Tratamiento combinado con hiperoxia e inhibidores de PARP para contrarrestar la progresión tumoral

• Autores: Ana Belén Herrera Campos
• Directores de la Tesis: Francisco Javier Oliver Pozo (dir. tes.), Ángel García Díaz (codir. tes.)
• Lectura: En la Universidad de Granada ( España ) en 2026
• Idioma: español
• ISBN: 9791370151607
• Número de páginas: 150
• Enlaces
  • Tesis en acceso abierto en: DIGIBUG
• Resumen

  • Uveal melanoma (UM) is a rare disease, yet it is the most common primary intraocular tumor and the most frequent non-cutaneous melanoma. Although the primary tumor can be successfully treated, UM is characterised by a high metastatic potential and resistance to conventional therapies, particularly in the liver and lungs, which substantially contributes to patient mortality. Once metastasis occurs, the mortality rate increases, making it necessary to search for therapeutics options to overcome its aggressiveness. Unlike cutaneous melanoma, UM presents low mutational rates and appears to maintain ocular immune privilege, which may explain the limited success of immunotherapies. A hallmark of metastatic lesions is the hypoxic tumor microenvironment (TME). Hypoxia drives tumor progression by promoting angiogenesis, immune evasion and resistance to apoptosis. In addition, hypoxia-inducible factors (HIFs) exacerbate therapeutic resistance, making the TME a critical target for novel intervention. Current treatments often fail to address challenges posed by hypoxia, necessitating innovative approaches to reoxygenate the TME and disrupt hypoxia-driven tumorigenesis. One such strategy is the use of supplemental oxygen (hyperoxia), already approved for the treatment of other diseases mainly in critical care. Moreover, benefits have been reported from combining hyperoxia with conventional therapies (chemotherapy and radiotherapy), and its influence on the immune system could enhance immunotherapy response. However, the damage associated with high oxygen levels due to ROS production must be taken into account. Poly (ADP-ribose) polymerases (PARPs) are a family of proteins involved in ADPribosylation processes. Specifically, PARP1 plays a role in DNA damage repair. Based on the concept of synthetic lethality, PARP inhibitors have been used clinically to selectively kill cancer cells deficient in homologous recombination repair. Olaparib, a PARP1 inhibitor, has shown efficacy in various cancers, particularly those bearing BRCA1 or BRCA2 mutations. A total of four PARP inhibitors have been approved by the FDA to treat various human malignancies with BRCA1/2 mutations. On the other hand, PARP inhibitors have been tested in non-oncologic diseases, showing effectiveness in those with an inflammatory component. Likewise, PARP1 has been described as a regulator of the inflammatory response through the NF- κB pathway. The use of PARP inhibitors has been proposed in other cancer types where the DNA damage repair pathways are altered beyond BRCA. In this context, BAP1 (BRCA1- associated protein 1) is a promising candidate. It is a tumor suppressor protein that binds to the BRCA1/BARD1 complex, an E3 ubiquitin ligase that also regulates the homologous recombination pathway. Approximately 80% of UM tumors and 5% of cutaneous melanoma tumors present mutations in BAP1 gene. Therefore, using PARP inhibitors in these tumors follows the same rationale as in BRCAness contexts. Our group recently reported that the human UM cell line, MUM2B, exhibits a genetic loss on chromosome 3 and a gain on chromosome 8, affecting BAP1 function, located on the short arm of chromosome 3 at position 21.1 (3p21.1). Additionally, this event enables these aggressive cells to maintain basal hypoxia. In view of these facts, we propose that combining hyperoxia with PARP inhibition represents a promising therapeutic strategy for addressing lung metastases in both uveal and cutaneous melanoma. By alleviating the hypoxic tumor microenvironment, hyperoxia may diminish resistance to PARP inhibitors and enhance their cytotoxic potential. Concurrently, olaparib targets deficiencies in DNA damage repair mechanisms, thereby increasing tumor sensitivity to the reoxygenating effects of hyperoxia. In the current research, we validate the efficacy of this combination, showing a significant differential impact between non-tumor and highly metastatic cells, affecting ROS production, inflammatory response, and commitment to cell death. Unlike apoptosis, a non-immunogenic form of cell death, we describe pyroptosis as the main mechanism underlying cell death in our model. Pyroptosis is a pro-inflammatory form of cell death generally associated with anti-tumor immunity and improved immunotherapy outcomes. Moreover, in vivo results show that hyperoxia alone -and to a lesser extent, its combination with olaparib- has a clear benefit in limiting lung metastatic spread. Overall, the findings suggest that hyperoxia, alone or in combination with PARP inhibition, cooperates in reducing pro-metastatic traits and may lay the conceptual groundwork for future clinical applications.