Posted September 1, 2017
André Lieber, M.D., Ph.D., University of Washington

While the majority of epithelial ovarian cancer (EOC) patients initially respond well to chemotherapy, most patients will eventually go on to experience disease recurrence and treatment resistance. Dr. Andre Lieber's work focuses on treatment resistance in patients with EOC. A common method of treatment resistance is the maintenance of tight junctions between cancerous cells. These tight junctions prevent therapeutic agents from penetrating into tumors. Dr. Lieber theorized that, if the tight junctions between tumor cells could be disrupted, resistance to treatment could be overcome, thus resulting in positive patient responses to treatment.

The Ovarian Cancer Research Program (OCRP) originally supported Dr. Lieber's research through a Translational Pilot Award granted to him in 2011. Dr. Lieber developed a set of proteins he terms "Junction Openers (JO)," which bind to desmoglein 2, a junction protein commonly overexpressed in ovarian cancers. The binding of JOs to desmoglein 2 triggers signaling pathways that result in temporary disruption of the tight junction. With his Translational Pilot Award, he tested the safety and efficacy of junction openers in combination with chemotherapeutics, such as PEGylated liposomal doxorubicin (PLD), in mice and non-human primates. Treatment with JO proteins successfully resulted in the transient opening of tight junctions between tumor cells, thus increasing the penetration and efficacy of chemotherapeutic drugs in tumors. This enhancement of therapeutic efficacy would suggest that patients treated with JO would be able to receive a lower dose of the chemotherapeutic agents, ultimately reducing unwanted side effects while maintaining drug activity.

Dr. Lieber's work has held such promise that, in 2016, Dr. Lieber was granted a Teal Expansion Award. The OCRP offers the Teal Expansion Award to give exemplary investigators the opportunity to expand upon promising research that was previously funded through the research program. Dr. Lieber plans to build upon his previous work in order to promote the clinical translation of Junction Opener/PEGylated Liposomal Doxorubicin (JO/PLD) therapy. Based on the results from his Translational Pilot Award, Dr. Lieber has submitted a pre-Investigational New Drug (IND) package for JO/PLD therapy, which was well reviewed by the Food and Drug Administration (FDA). As part of his Teal Expansion Award, Dr. Lieber has proposed manufacturing planning, preclinical toxicity studies, and a clinical trial, which will accelerate the FDA approval of JO/PLD therapy. He and his clinical collaborator, Dr. Charles Drescher, plan to have a full IND application submitted to the FDA by the end of year 2 of the award, and hopes to then initiate a Phase I clinical trial of JO/PLD therapy in EOC patients. Dr. Lieber's success could lead to a novel, FDA-approved therapeutic requiring lower dosages of chemotherapeutic agents while increasing their efficacy and tumor penetration. This new approach will not only result in better outcomes for ovarian cancer patients, but can also potentially be expanded to treat other patients with solid tumor cancers.

Link:

Public and Technical Abstracts: Combination Therapy of JO-c and PEGylated Liposomal Doxorubicin/Doxil in Ovarian Cancer Patients

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