Novel Platinum/Taxane-Based Drug Combinations (Preclinical) for Ovarian Cancer
Abstract
Ovarian cancer often spreads within the abdomen, spreading in what is called the intraperitoneal space where intestines and other organs live. The intraperitoneal spreading of ovarian cancer is difficult to treat, and direct intraperitoneal injection of chemotherapy is being investigated in ovarian cancer clinical trials. We propose to identify new drug combinations that improve the activity of drugs commonly used to treat ovarian cancer, namely cisplatin + drugs that attack the microtubules used in cell division known as taxanes (taxanes include paclitaxel and docetaxel). We will study our new drug combinations using novel intraperitoneal patient-derived, ovarian cancer xenograft models (PDX). Xenografts are human tumors grown in special mice that lack an immune system, and the PDX models are xenografts where tumors from patients are implanted directly into special mice that lack an immune system and can thus grow human cells. Fenretinide (4-HPR) is an anticancer drug based on vitamin A that has been shown to kill ovarian cancer cells and to enhance cisplatin activity against ovarian cancer cells grown in the laboratory; such growing cells are called cell lines. We carried out previously a clinical trial in ovarian cancer of a 4-HPR capsule formulation, and we showed that women achieving higher 4-HPR drug plasma levels had a higher event-free survival. Our novel formulations of 4-HPR reliably achieve higher plasma levels than the older capsule formulation and have achieved multiple, sustained, complete responses in Phase I clinical trials of relapsed neuroblastoma and T-cell lymphomas. Our 4-HPR/LXS oral powder formulation is now used together with the well-tolerated anti-fungus drug ketoconazole. Ketoconazole blocks breakdown of 4-HPR and further increases 4-HPR plasma levels and is currently being tested in a Phase I/II ovarian cancer clinical trial. EpHA2 is a molecule found on the cell surface of ovarian cancers that can serve as a target for antibodies. MM-310 is a novel formulation of the taxane docetaxel that is targeted to ovarian cancer by using an antibody that binds to EpHA2 and is thus expected to enhance taxane activity against ovarian cancer. We will test novel drug combinations in which we combine fenretinide with a taxane drug commonly to treat ovarian cancer and test the new combination of drugs against patient-derived intraperitoneal ovarian cancer xenografts, with a goal being to demonstrate that the novel drug combinations will have better anti-cancer activity then the older drug. In Aim 1 we will test 4-HPR/ketoconazole combined with the taxane drug paclitaxel. In Aim 2 will test 4-HPR/ketoconazole combined with a new version of a taxane drug, EphA2-targeted docetaxel (MM-310), and compare that to untargeted docetaxel. Finally, in Aim 3 we will compare the antitumor activity of the most active taxane combination (from Aims 1 and 2) in combination with cisplatin. We will take tumor cells growing from our 12 intraperitoneal human ovarian cancer xenograft (growing in special mice) models and measure how much ovarian cancer cell killing is observed in the test tube when combining 4-HPR + paclitaxel. We will determine the activity and tolerability of the 4-HPR-based drug combinations (as described above in the specific aims) in three i.p. patient-derived xenograft (PDX) models of intraperitoneal ovarian cancer. As a comparator to previously published ovarian cancer preclinical models, we will assess the most active drug combination in three ovarian cancer intraperitoneal PDX models and two PDX models where the ovarian cancer is grown subcutaneously (just under the skin, a typical model for cancer drug testing). Our proposed studies are innovative as few ovarian cancer preclinical studies employ intraperitoneal xenograft models and drug testing against intraperitoneal ovarian cancer PDX models is very novel. Our novel 4-HPR formulation (especially when combined with ketoconazole) allow
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610381
Entities
People
- Patrick Reynolds
Organizations
- Texas Tech University Health Sciences Center
- United States Army