University Cancer Research Fund
 June 2008 Innovation Awards
P.I.: Gehrig, Paola A.
Department: Division of Gyn Oncology, Department of OB/GYN
Title: Pilot Study Evaluating Phenotypic Measures of Reticuloendothelial System as Predictors of Doxil Pharmacokinetic and Pharmacodynamic Disposition in Patients with Recurrent Gynecological Malignancies

We propose to perform the first pilot study to evaluating the relationship between Doxil® pharmacokinetic (PK) and pharmacodynamic (PD) disposition and a phenotypic imagining probe of the reticuloendothelial system (RES) in patients with recurrent gynecologic malignancies. Ovarian cancer is a disease of the peritoneal cavity, which often presents and recurs with massive abdominal ascites. Monocytes and macrophages (MO/MA), the primary cells of the RES, represent a major subpopulation of the mononuclear leukocytes in ascites of ovarian cancer patients and may be a prognostic factor. One of the more promising drugs approved for the treatment of recurrent ovarian cancer is a pegylated-nanosomal doxorubicin (Doxil®). Nanosomes are liposomes with a hydrodynamic diameter < 100 nm that are used as carriers for chemotherapy that may provide increased tumor delivery and the antitumor activity. There is significant variability in the PK and PD response and toxicity (especially the hand-foot syndrome) associated with Doxil®. Thus, there is a need to identify the factors associated with the variability of drug related toxicities as well as investigate potential predictors of therapeutic response.

The clearance of nanosomes is related to the RES in the liver and spleen. We have reported that the tumor delivery and the antitumor activity of nanosomal agents are also related to the MO/MA in tumor models of ovarian cancer. These results suggest that tumors with greater MO/MA will be more likely to respond to nanosomal agents. The PK-PD interaction between Doxil® and MO/MA may also explain the hand-foot syndrome. We have also reported that patients that are > 60 years of age have a reduced uptake of nanosomal agents by monocytes, a lower clearance of Doxil®, and are at increased risk of toxicity. This is critical as the median age at presentation for ovarian cancer patients is 62.

Thus, the development of a non-invasive phenotypic imaging probe to evaluate RES activity in the liver and spleen (PK), tumor (efficacy), and hand (toxicity) may be used as a surrogate classifier to increase the antitumor activity and reduce toxicity of Doxil® by individualizing therapy. We propose to evaluate Tc-99m-sulfur colloid (TSC), an approved nuclear imaging agent used for liver and spleen scans and a measure of RES activity, as a phenotypic probe of Doxil® PK and PD disposition in patients with recurrent gynecologic malignancies (Figure 1). The rate of TSC uptake by the liver and spleen, as measured by dynamic and SPECT/CT imaging scans, and the clearance of TSC from the blood will be compared to Doxil® clearance. The rate of TSC uptake into tumor and the right hand will be compared to Doxil® associated response and hand-foot syndrome, respectively.

This proposal is innovative because the importance of MO/MA in ovarian cancer and other malignancies and the effect of the MO/MA on nanosomal anticancer agents in ovarian cancer have only recently been reported. In addition, the TSC phenotypic imaging and the pharmacologic methods required for these studies are unique to our group. The ultimate goal of this proposal is to translate the results to patients with ovarian cancer as a method to increase the antitumor activity and reduce toxicity of Doxil® by individualizing therapy. In addition, this protocol can act as a catalyst to guide the development of other nanosomal and nanoparticle anticancer agents in the treatment of cancer, thereby providing unique treatment opportunities for women with ovarian cancer.