RNAi-based technologies have the potential to enhance many aspects of the anti-cancer drug development process. The increased use of anti-cancer therapeutics targeting specific genetic characteristics (e.g., a fusion transcript or over-expression/amplification of a gene) illustrates the impact molecular analysis has had on the development of anti-tumor agents. Further, there is growing awareness that the genetic background of an individual can influence a patients response to anti-cancer therapeutics. Studies focused on assessing the contribution of genetic and transcriptional variation to a drug response phenotype have become more sophisticated as larger data sets integrating drug-activity with genome-wide DNA/RNA analysis are reported. However, functional approaches to understanding the relationships predicted by these studies have been lacking. We are using RNAi analysis and screening to probe the impact of gene-specific expression on drug-activity, including identification of new proteins that directly or indirectly modulate the pharmacology of anti-cancer therapeutics. The identification of molecular targets that can act to modulate the activity of anti-cancer drugs has become an important application for RNAi screening approaches. This approach combines RNAi with administration of a small molecule compound or biologic to identify proteins whose down-regulation modulates the activity of a therapeutic agent. This approach has the potential to enhance the clinical application of an established or investigational drug by: (1) identifying synergistic molecular targets that exploit complementary vulnerabilities within a cancer cell, (2) enabling the use of lower concentrations of a drug that exhibits dose-dependent non-specific toxicities, (3) overcoming drug resistance, and, (4) broadening the clinical application of a drug to other cancer types. We are currently using RNAi screening strategies to identify (1) regulators of TRAIL-mediated apoptosis and (2) proteins that when silenced sensitize breast cancer cells to rapamycin.
|Ou, Oliver; Huppi, Konrad; Chakka, Sirisha et al. (2014) Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity. Cancer Lett 354:336-47|
|Garimella, Sireesha V; Gehlhaus, Kristie; Dine, Jennifer L et al. (2014) Identification of novel molecular regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in breast cancer cells by RNAi screening. Breast Cancer Res 16:R41|
|Zhang, Yong-Wei; Jones, Tamara L; Martin, Scott E et al. (2009) Implication of checkpoint kinase-dependent up-regulation of ribonucleotide reductase R2 in DNA damage response. J Biol Chem 284:18085-95|
|Calcagno, A M; Fostel, J M; To, K K W et al. (2008) Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes. Br J Cancer 98:1515-24|