Research Article: Cancer-Drug Associations: A Complex System

Date Published: April 2, 2010

Publisher: Public Library of Science

Author(s): Ertugrul Dalkic, Xuewei Wang, Neil Wright, Christina Chan, Jörg Hoheisel.

Abstract: Network analysis has been performed on large-scale medical data, capturing the global topology of drugs, targets, and disease relationships. A smaller-scale network is amenable to a more detailed and focused analysis of the individual members and their interactions in a network, which can complement the global topological descriptions of a network system. Analysis of these smaller networks can help address questions, i.e., what governs the pairing of the different cancers and drugs, is it driven by molecular findings or other factors, such as death statistics.

We defined global and local lethality values representing death rates relative to other cancers vs. within a cancer. We generated two cancer networks, one of cancer types that share Food and Drug Administration (FDA) approved drugs (FDA cancer network), and another of cancer types that share clinical trials of FDA approved drugs (clinical trial cancer network). Breast cancer is the only cancer type with significant weighted degree values in both cancer networks. Lung cancer is significantly connected in the FDA cancer network, whereas ovarian cancer and lymphoma are significantly connected in the clinical trial cancer network. Correlation and linear regression analyses showed that global lethality impacts the drug approval and trial numbers, whereas, local lethality impacts the amount of drug sharing in trials and approvals. However, this effect does not apply to pancreatic, liver, and esophagus cancers as the sharing of drugs for these cancers is very low. We also collected mutation target information to generate cancer type associations which were compared with the cancer type associations derived from the drug target information. The analysis showed a weak overlap between the mutation and drug target based networks.

The clinical and FDA cancer networks are differentially connected, with only breast cancer significantly connected in both networks. The networks of cancer-drug associations are moderately affected by the death statistics. A strong overlap does not exist between the cancer-drug associations and the molecular information. Overall, this analysis provides a systems level view of cancer drugs and suggests that death statistics (i.e. global vs. local lethality) have a differential impact on the number of approvals, trials and drug sharing.

Partial Text: Cancer is a complex disease, with many subtypes, affecting various tissues in diverse ways, thus giving rise to an abundance of chemotherapies. Taken together, cancers are the second leading cause of death in the United States [1]. The common features of cancer include uncontrolled cell growth, reduction in apoptosis, and loss of cell cycle regulation, while other features are more tissue specific and thus differentiate them and their chemotherapies.



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