Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations.
Cancer therapies that target key molecules have not fulfilled expected promises for most common malignancies. Major challenges include the incomplete understanding and validation of these targets in patients, the multiplicity and complexity of genetic and epigenetic changes in the majority of cancers, and the redundancies and cross-talk found in key signaling pathways. Collectively, the uses of single-pathway targeted approaches are not effective therapies for human malignancies. To overcome these barriers, it is important to understand the molecular cross-talk among key signaling pathways and how they may be altered by targeted agents. Innovative approaches are needed, such as understanding the global physiologic environment of target proteins and the effects of modifying them without losing key molecular details. Such strategies will aid the design of novel therapeutics and their combinations against multifaceted diseases, in which efficacious combination therapies will focus on altering multiple pathways rather than single proteins. Integrated network modeling and systems biology have emerged as powerful tools benefiting our understanding of drug mechanisms of action in real time. This review highlights the significance of the network and systems biology-based strategy and presents a proof of concept recently validated in our laboratory using the example of a combination treatment of oxaliplatin and the MDM2 inhibitor MI-219 in genetically complex and incurable pancreatic adenocarcinoma.
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R St, Detroit, Michigan 48201, USA.
Asfar S
AS
Azmi
Zhiwei
Z
Wang
Philip A
PA
Philip
Ramzi M
RM
Mohammad
Fazlul H
FH
Sarkar
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D015398:Signal Transduction; D049490:Systems Biology