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Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives
João Lobo1,2,3, Carmen Jerónimo1,3, Rui Henrique1,2,3
1Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) & Porto Comprehensive Cancer Center (P.CCC), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
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.
Insights
Cisplatin resistance in testicular germ cell tumors is a major challenge, leading to poor outcomes. Understanding the complex mechanisms of this resistance is crucial for developing new, effective treatments for patients with testicular cancer.
Area of Science:
- Oncology
- Genitourinary Cancer Research
- Cancer Therapeutics
Background:
- Testicular germ cell tumors (TGCTs) are highly sensitive to cisplatin, resulting in good prognoses.
- A subset of patients develop cisplatin resistance, leading to poor quality of life and disease mortality.
- Current treatment options for cisplatin-resistant TGCTs are limited due to poorly understood resistance mechanisms.
Purpose of the Study:
- To provide a comprehensive overview of cisplatin resistance in TGCTs.
- To explore the clinical, pathobiological, and experimental aspects of cisplatin resistance.
- To summarize mechanisms contributing to the resistant phenotype and discuss potential therapeutic targets.
Main Methods:
- Systematic review of pre-target, on-target, post-target, and off-target resistance mechanisms.
- Analysis of data from preclinical studies and clinical sample validation.
- Inclusion of research on specific alterations as therapeutic targets and ongoing clinical trials.
Main Results:
- Cisplatin resistance in TGCTs is multifactorial, involving various molecular mechanisms.
- Specific alterations are being explored as therapeutic targets, with some in clinical trials.
- Resistance mechanisms in teratoma (differentiated) phenotypes, including growing teratoma syndrome, are discussed.
Conclusions:
- Cisplatin resistance in TGCTs is a complex, multifactorial issue.
- Further research into resistance mechanisms is needed to develop effective therapies.
- Combination therapeutic strategies are likely to offer the best clinical benefit for cisplatin-resistant TGCTs.
