Ovarian cancer grows without clear symptoms, and in most cases it is only found when it has invaded other organs. At these advanced stages, it is difficult to treat. Upon diagnosis, ovarian cancer is treated by surgery and platinum-based chemotherapy. However, in many patients, the median progression-free survival time is only 18 months, and the cancer comes back. Recurrent cancer is often resistant to treatment and has a poor prognosis. Ovarian cancer chemotherapy is given through intravenous infusion and reaches the tumor through the blood circulation. A problem is that drugs diffuse only a few cell layers away from the blood vessel into the tumor. This implies that more-distant tumor cells receive only subtoxic drug concentrations and survive the chemotherapy. Recent research has shown that the remaining tumor cells transition into a cancer stem cell-like stage that becomes resistant to chemotherapy. One of the reasons for the poor drug penetration in tumors is the fact that tumor cells are glued together through epithelial junction proteins. Tumors maintain these junctions to protect themselves from the immune system. These junctions are also a basic resistance mechanism for treatment. My laboratory has worked for over 20 years on adenoviruses, viruses that can cause a cold.

In this context, we have understood how these viruses penetrate into the respiratory system of humans. The barriers in the airway tract are also formed by epithelial junctions, and adenoviruses have evolved a mechanism to open these junctions. We have delineated the adenovirus proteins that are capable of "junction opening" and generated the recombinant protein JO ("Junction Opener"). JO can easily be produced in E. coli bacteria and therefore has a low manufacturing cost. We have tested JO in combination with cancer therapy drugs in mice with human or mouse tumors. These models included ovarian, breast, colon, gastric, lung, and prostate cancer. In all models, JO increased the efficacy of the cancer drugs, including monoclonal antibodies such as Herceptin and Erbitux and chemotherapy drugs such as Taxol, Abraxane, Doxil, and Irintorecan. JO also improved that therapeutic outcome with newer cancer drugs, such oncolytic viruses and "tumor-melting" CAR T-cells. In mouse models, we have also shown that, upon JO treatment, more drug accumulates in the tumor, implying less exposure of normal tissues to toxic chemotherapy drugs. The latter is important because many chemotherapy drugs cause side effects that often greatly affect the life quality of the patient. For example, Doxil, a drug used in ovarian cancer patients, involving four treatment cycles, causes swelling, numbness, skin peeling on palms of the hands and soles of the feet, and toxicity to the heart, which often requires that Doxil doses have to be lowered after the second treatment cycle.

Our goal is to improve the efficacy and safety of Doxil by co-treatment with JO. In preparation of a clinical trial, we have performed a series of efficacies studies in ovarian cancer mouse models. We also demonstrated excellent safety of the approach in monkeys, where we tested JO in combination with Doxil at doses that we would use in patients. These studies were supported by an Ovarian Cancer Research Program (OCRP) Translational Pilot Award. The results of these are published in a series of papers and were summarized in a pre-Investigational New Drug (IND) package that was submitted to the Food and Drug Administration (FDA).

The FDA's straightforward suggestions for JO manufacturing, preclinical toxicity studies, and the clinical trial have been addressed in the research plan of this proposal. In our proposal for an OCRP Teal Expansion Award, we plan to conduct a Phase I trial with JO and Doxil in patients with progressive, persistent, or recurrent ovarian/fallopian tube cancers who have previously received standard therapies. The primary goal of this trial is to confirm the safety of the treatment. Clearly, we will also evaluate therapeutic responses. Furthermore, we will use serum samples and, if available, tumor biopsies, to learn more about the interaction of JO with the body and the tumor. The trial will be coordinated through the Pacific Ovarian Cancer Research Consortium Clinical Core and performed at the Swedish Cancer Institute at Swedish Medical Center in Seattle, Washington, in a dedicated Phase I trial unit. We expect that, at this stage, up to 15 patients will be required. In years 1 and 2 of the funding period, we will manufacture JO at clinical grade, perform toxicology studies in mice and monkeys, and receive IND approvals. We plan to start enrolling patients at the end of year 2 and complete the trial in year 4. We expect to demonstrate that the treatment is safe with increased efficacy of Doxil treatment, reflected by (a) increased therapeutic response compared to historical data and (b) therapeutic efficacy in patients with progressive disease that became resistant to Doxil. In follow-up trials, we also expect to maintain the therapeutic efficacy of Doxil when lowering of treatment doses is required due to toxic side effects. In future clinical trials, reduced Doxil dosing will also facilitate incorporation of Doxil in combination regimens, including, in particular, cytotoxic and/or biologic agents with overlapping toxicities.

The Principal Investigator's group at the University of Washington has formed an alliance with industry partners at PAI Life Sciences, Inc., and Compliment Corp. This partnership has been successful in supplementing National Institutes of Health funding to initiate clinical studies with another technology to improve cancer therapy. We plan to use a similar pathway to complete the studies with JO outlined in this proposal.