Posted September 21, 2018
Geeta Mehta, Ph.D., University of Michigan

Currently, preliminary drug screening for potential therapeutic compounds occurs in vitro in a two-dimensional (2D) monolayer of adherent cell culture. While this is both convenient and economical for large-scale screening, it does not mirror the cellular environment inside the body. As a result, anticancer drugs will often display much different reactions in a 2D cell culture environment versus that observed in patients. Dr. Mehta was awarded a Fiscal Year 2012 (FY12) Ovarian Cancer Research Program (OCRP) Ovarian Cancer Academy Award to support the development of a platform that more adequately mimics the 3D environment inside the body; she then used this platform to test drug responses in patient ovarian cancer cells.

Ovarian cancer patients have a poor 5-year survival rate of approximately 50%. One of the main reasons for the poor survival rate among ovarian cancer patients is resistance to chemotherapy. Current evidence suggests that ovarian cancer stem cells (OvCSCs) are responsible for therapy resistance. OvCSCs make up a small subpopulation of tumor cells capable of self-renewal and differentiation into new tumors. Dr. Mehta developed her 3D platform with OvCSCs with the hope of finding new drugs to target their chemoresistance and tumorigenicity.

Dr. Mehta grew patient OvCSCs in 3D spheroids, which more accurately mimic the cells� in vivo environment. This 3D spheroid platform was developed in an easy-to-use, high-throughput, 384-well hanging drop array. It has the capability of analyzing a large number of drug responses simultaneously, with a mere 10 ovarian cancer cells per well, a highly attractive capability, as OvCSCs make up only 0.1% of the cells found in primary ovarian tumors. Dr. Mehta determined that the OvCSCs grown in this 3D platform were viable and capable of initiating tumors in a mouse model. Next, drug responses were tested in the 3D platform and compared to 2D cultures, as well as in vivo animal model results. In cases where a drug response in a 2D platform produced a different response compared to the in vivo mouse model, Dr. Mehta's 3D platform produced a response more comparable to the mouse model. This illustrates that the 3D platform is capable of maintaining and growing populations of OvCSCs similar to what would occur in the 3D environment in the patient's body, making drug studies physiologically relevant.

The success of Dr. Mehta's 3D spheroid platform prompted the OCRP to support further research with the platform through an FY15 Ovarian Cancer Research Program (OCRP) Pilot Award. With this award, Dr. Mehta and her colleagues from the University of Michigan, Drs. Nouri Neamati and Mats Ljungman, have begun to use the 3D platform to identify novel drugs that target OvCSCs from a panel of 650 small molecules. One molecule, N7-73, displayed remarkable potency in chemoresistant OvCSCs.

The OCRP recognized the potential of N7-73, and awarded Dr. Mehta, along with Drs. Neamati and Ljungman an FY17 OCRP Investigator-Initiated Research Award to research the impact of N7-73 in ovarian cancer and, importantly, in therapy-resistant ovarian cancer. They will try to understand N7-73's mechanisms of action and assess its efficacy in a mouse model of human ovarian cancer. This project will hopefully lead to a clinical trial to directly assess the therapeutic use of N7-73 in ovarian cancer.

Dr. Mehta's platform has proven to be a more reliable high-throughput means of predicting drug response. This patient-derived 3D platform could be used as a personalized medicine approach to quickly identify the best treatment for an individual patient, thereby improving clinical outcomes. Impressively, this platform may have uncovered a highly desirable drug that has the potential to be effective against chemoresistant ovarian cancer.

References:

Raghavan S, Mehta P, Ward MR, et al. 2017. Personalized medicine-based approach to model patterns of chemoresistance and tumor recurrence using ovarian cancer stem cell spheroids. Clin Cancer Res. 23(22):6934-6945.

Mehta P, Novak C, Raghavan S, et al. 2018. �Self-Renewal and CSCs In Vitro Enrichment: Growth as Floating Spheres,� Cancer Stem Cells: Methods and Protocols. Papaccio G, Desiderio V, Ed. Springer Publishing Company, New York, NY. pp. 61-75.

Raghavan S, Mehta P, Horst EN, et al. 2016. Comparative analysis of tumor spheroid generation techniques for differential in vitro drug toxicity. Oncotarget. 7: 16948-61.

Raghavan S, Ward MR, Rowley KR, et al. 2015. Formation of stable small cell number three-dimensional ovarian cancer spheroids using hanging drop arrays for preclinical drug sensitivity assays. Gynecologic Oncology. 138: 181-9.

Links:

Public and Technical Abstracts: High-Throughput Platform for Patient-Derived, Small Cell Number, Three-Dimensional Ovarian Cancer Spheroids

Public and Technical Abstracts: Identification of Distinctly Expressed Genes and Altered Metabolic Pathways in a Physiologically Relevant 3D Spheroid Model of Ovarian Cancers

Public and Technical Abstracts: N7-73 as a Novel Therapeutic Agent for Targeting Epithelial Ovarian Cancers

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