Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer.
OBJECTIVE
Epithelial ovarian cancer (EOC) is the fifth leading cause of death in women diagnosed with gynecologic malignancies. The low survival rate is because of its advanced-stage diagnosis and either intrinsic or acquired resistance to standard platinum-based chemotherapy. So, the development of effective innovative therapeutic strategies to overcome cisplatin resistance remains a high priority.


METHODS
To investigate new treatments in in vivo models reproducing EOCs tumor growth, we generated a preclinical model of ovarian cancer after orthotopic implantation of a primary serous tumor in nude mice. Further, matched model of acquired cisplatin-resistant tumor version was successfully derived in mice. Effectiveness of lurbinectedin (PM01183) treatment, a novel marine-derived DNA minor groove covalent binder, was assessed in both preclinical models as a single and a combined-cisplatin agent.


RESULTS
Orthotopically perpetuated tumor grafts mimic the histopathological characteristics of primary patients' tumors and they also recapitulate in mice characteristic features of tumor response to cisplatin treatments. We showed that single lurbinectedin or cisplatin-combined therapies were effective in treating cisplatin-sensitive and cisplatin-resistant preclinical ovarian tumor models. Furthermore, the strongest in vivo synergistic effect was observed for combined treatments, especially in cisplatin-resistant tumors. Lurbinectedin tumor growth inhibition was associated with reduced proliferation, increased rate of aberrant mitosis, and subsequent induced apoptosis.


CONCLUSIONS
Taken together, preclinical orthotopic ovarian tumor grafts are useful tools for drug development, providing hard evidence that lurbinectedin might be a useful therapy in the treatment of EOC by overcoming cisplatin resistance.
Department of Pathology, Hospital Universitari de Bellvitge, Spain.
August
A
Vidal
Clara
C
Muñoz
María-José
MJ
Guillén
Jemina
J
Moretó
Sara
S
Puertas
María
M
Martínez-Iniesta
Agnés
A
Figueras
Laura
L
Padullés
Francisco J
FJ
García-Rodriguez
Mireia
M
Berdiel-Acer
Miguel A
MA
Pujana
Ramón
R
Salazar
Marta
M
Gil-Martin
Lola
L
Martí
Jordi
J
Ponce
David G
DG
Molleví
Gabriel
G
Capella
Enric
E
Condom
Francesc
F
Viñals
Dori
D
Huertas
Carmen
C
Cuevas
Manel
M
Esteller
Pablo
P
Avilés
Alberto
A
Villanueva
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002243:Carbolines / Q000008:administration & dosage*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D002243:Carbolines; D006576:Heterocyclic Compounds, 4 or More Rings; C568606:PM 01183; D002945:Cisplatin