College
College of Engineering
Mentor Information
Erin M. George, MD
Description
High-Grade Serous Ovarian Cancer (HGSOC) remains the most lethal gynecologic malignancy. Although most patients achieve complete responses to frontline surgery and platinum-based chemotherapy, approximately 85% recur. These patients are incurable. Targeted therapies are emerging; however, they are often insufficient as monotherapy and may have overlapping toxicities in combination. Our preliminary data identified the combination of simurosertib (CDC7 inhibitor; CDC7i) and lunresertib (PKMYT1 inhibitor; PKMYT1i) as a promising strategy in recurrent HGSOC. Our findings also suggest that sequential administration may be beneficial compared to concomitant therapy. This study aims to evaluate and optimize sequential versus concomitant CDC7i-PKMYT1i treatment using colony-forming assays. Colony-forming assays (CFAs) with crystal violet staining were optimized to assess the effects of monotherapy, concomitant, and sequential treatment on clonogenic growth. OVCAR3 and OVCAR4 cell lines were selected based on their key molecular features of HGSOC. Colony area and number were quantified across multiple dosing conditions. Statistical comparisons were performed using one-way ANOVA. Synergy was assessed using the Coefficient of Drug Interaction (CDI). Combination CDC7i-PKMYT1i resulted in statistically significant reductions in colony formation relative to control and monotherapies (p<0.05). CDI analysis indicated synergistic interactions. Preliminary evaluation of sequential dosing suggests comparable inhibitory effects on colony formation to concomitant therapy, with greater suppression than monotherapy. Dual targeting of CDC7 and PKMYT1 demonstrates synergistic suppression of colony formation in HGSOC models. These findings support CDC7i-PKMYT1i as a rational therapeutic combination. Sequential scheduling may preserve efficacy while mitigating overlapping toxicity. Further optimization of treatment sequencing may inform translational strategies for recurrent HGSOC.
Evaluation of Combined Targeted Therapies in High-Grade Serous Ovarian Cancer Using Colony-Forming Assays
High-Grade Serous Ovarian Cancer (HGSOC) remains the most lethal gynecologic malignancy. Although most patients achieve complete responses to frontline surgery and platinum-based chemotherapy, approximately 85% recur. These patients are incurable. Targeted therapies are emerging; however, they are often insufficient as monotherapy and may have overlapping toxicities in combination. Our preliminary data identified the combination of simurosertib (CDC7 inhibitor; CDC7i) and lunresertib (PKMYT1 inhibitor; PKMYT1i) as a promising strategy in recurrent HGSOC. Our findings also suggest that sequential administration may be beneficial compared to concomitant therapy. This study aims to evaluate and optimize sequential versus concomitant CDC7i-PKMYT1i treatment using colony-forming assays. Colony-forming assays (CFAs) with crystal violet staining were optimized to assess the effects of monotherapy, concomitant, and sequential treatment on clonogenic growth. OVCAR3 and OVCAR4 cell lines were selected based on their key molecular features of HGSOC. Colony area and number were quantified across multiple dosing conditions. Statistical comparisons were performed using one-way ANOVA. Synergy was assessed using the Coefficient of Drug Interaction (CDI). Combination CDC7i-PKMYT1i resulted in statistically significant reductions in colony formation relative to control and monotherapies (p<0.05). CDI analysis indicated synergistic interactions. Preliminary evaluation of sequential dosing suggests comparable inhibitory effects on colony formation to concomitant therapy, with greater suppression than monotherapy. Dual targeting of CDC7 and PKMYT1 demonstrates synergistic suppression of colony formation in HGSOC models. These findings support CDC7i-PKMYT1i as a rational therapeutic combination. Sequential scheduling may preserve efficacy while mitigating overlapping toxicity. Further optimization of treatment sequencing may inform translational strategies for recurrent HGSOC.
