Cancer testis antigens: Emerging therapeutic targets leveraging genomic instability in cancer

Abstract

Cancer care has witnessed remarkable progress in recent decades, with a wide array of targeted therapies and immune-based interventions being added to the traditional treatment options such as surgery, chemotherapy, and radiotherapy. However, despite these advancements, the challenge of achieving high tumor specificity while minimizing adverse side effects continues to dictate the benefit-risk balance of cancer therapy, guiding clinical decision making. As such, the targeting of cancer testis antigens (CTAs) offers exciting new opportunities for therapeutic intervention of cancer since they display highly tumor specific expression patterns, natural immunogenicity and play pivotal roles in various biological processes that are critical for tumor cellular fitness. In this review, we delve deeper into how CTAs contribute to the regulation and maintenance of genomic integrity in cancer, and how these mechanisms can be exploited to specifically target and eradicate tumor cells. We review the current clinical trials targeting aforementioned CTAs, highlight promising pre-clinical data and discuss current challenges and future perspectives for future development of CTA-based strategies that exploit tumor genomic instability.

Keywords: DNA repair; MT: Regular Issue; cancer testis antigen; genomic integrity; therapeutic intervention; tumor cellular fitness.

The various roles of CTAs in regulating and maintaining genomic integrity provide novel opportunities for therapeutic intervention by tipping the balance of tumor cellular fitness towards unsustainable genomic instability.

Figure 1

Diverse roles of cancer testis antigens in biological processes that regulate genomic integrity in cancer Tumoral expression of distinct CTAs impacts tumor cellular fitness through their role in DNA damage repair, G0/G1-S cell cycle transition, DNA replication, chromosome segregation and cytokinesis. CTAs highlihgted in bold exert multiple regulatory functions.

Figure 2

Therapeutic potential of targeting CTAs involved in regulating genomic integrity in cancer The clinical value of targeting specific CTAs that play key roles in regulating tumor genomic integrity is currently studied in phase I and phase II clinical trials. To date, the majority of clinical studies focus on targeting TTK/Mps1, MAGE-A4 and MAGE-C2 with few trials investigating the safety and anti-tumor activity of targeting MPHOSPH1 and SSX2. DC, dendritic cell; TAA, tumor associated antigen.