Department of Hematology and Cellular Therapy, Tours University Hospital, Tours, France.
Department of Hematology, Adolescent and Young Adults Unit, Fertility Preservation, Saint Louis Hospital, AP-, HP, Paris, France.
Oncologist. 2021 Jun;26(6):492-503. doi: 10.1002/onco.13675. Epub 2021 Jan 29.
Preventing premature ovarian failure (POF) is a major challenge in oncology. With conventional regimens, cytotoxicity-associated POF involves primordial follicles (PF) pool depletion by apoptosis or overactivation mechanisms, notably mediated by the ABL/TAp63 and PI3K/Akt/mTOR pathways. New anticancer treatments have been designed to target pathways implicated in tumor growth. Although concerns regarding fertility arise with these targeted therapies, we hypothesized that targeted therapies may exert off-tumor effects on PF that might delay POF. We provide an overview of evidence concerning these off-tumor effects on PF. Limitations and future potential implications of these findings are discussed.
PubMed was searched by combining Boolean operators with the following keywords: fertility, ovarian, follicle, anti-tumoral, cancer, targeted, cytotoxic, and chemotherapy.
Cisplatin-related PF apoptosis via the ABL/TAp63 pathway was targeted with a tyrosine kinase inhibitor, imatinib, in mice, but effects were recently challenged by findings on human ovarian xenografts in mice. In cyclophosphamide-treated mice, PI3K/Akt/mTOR pathway inhibition with mTOR inhibitors and AS101 preserved the PF pool. Proteasome and GSK3 inhibitors were evaluated for direct and indirect follicle DNA damage prevention. Surprisingly, evidence for cytotoxic drug association with PF pool preservation was found. We also describe selected non-anticancer molecules that may minimize gonadotoxicity.
Not all anticancer treatments are associated with POF, particularly since the advent of targeted therapies. The feasibility of associating a protective drug targeting PF exhaustion mechanisms with cytotoxic treatments should be evaluated, as a way of decreasing the need for conventional fertility preservation techniques. Further evaluations are required for transfer into clinical practice.
Anticancer therapies are associated with infertility in 10%-70% of patients, which is the result of primordial follicles pool depletion. Alone or associated with gonadotoxic treatments, some targeted therapies may exert favorable off-targets effects on the primordial follicle pool by slowing down their exhaustion. Current evidence of these effects relies on murine models or human in vitro models. Evaluation of these protective strategies in humans is challenging; however, if these results are confirmed with clinical and biological data, it not only could be a new approach to female fertility preservation but also would change standard fertility strategies.
预防卵巢早衰（POF）是肿瘤学的一大挑战。在常规治疗方案中，细胞毒性相关的 POF 通过凋亡或过度激活机制导致原始卵泡（PF）池耗竭，特别是由 ABL/TAp63 和 PI3K/Akt/mTOR 途径介导。新的抗癌治疗方法旨在针对肿瘤生长相关的途径。尽管这些靶向治疗会引起对生育能力的关注，但我们假设靶向治疗可能会对 PF 产生肿瘤外效应，从而延迟 POF。我们提供了有关这些 PF 肿瘤外效应的证据概述。讨论了这些发现的局限性和未来的潜在影响。
通过将布尔运算符与以下关键字结合，在 PubMed 上进行了搜索：生育力、卵巢、卵泡、抗瘤、癌症、靶向、细胞毒性和化疗。
在小鼠中，使用酪氨酸激酶抑制剂伊马替尼靶向顺铂相关的 PF 凋亡通过 ABL/TAp63 途径，但最近在小鼠卵巢异种移植中的发现对这一结果提出了质疑。在环磷酰胺治疗的小鼠中，使用 mTOR 抑制剂和 AS101 抑制 PI3K/Akt/mTOR 途径可保留 PF 池。评估蛋白酶体和 GSK3 抑制剂以防止直接和间接卵泡 DNA 损伤。令人惊讶的是，发现了与 PF 池保护相关的细胞毒性药物的证据。我们还描述了一些可能最小化性腺毒性的选定非抗癌分子。
并非所有抗癌治疗都与 POF 相关，特别是自从靶向治疗出现以来。应该评估将靶向 PF 衰竭机制的保护药物与细胞毒性治疗相结合的可行性，以减少对常规生育力保存技术的需求。需要进一步评估以将其转化为临床实践。
在 10%-70%的患者中，抗癌治疗会导致不孕，这是原始卵泡池耗竭的结果。单独或与性腺毒性治疗联合使用时，一些靶向治疗可能会通过减缓其衰竭来对原始卵泡池产生有利的非靶标作用。这些效应的当前证据依赖于小鼠模型或人类体外模型。评估这些保护策略在人类中的作用具有挑战性；但是，如果这些结果得到临床和生物学数据的证实，这不仅可能成为女性生育力保存的新方法，而且还将改变标准的生育力策略。
