Platinum-resistant Ovarian Tumors
William Ricketts, Ph.D., director of research for Oncotech (www.oncotech.com), described studies aimed at identifying specific pathways in ovarian cancer cells that were altered in cisplatin-resistant tumor cells. He cited the ongoing need for the development of sophisticated diagnostics to predict the responses of individual tumors to chemotherapy, pointing out that the initial clinical response to platinum is a major determinant of clinical outcome for patients with ovarian cancer.
“Clinical investigators have shown that patients with tumors determined to be resistant in vitro to platinum compounds are at a greatly increased risk for disease progression and death when treated with standard platinum-based regimens. The determination of drug-resistance patterns for a given tumor is important for selecting the most effective therapy and minimizing side effects from drugs to which tumors are unresponsive,” said Dr. Ricketts.
The Oncotech research team has access to primary human tumors (both cryopreserved and paraffin-embedded) and the drug-resistance data based on the company’s Extreme Drug Resistance™ assay, which has been offered clinically for almost 20 years. Researchers selected tumor cells for this study that had been identified as cisplatin resistant using the Extreme Drug Resistance Assay, a clinically validated assay that Oncotech says is 99% accurate in determining tumor-cell drug resistance.
The assay separates cancer cells into one of three groups—extreme drug resistant (EDR), intermediate drug resistant (IDR), or low drug resistant (LDR). The ovarian tumors studied by Dr. Ricketts were from previously untreated patients and had an LDR response to all other drugs tested. The scientists analyzed cell-signaling pathways using applied gene array technology, PathArt analysis (a software analysis tool that classifies genes into pathways developed by Jubilant Biosys (www.jubilantbiosys.com), and In Cell Westerns (a high-throughput detection system developed by Li-Cor Biosciences (www.licor.com) for simultaneous analyses of protein expression and phosphorylation state to conclude that differences in signal-transduction pathways are present at the gene and protein level in human tumors with differing cisplatin responses.
They further found that proteins with altered expression tend to be “intermediate signaling molecules”, such as Erk, Akt, b-catenin, and STAT3, possibly indicating that the significant determinant in drug resistance is not how the cell “sees” the signal but how it “interprets” it and responds through signal amplification or altered gene expression.
Oncotech’s ultimate goal, Dr. Ricketts, explained, is to develop molecular diagnostics that go beyond the EDR soft agar assay and reach into the signaling pathways that contribute to drug resistance by their activation and underlying genetics of resistance. He pointed out, for example, that diagnostics to determine treatment can detect overexpression of a drug or antibody target such as the EGF receptor, but yield no information about whether pathways regulated by the target that may also influence drug response are activated.
“Activated pathways that are altered in resistant tumors may provide biomarkers of drug resistance but may also provide second-line indication for many targeted therapies,” Dr. Ricketts said.