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TGen Study Suggests Potential for RNAi Screening in Developing Combo Treatments for Cancer

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By Turna Ray

Researchers at the Translational Genomics Research Institute have published data that suggests the possibility of using RNAi screening to develop targeted combination treatments for ovarian cancer.

Last month in Gynecologic Oncology, Shilpi Arora of TGen's Pharmaceutical Genomics Division and colleagues published results from a study in which they searched for proteins linked to cisplatin response by conducting a high-throughput RNAi screen of 572 kinases in the ovarian cancer cell line SKOV3.

"Our data provides kinase targets that could be exploited to design better therapeutics for ovarian cancer patients," the study authors reported. In the study, researchers also demonstrate "the effectiveness of high-throughput RNAi screening as a tool for identifying sensitizing targets to known and established chemotherapeutic agents."

The researchers discovered 55 siRNAs that augmented cisplatin's ability to inhibit the growth of ovarian cancer cells. According to the paper, inhibition of ATR and CHK1 "resulted in the greatest modulation of cisplatin response."

In order to examine the therapeutic implications of this finding, the researchers blocked CHK1 with a small molecule agent, PD 407824, and found that it sensitized the cancer cells to cisplatin.

Although the concepts being explored by TGen require validation, there is certainly potential for applying the RNAi screening hypothesis generated by TGen's research in commercial drug development. The hypothesis may be of interest to several drug companies currently exploring investigational CHK1 inhibitors in combination with other chemotherapeutic agents including Pfizer, Merck, Lilly, and AstraZeneca.

In March, TGen published a paper in Drug Discovery in Pancreatic Cancer, titled "Application of High-Throughput RNAi in Pancreatic Cancer Target Discovery and Drug Development," which discussed the application of genome-scale RNAi to identify therapeutic targets.

Raoul Tibes, senior co-author on the Gynecologic Oncology paper, confirmed that TGen Clinical Research Services "has a study with a CHK inhibitor in pancreatic cancer patients," but did not identify the agent.

Additionally, Tibes' lab has performed large-scale RNAi studies in leukemias and identified "potent sensitizers" to readily used chemotherapies. He said he and his research team are working on bringing combinations of chemotherapies with CHK1 inhibitors and other inhibitors that interfere with DNA repair into the clinic for patients with leukemias and hematological malignancies.

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