An Implantable Microdevice for Efficient In Vivo Testing of Targeted Therapies in Ovarian Clear Cell Cancer
Abstract
Rationale And Objectives: Ovarian clear cell cancer (OCCC) is an aggressive subtype of ovarian cancer with few targeted treatments in clinical use. We propose to use an innovative technology called an implantable microdevice to test multiple candidate drugs simultaneously within OCCC tumors. The microdevice is a medical device, smaller than a grain of rice, that can be placed inside ovarian tumors. The drug has many separate reservoirs that each release a miniscule amount of drug into the cancer tissue surrounding the device. The design of the device and the formulation of the drugs is optimized so that each sector of tumor tissue is exposed to just one drug. Following drug exposure, the tumor tissue is collected and analyzed to determine whether each drug killed the cancer cells. Importantly, the microdevice allows testing of up to 20 drugs at once. Thus, we can measure the effects of many drugs on the same tumor in a single experiment. The goal of this study is to apply the microdevice technology to efficiently test new drugs and drug combinations in animal models of OCCC. Clinical Problem in Ovarian Cancer Addressed by this Project: OCCC is a rare subtype of ovarian cancer that has a worse prognosis in advanced stages, despite treatment with standard-of-care surgery and chemotherapy. OCCC is more resistant to platinum chemotherapy and to poly(ADP-ribose) polymerase (PARP) inhibitors compared to the more common subtype, high-grade serous ovarian cancer. OCCC also has a markedly different genetic profile and biology than other types of ovarian cancer, and therefore requires new and different therapeutic strategies. Although laboratory studies have given rise to preclinical and clinical studies of several drugs targeting the unique genetic features and signaling pathways in OCCC, most clinical trials have not shown benefit in patients, and no targeted therapies are available specifically for OCCC. We propose that testing a panel of candidate drugs and drug combinations in vivo in multiple OCCC models using an implantable microdevice will more rapidly prioritize promising drug candidates for OCCC patients. In this study, we plan to test up to 30 potential drugs for OCCC in six different OCCC models in animals using microdevices. We will select the top three drugs that are most broadly effective and will evaluate these in a more traditional animal study with administration of the drug into the veins – this will assess whether the microdevice study accurately predicted the sensitivity or resistance of a specific model to the drug. In addition, we will study specific proteins in the cancer cells to determine whether changes in a selected protein correlate with sensitivity to the drug, thereby identifying candidate biomarkers of drug response. Finally, we will leverage the efficiency of the microdevices to study new two-drug combinations for OCCC. In patients, combination regimens have the potential to generate stronger and longer lasting anti-tumor responses compared to single drugs alone. With this technology, we can quickly test many combinations of two drugs to determine which pairs have the most activity against OCCC. Innovation: Currently, drug development studies in cancer often involve testing new drugs in cell line models then confirming promising drugs in a small number of animal models, a process that is bottlenecked by the time and expense of the animal studies: only a small number of drugs or combinations can be tested in a few models. Our innovative new approach with in-tumor drug sensitivity testing using microdevices will allow us to vet dozens of new candidate drugs simultaneously, across many different OCCC models, in the same experiment. We believe this will accelerate research on drug treatments for OCCC and help to prioritize selected drugs that have the most activity in OCCC for development in clinical trials. In the future, the microdevices may be used in the clinical care of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211090
Entities
People
- Elizabeth H Stover
Organizations
- Dana–Farber Cancer Institute
- United States Army