Abstract 162: Individualizing treatment using patient derived organoids, BH3 profiling and microfluidics: A proof of concept in a patient with low-grade serous ovarian carcinoma
Authors: Meisenheimer Brittany , Vo Ha V. , McQueeney Kelley E. , Saldanha Aisha L. , Feeney Carina , Qi Courtney H. , Narayan Swati , Curtis Jennifer D. , Nucci Marisa R. , Letai Anthony , Paweletz Cloud P. , Liu Joyce F. , Matulonis Ursula A. , Ivanova Elena 
Published: April 2023

Background N of 1 treatment paradigms represent the pinnacle of personalized medicine in which a patient’s tumors are profiled to guide treatment. Low-grade serous ovarian cancer (LGSC) is a distinct subtype of ovarian cancer, comprising ~10% of serous carcinomas and typically characterized by a younger age of onset. Molecularly, these tumors are often characterized by alterations within the Ras signaling pathway, including KRAS mutations. Clinically, LGSC is often resistant to standard cytotoxic chemotherapy, but may have sensitivity to hormonal therapy or MEK inhibitors. Here we report on a platform and proof of concept in one LGSC patient to evaluate personalized tumor-directed therapy regimens using patient-derived organoids (PDOs), BH3 profiling and viability evaluation in 3D microfluidic devices.

Methods A patient with LGSC presented to the Dana Farber Cancer Institute and was treated with carboplatin and paclitaxel before a total abdominal hysterectomy with a bilateral salpingo-oophorectomy. Tissue was obtained under an IRB approved protocol and PDOs were established. Standard of care and non-standard of care treatments including doxorubicin, abemaciclib, letrozole, alpelisib, tamoxifen, trametinib, venetoclax, and navitoclax were evaluated by two orthogonal assays. First, they were tested for delta priming by BH3 profiling (Bhola et.al., Sci Signal. 2020 ) and second for cell viability using 3D microfluidic devices by TMRM/DRAQ7 dual-color fluorescent staining. Standard of care treatments carboplatin and paclitaxel were evaluated as individual treatments and in combination in 3D microfluidic devices.

Results We successfully established a PDO model from the patient’s tumor sample in 14 days. BH3 profiling at 24 hours and viability in 3D microfluidic devices after 6 days in treatment showed that from the eight tested drugs, the model was sensitive to navitoclax and venetoclax. Average percent change in viability was -91.5% and -89.9%, respectively, and the drugs had a dynamic BH3 profiling index of 551.4 AUC (+/- 76.63) and 488.9 AUC (+/- 21.46) with the threshold of response being &gt;175 for BH3 profiling. Trametinib showed a clear response in 3D, with an average percent change of -72.6% compared to the control but no significant response in BH3 profiling. Neither carboplatin and paclitaxel alone, nor in combination, elicited a significant change in viability. This observation was consistent with the patient’s history prior to surgery, where the tumor did not demonstrate significant clinical response to neoadjuvant carboplatin and paclitaxel therapy.

Conclusions We describe a proof of concept of a N of 1 response assessment platform for LGSC using PDOs, BH3 profiling and live/dead fluorescent staining in microfluidic devices and demonstrate that BH3 profiling and 3D viability assessment assays show good congruity.

Citation Format: Brittany Meisenheimer, Ha V. Vo, Kelley E. McQueeney, Aisha L. Saldanha, Carina Feeney, Courtney H. Qi, Swati Narayan, Jennifer D. Curtis, Marisa R. Nucci, Anthony Letai, Cloud P. Paweletz, Joyce F. Liu, Ursula A. Matulonis, Elena Ivanova. Individualizing treatment using patient derived organoids, BH3 profiling and microfluidics: A proof of concept in a patient with low-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 162.