Role of the ATP7A Transporter in Ovarian Cancer
Condition: Gynecologic Cancer; Ovarian Cancer; High Grade Serous Carcinoma; Chemotherapy Effect
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous
Study type: Interventional

Summary: 
      Ovarian cancer has the highest mortality rate among all gynecologic cancers, with most
      patients presenting with advanced stage tumors. About a third of patients do not respond to
      primary platinum-based chemotherapy treatment, and over time up to 80 % of others develop
      chemoresistance, rendering recurrent disease incurable. Despite all the studies published in
      the literature, it has not been proven that the number of cells with expressed ATP7A in
      certain tumors increases independently of the therapy. In addition, no study has been
      conducted on a sample of patients with confirmed serous histology of ovarian cancer only. The
      aim of the study is to demonstrate increased expression of the ATP7A transporter in cells
      resistant to carboplatin.
    

Detailed description: 
      RATIONALE:

      Recent studies suggest that the copper efflux transporters ATP7A plays an important role in
      platinum resistance. Despite all the studies published in the literature, it has not been
      proven that the number of cells with expressed ATP7A in certain tumors increases
      independently of the therapy. In addition, no study has been conducted on a sample of
      patients with confirmed serous histology of ovarian cancer only. The literature concludes
      that new methods are required to detect resistant tumor cells at an early chemotherapy stage
      and suitably adapt treatment. There is still much uncertainty regarding how the fate of
      platinum compounds in a cell follows the regulatory copper pathways, especially during
      transport from the cell. The question is also to what extent these processes are
      cell-specific, especially because experiments to date regarding the role of ATP7A in
      resistance to platinum compounds have been conducted on nonserous cell lines (especially of
      the endometrioid histological type).

      AIM OF THE STUDY:

      Study will evaluate the ATP7A transporter as an important mediator of chemoresistance to
      platinum compounds to obtain an additional criterion for the optimal treatment strategy for
      serous ovarian cancer patients. The focus will primarily be on intrinsic chemoresistance,
      which determines the initial response to chemotherapy. Research to date has failed to
      evaluate the influence of ATP7A transporter expression solely on serous ovarian cancer.

      The study will demonstrate increased expression of the ATP7A transporter in cells resistant
      to carboplatin. Because the measurement of ATP7A in bodily fluids is unreliable, the plan is
      to measure ceruloplasmin in the patients' ascites. Ceruloplasmin is the main
      copper-transporting protein in the blood. It is synthesized in the cell and, according to
      findings in the literature, it is ATP7A that is responsible for delivering copper to
      ceruloplasmin. When copper binds to ceruloplasmin, there is no other way for it to cross the
      plasma membrane than via the ATP7A transporter. By measuring the ceruloplasmin level in the
      ascites, ATP7A activity or its localization on the plasma membrane could indirectly be
      measured as well. To confirm the suitable measurement of ceruloplasmin in the ascites, its
      values in the patients' blood plasma and tissue will be measured.

      METHODS:prospective clinical trial It will include 30 high-grade serous ovarian cancer
      patients (FIGO stages III and IV) with ascites. The patients will be presented to the
      gynecological-oncological consultation team at the Ljubljana Division of Gynecology and
      Obstetrics. Patients for whom neoadjuvant chemotherapy is recommended will be included in the
      trial.

      STATISTICAL ANALYSES: The normality of numerical variables' distribution will be tested with
      the Shapiro-Wilk test. Relevant parametric tests (Student's t-test) or nonparametric tests
      (the two-tailed Mann-Whitney U-test) will be used to compare groups.
    

Intervention name(s): Carboplatin
Intervention type(s): Drug
Intervention description(s): Patients will receive neoadjuvant chemotherapy according to ESGO guidelines
Intervention MeSH terms: Carboplatin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Screening
Keywords: Ovarian cancer; Chemoresistance; Predictive marker; ATP7A