Arnab Ghosh

Fusobacterium nucleatum: An Overview of Evidence, Demi-Decadal Trends, and Its Role in Adverse Pregnancy Outcomes and Various Gynecological Diseases, including Cancers

Gynecological and obstetric infectious diseases are crucial to women’s health. There is growing evidence that links the presence of Fusobacterium nucleatum (F. nucleatum), an anaerobic oral commensal and potential periodontal pathogen, to the development and progression of various human diseases, including cancers. While the role of this opportunistic oral pathogen has been extensively studied in colorectal cancer in recent years, research on its epidemiological evidence and mechanistic link to gynecological diseases (GDs) is still ongoing. Thus, the present review, which is the first of its kind, aims to undertake a comprehensive and critical reappraisal of F. nucleatum, including the genetics and mechanistic role in promoting adverse pregnancy outcomes (APOs) and various GDs, including cancers. Additionally, this review discusses new conceptual advances that link the immunomodulatory role of F. nucleatum to the development and progression of breast, ovarian, endometrial, and cervical carcinomas through the activation of various direct and indirect signaling pathways. However, further studies are needed to explore and elucidate the highly dynamic process of host–F. nucleatum interactions and discover new pathways, which will pave the way for the development of better preventive and therapeutic strategies against this pathobiont.

Dual targeting of Aurora Kinase A and poly (ADP-ribose) polymerase as a therapeutic option for patients with ovarian cancer: preclinical evaluations

Epithelial ovarian cancers (EOCs) are often diagnosed at an advanced stage, leading to poor survival outcomes despite chemotherapeutic and surgical advances. Precision oncology strategies have been developed to treat EOCs characterized by BRCA1 and BRCA2 inactivation with consequent homologous recombination (HR) repair defects. HR deficiency enhances tumor sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), approved for EOCs as maintenance therapy, although they have been discontinued as recurrent EOC monotherapy. However, combination treatment with PARPis may be a viable alternate strategy for EOCs. Moreover, EOC patients with wild-type BRCA are ineligible for PARPs, necessitating novel approaches. We previously discovered that inhibiting Aurora kinase A (AURKA) downregulates PARP and BRCA1/2 expression in EOCs and may constitute a viable approach for EOCs. Herein, we evaluated combined PARPi olaparib with the selective AURKA inhibitor (AURKAi) VIC-1911 in six different patient-derived xenograft (PDX) EOC models, including two with mutant BRCA1, two with mutant BRCA2, one with mutant BRCA1/2, and one with wild-type BRCA1/2. We found that combined olaparib + VIC-1911 treatment reduced tumor volumes and weights by up 90% in some PDX models, with synergistic effect compared to olaparib and VIC-1911 monotherapy. Additionally, combined olaparib + VIC-1911 treatment improved survival of mice harboring both mutant BRCA1 and wild-type BRCA1/2 PDXs. Generally, mice tolerated the drug combinations well during treatment, though loss of body weight was observed at higher drug dosages and with intensive treatment regimens. Our studies indicate a synergistic benefit from combined PARPi and AURKAi in mutant and wild-type BRCA EOC tumors.