Cancer Stem Cell Assay for the Treatment of Platinum-Resistant Recurrent Ovarian Cancer

Abstract

Background: Disease recurrence and progression of ovarian cancer is a common event, which is accompanied by the development of platinum-resistant or refractory disease. The presence of chemo-resistant Cancer Stem Cells (CSCs) contribute to tumor propagation, maintenance, and treatment resistance of this difficult to treat disease. We have developed ChemoID, a cytotoxic synergy assay against CSCs that identifies the most effective chemotherapy treatment from a panel of FDA-approved chemotherapies using fresh cancer biopsies.

Patients and methods: Ascites or interventional radiology biopsies were collected under physician order from 78 consecutive patients affected by 3rd relapsed ovarian cancer. Test results from the assay were used when possible to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, if needed. A chart analysis and review of CT and PET scans were performed to determine patients' outcomes for tumor response, Progression-Free Survival (PFS), and Overall Survival (OS).

Results: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the CSCs drug response assay had an improvement in their median PFS and OS when compared to historical median PFS and OS and/or when compared to patients who could not receive high cell kill chemotherapies (PFS low cell kill 3.5 months vs. high cell kill 12.0 months; OS low cell kill 6.0 months vs. high cell kill 15.0 months).

Conclusion: This data indicates that the drug cytotoxicity assay aimed at targeting CSCs may be a useful tool for optimizing treatment selection when first-line therapy fails, and when there are multiple clinically-acceptable and -equivalent treatments available.

Keywords: Cancer stem cells; ChemoID; Chemotherapy; Ovarian cancer; Personalized medicine; Platinum resistant ovarian cancer.

Conflict of interest statement

9. Conflict of Interest Authors P.P.C. and J.V. hold intellectual property rights on the use of the ChemoID cancer stem cell assay. All other authors have no relevant disclosures to declare.

Figures

Figure 1:

Limiting dilution assay of patient-derived CSC and non-CSC injected intraperitoneally in nude mice. Arrows point tumors formed following injections of CSC sorted from biopsies of ovarian cancer. A) Intraperitoneal tumors formed following injection of 1×10^2 CD44(+) CSCs. B) Intraperitoneal tumors formed following injection of 1×10^2 CD133(+) CSCs. C) Intraperitoneal tumors formed following injection of 1×10^2 CD117(+) CSCs. D) Intraperitoneal tumors formed following an injection of 1×10^2 ChemoID enriched CSCs. E) Single intraperitoneal tumor formed, as evidenced by the arrow, following injection of 1×10^6 non-CSCs (negative for CD44, CD133, or CD117) sorted from a biopsy obtained from a patient affected by ovarian cancer.

Figure 2:

Kaplan Meier analysis of progression-free survival (PFS) of 78 real-world recurrent ovarian cancer patients treated with ChemoID-guided therapy.

Figure 3:

Kaplan Meier analysis of Progression-Free Survival (PFS) of 78 real-world recurrent ovarian cancer patients stratified by responding drugs vs. non responding drugs according to the percentage of cell kill on CSC and Bulk of Tumor found by the ChemoID assay.

Figure 4:

Patients are represented as red empty circles who manifested a recurrence of their ovarian cancer within 6-months from therapy start or as blue circles who didn’t manifest recurrence in the same period of time. % cell kill cut-offs were identified for CSCs (40%) and bulk of tumor (55%).

Figure 5:

Patients are represented as red empty circles who manifested a recurrence of their ovarian cancer within 9-months from therapy start or as blue circles who didn’t manifest recurrence in the same period of time. % cell kill cut-offs were identified for CSCs (40%) and bulk of tumor (55%).

Figure 6:

Patients are represented as red empty circles who manifested a recurrence of their ovarian cancer within 12-months from therapy start or as blue circles who didn’t manifest recurrence in the same period of time. % cell kill cut-offs were identified for CSCs (40%) and bulk of tumor (55%).

Figure 7:

Patients represented as red empty circles died for recurence of their ovarian cancer within 6-months from therapy start. Patients represented as blue circles were alive at 6-months from therapy start. % cell kill cut-offs were identified for CSCs (40%) and bulk of tumor (55%).

Figure 8:

Patients represented as red empty circles died for recurrence of their ovarian cancer within 9-months from therapy start. Patients represented as blue circles were alive at 9-months from therapy start. % cell kill cut-offs were identified for CSCs (40%) and bulk of tumor (55%).

Figure 9:

Patients represented as red empty circles died for recurrence of their ovarian cancer within 12-months from therapy start. Patients represented as blue circles were alive at 12-months from therapy start. % cell kill cut-offs were identified for CSCs (40%) and bulk of tumor (55%).

Figure 10:

Kaplan Meier analysis of Overall Survival (OS) of 78 real-world recurrent ovarian cancer patients treated with ChemoID–guided therapy.

Figure 11:

Kaplan Meier analysis of Overall Survival (OS) of 78 real-world recurrent ovarian cancer patients stratified by responding drugs vs. non responding drugs according to the percentage of cell kill on CSC and Bulk of Tumor found by the ChemoID assay.