Abstract
Testicular germ cell tumors share a marked sensitivity to cisplatin, contributing to their overall good prognosis. However, a subset of patients develop resistance to platinum-based treatments, by still-elusive mechanisms, experiencing poor quality of life due to multiple (often ineffective) interventions and, eventually, dying from disease. Currently, there is a lack of defined treatment opportunities for these patients that tackle the mechanism(s) underlying the emergence of resistance. Herein, we aim to provide a multifaceted overview of cisplatin resistance in testicular germ cell tumors, from the clinical perspective, to the pathobiology (including mechanisms contributing to induction of the resistant phenotype), to experimental models available for studying this occurrence. We provide a systematic summary of pre-target, on-target, post-target, and off-target mechanisms putatively involved in cisplatin resistance, providing data from preclinical studies and from those attempting validation in clinical samples, including those exploring specific alterations as therapeutic targets, some of them included in ongoing clinical trials. We briefly discuss the specificities of resistance related to teratoma (differentiated) phenotype, including the phenomena of growing teratoma syndrome and development of somatic-type malignancy. Cisplatin resistance is most likely multifactorial, and a combination of therapeutic strategies will most likely produce the best clinical benefit.
Highlights
A Brief Overview over Testicular Germ Cell TumorsTesticular germ cell tumors (TGCTs) are the most frequent solid neoplasms arising in men aged until 34 years, and their incidence is rising worldwide [1]
We sought to briefly present the clinical scenario of a cisplatin-resistant disease in TumorsTesticular germ cell tumors (TGCTs), critically summarize the various mechanisms potentially involved in this event, indicate which tools are available for illuminating this event, and, approach some promising therapeutic options for these patients
The acquisition of resistance to platinum-based drugs is common to other tumor models, like bladder and ovarian cancer, all having in common a poor prognosis and lack of effective alternative therapies
Summary
Testicular germ cell tumors (TGCTs) are the most frequent solid neoplasms arising in men aged until 34 years, and their incidence is rising worldwide [1]. Among GCTs, which include ovarian and extragonadal tumors of all age groups (pediatric and adult), type II TGCTs stand out as the most frequent and clinically challenging due to their malignant behavior They have a unique pathobiology, deriving from primordial germ cells (PGCs)/gonocytes that are arrested in their maturation, and evolve towards a precursor neoplastic lesion, germ cell neoplasia in situ (GCNIS) [4]. In other words, avoiding overtreatment should be a major aim of current clinical research; on the other side of the spectrum, there are TGCT that develop resistance to cisplatin This is an uncommon event but long recognized and clinically meaningful, since there is a lack of alternative treatments for these patients, which are the ones experiencing important morbidity (and mortality) [14]. We sought to briefly present the clinical scenario of a cisplatin-resistant disease in TGCT, critically summarize the various mechanisms potentially involved in this event, indicate which tools are available for illuminating this event, and, approach some promising therapeutic options for these patients
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