Cisplatin-based chemotherapy is the basis for the treatment of several tumor types, including testicular germ cell tumors (TGCT), ovarian cancer and lung cancer. In these cases, acquired resistance to cisplatin/carboplatin after treatments represents an important clinical limitation for the survival of patients.
Testicular germ cell tumors (TGCT) of adolescents and young adults are the most common malignancy in young men. TGCTs can be classified as seminomas (SE) (originating in the epithelium of the seminiferous tubules), which represent about 40% of cases, and not seminomas (NSE) (60%). Seminomas are sensitive to radio and chemotherapy and, therefore, highly curable in all stages. NSEs are also very sensitive to cisplatin-based chemotherapy and, when combined with surgery, patients achieve high cure rates.
In contrast to most advanced solid tumors, approximately 85-90% of metastatic TGCTs are cured after being treated with cisplatin. However, 10-15% of these tumors become resistant and patients die due to refractoriness to cisplatin and the absence of effective alternative therapies. For these reasons, elucidating the mechanisms associated with the acquisition of TGCT resistance would allow improving the treatment of patients by identifying effective therapies. Some therapies that, in addition, could be applied in other more relevant pathologies from the point of view of the number of patients, such as ovarian and lung cancer, which are also treated with cisplatin.
Pursuing these objectives, researchers from the Bellvitge Biomedical Research Institute (IDIBELL) and the Catalan Institute of Oncology (ICO) have led a strategy for the generation of advanced preclinical models (or orthoxenografts) through the implantation in the testes of athymic mice (orthotopic implantation) of small fragments/biopsies freshly obtained after the surgery of non-seminomas. In this way, researchers have generated the first collection (of 14 animals) of orthoxenografts/PDOX. These models have evolved in the mouse to models of acquisition of resistance to cisplatin, for which mice with tumors in their testes were treated with cisplatin in a similar way as is done in patients.
With these experimental models, researchers identified a genomic region located on chromosome 9 (9q32-q33.1) that is gained during the acquisition of resistance. Subsequent studies on tumors and with the C.elegans worm allowed the identification of a gene called glucosylceramide synthase (GCS) that is deregulated in tumors resistant to cisplatin. Subsequently, it was demonstrated that the inhibition of GCS ‑a fundamental protein in the synthesis of glycosphingolipids‑ with a drug (DL-threo-PDMP) already used in the treatment of certain metabolic diseases such as Gaucher, Niemam-Pick and diabetes, is effective in the treatment of resistant tumors of testicular cancer. The resulting work, published in the Clinical Cancer Research journal, shows that in the TGCT orthoxenografts generated, as well as in others of ovarian cancer, the drug DL-threo-PDMP re-sensitizes the resistant tumors back to cisplatin.
This publication is an example of multidisciplinary research, thanks to the participation of many professionals, both from ICO, IDIBELL and Bellvitge University Hospital, among others, under the co-direction of Alberto Villanueva and Julian Cerón. The results show that the in vivo integration of two very powerful preclinical approaches, such as orthoxenografts and the model organism C.elegans, will make it possible to improve the treatment of cisplatin-resistant patients.