Prognostic Value of (DHODH) Expression in (HGSOC): A Comparative Study Between Neoadjuvant and Adjuvant Chemotherapy Settings

Heba Ahmed Mohamed

Status: Begins enrollment in 3 months

Conditions: HGSOC

Treatments: Other: Immunohistochemical (IHC) assessment of DHODH expression; Other: No interventions as it is observational study

Study type: Observational

Funder types: Other

Identifiers

NCT07366242

assiut university (Other Identifier)

DHODH in HGSOC

Details and patient eligibility

About

• To compare DHODH protein expression in HGSC tissues from patients undergoing Primary Debulking Surgery (PDS - Chemo-naive) versus Interval Debulking Surgery (IDS - Post-NACT).
• To evaluate the association between DHODH expression and the degree of chemotherapy response (using the Chemotherapy Response Score - CRS for NACT cases).
• To determine the prognostic value of DHODH expression in predicting Platinum-Free Interval (PFI) ,Progression -Free Survival (PFS) and Overall Survival (OS) across both groups.

Full description

High-grade serous ovarian carcinoma (HGSC) is the most aggressive and lethal subtype of epithelial ovarian cancer, accounting for nearly 70% of ovarian cancer-related deaths worldwide (1). Despite initial sensitivity to platinum-based chemotherapy, the majority of patients eventually develop chemoresistant disease, leading to recurrence and poor long-term survival (2). The biological mechanisms underlying platinum resistance remain incompletely understood, but increasing evidence indicates that metabolic reprogramming and redox adaptation play a central role in tumor cell survival under therapeutic stress (3).

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation, and it has recently emerged as an important vulnerability in cancer cells exposed to chemotherapy (4). Cancer cells that survive platinum-based therapy frequently upregulate antioxidant and lipid-repair systems that protect them from ferroptotic death (5). Among these systems, dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in de novo pyrimidine biosynthesis, has been identified as a key suppressor of mitochondrial lipid peroxidation and ferroptosis (6).

DHODH is localized on the inner mitochondrial membrane and catalyzes the oxidation of dihydroorotate to orotate, coupling pyrimidine synthesis to the mitochondrial respiratory chain (7). Recent work has shown that DHODH acts in parallel with glutathione peroxidase-4 (GPX4) to protect cells from ferroptosis, particularly within the mitochondrial compartment (8). Inhibition of DHODH sensitizes cancer cells to oxidative damage and restores ferroptotic cell death, especially in tumors with high mitochondrial metabolism.

In ovarian cancer, platinum resistance has been linked to enhanced mitochondrial function, redox buffering, and metabolic plasticity ( 9). Neoadjuvant chemotherapy (NACT), which is increasingly used in advanced HGSC, exposes tumor cells to intense oxidative and genotoxic stress prior to surgical removal (10). This creates a strong evolutionary pressure favoring tumor clones capable of surviving chemotherapy-induced metabolic and redox stress.

However, the expression and clinical significance of DHODH in HGSC, particularly in the context of neoadjuvant chemotherapy exposure, has not been systematically investigated. No studies have directly compared DHODH expression in chemo-naïve primary debulking surgery (PDS) specimens versus post-NACT interval debulking surgery (IDS) specimens, nor correlated DHODH with chemotherapy response and survival outcomes. Understanding whether NACT selects for DHODH-high, ferroptosis-resistant tumor cells could provide novel insights into platinum resistance and identify a new therapeutic vulnerability in HGSC.

Enrollment: 72 estimated patients

Sex: Female

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically confirmed high-grade serous ovarian carcinoma
• Availability of adequate FFPE tumor tissue
• Known treatment modality (PDS or IDS)
• Available clinical follow-up including platinum-free interval and survival data

Exclusion criteria

• Non-serous histological subtypes
• Low-grade serous carcinoma
• Inadequate tissue for immunohistochemistry
• Missing clinical or follow-up data

Trial design

72 participants in 2 patient groups

Group A chemo naive and Group B neoadjuvant group

Description:

Group A (Chemo-naïve group) 36 Patients who underwent primary debulking surgery (PDS) followed by adjuvant platinum-based chemotherapy. Group B (Neoadjuvant group) 36 Patients who received 3-4 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery (IDS).

Treatment:

Other: No interventions as it is observational study

Other: Immunohistochemical (IHC) assessment of DHODH expression

Group A (Chemo-naïve group) 36 Patients and Group B (neoadjuvant) group

Description:

Group A (Chemo-naïve group) 36 Patients who underwent primary debulking surgery (PDS) followed by adjuvant platinum-based chemotherapy. Group B (Neoadjuvant group) 36 Patients who received 3-4 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery (IDS).

Treatment:

Other: No interventions as it is observational study

Other: Immunohistochemical (IHC) assessment of DHODH expression