergy with conventional cytotoxic chemotherapy, and is a novel targeted agent that warrants further study in RMS.
Sunshine Project Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Elliot
E
Kahen
Sunshine Project Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Diana
D
Yu
Division of Pediatrics, MD Anderson Cancer Center, Houston, TX, USA.
Douglas J
DJ
Harrison
Sunshine Project Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Justine
J
Clark
Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA.
Pooja
P
Hingorani
Sunshine Project Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.|Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Christopher L
CL
Cubitt
Sunshine Project Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. damon.reed@moffitt.org.|Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. damon.reed@moffitt.org.|Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. damon.reed@moffitt.org.|Adolescent and Young Adult Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, 33612, Tampa, FL, USA. damon.reed@moffitt.org.
Damon R
DR
Reed
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D002648:Child; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D058990:Molecular Targeted Therapy / Q000379:methods*; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents
AZD1775; Clinically achievable concentrations; Combination chemotherapy; Cyclophosphamide; Etoposide; Irinotecan; Rhabdomyosarcoma