Romi Gupta

Exploring the therapeutic use and outcome of antibody-drug conjugates in ovarian cancer treatment

Abstract Ovarian cancer remains a leading cause of cancer-related deaths due to late-stage diagnosis and treatment resistance. While surgery and chemotherapy are standard treatments, challenges such as platinum resistance, tumor heterogeneity, and limited therapeutic options persist. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic strategy for treating ovarian cancer (OC), particularly in cases of platinum-resistant ovarian cancer (PROC). In OC, various ADCs targeting antigens such as folate receptor alpha (FRα), trophoblast cell surface antigen 2 (TROP-2), mesothelin (MSLN), sodium-dependent phosphate transport protein 2B (NaPi2b), and human epidermal growth factor receptor 2 (HER2) have shown encouraging preclinical results and significant clinical activity. However, challenges like antigen heterogeneity, off-target toxicity, and resistance mechanisms remain. This review highlights the current ADCs used in the clinic for the treatment of ovarian cancer, their challenges, and the future potential of ADC-based therapies in overcoming resistance and improving patient outcomes.

ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE

AbstractOvarian cancer is a complex disease associated with multiple genetic and epigenetic alterations. The emergence of treatment resistance in most patients causes ovarian cancer to become incurable, and novel therapies remain necessary. We identified epigenetic regulator ATPase family AAA domain-containing 2 (ATAD2) is overexpressed in ovarian cancer and is associated with increased incidences of metastasis and recurrence. Genetic knockdown of ATAD2 or its pharmacological inhibition via ATAD2 inhibitor BAY-850 suppressed ovarian cancer growth and metastasis in both in vitro and in vivo models. Transcriptome-wide mRNA expression profiling of ovarian cancer cells treated with BAY-850 revealed that ATAD2 inhibition predominantly alters the expression of centromere regulatory genes, particularly centromere protein E (CENPE). In ovarian cancer cells, changes in CENPE expression following ATAD2 inhibition resulted in cell-cycle arrest and apoptosis induction, which led to the suppression of ovarian cancer growth. Pharmacological CENPE inhibition phenotypically recapitulated the cellular changes induced by ATAD2 inhibition, and combined pharmacological inhibition of both ATAD2 and CENPE inhibited ovarian cancer cell growth more potently than inhibition of either alone. Thus, our study identified ATAD2 as regulators of ovarian cancer growth and metastasis that can be targeted either alone or in combination with CENPE inhibitors for effective ovarian cancer therapy.