Hypoxia and its therapeutic possibilities in paediatric cancers

Abstract

In tumours, hypoxia—a condition in which the demand for oxygen is higher than its availability—is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.

Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma

“…This increasing interest in targeting the tumor microenvironment has made tumor hypoxia one the most promising targets of therapy in several types of tumors [ 30 ], including NB [ 29 ]. Meanwhile, hypoxia-targeted treatment strategies have progressed into clinical trials [ 4 ], although many of these approaches have not been successfully implemented in the clinic, largely because trial designs have not included methods to identify and select patients with hypoxic tumors prior to enrolment. Therefore, the necessity to include reliable biomarkers that could be predictive of a positive response to hypoxia-targeted treatment strategies in future clinical trials has been pointed out [ 4 ].…”

“…Meanwhile, hypoxia-targeted treatment strategies have progressed into clinical trials [ 4 ], although many of these approaches have not been successfully implemented in the clinic, largely because trial designs have not included methods to identify and select patients with hypoxic tumors prior to enrolment. Therefore, the necessity to include reliable biomarkers that could be predictive of a positive response to hypoxia-targeted treatment strategies in future clinical trials has been pointed out [ 4 ]. We previously designed a biology-driven approach to assess the hypoxic status of NB primary tumors from the analysis of the gene expression profile of 11 distinct NB cell lines cultured under hypoxic and normoxic conditions for 18 h, deriving a robust 62 probesets signature (NB-hypo).…”

“…Pathologic hypoxia is a condition of low oxygen tension that occurs in most human solid tumors, including NB, promoting proliferation, angiogenesis, epithelial-to-mesenchymal transition, invasion, metastasis, stem cell maintenance, and resistance to radio- and chemo-therapy [ 4 ]. Hypoxia is an unfavorable condition affecting the tumor microenvironment and is a well-known therapeutic target [ 4 , 5 ]. Responses to hypoxia are orchestrated in part through the activation of the hypoxia-inducible-factor (HIF)-1 and HIF-2, which transactivate several hypoxia-responsive genes [ 6 , 7 ].…”

Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours

“…Similarly, Bhoopathi et al demonstrated that the Secreted Protein Acidic and Rich in Cysteine (SPARC) overexpression in neuroectodermal tumours induces autophagymediated apoptosis and enhances the efficacy of radiation therapy [70,71]. However, when combined with chemotherapy instead of radiation therapy, SPARC expression induces chemoresistance; particularly, it suppresses cisplatin sensitivity in MB cells due to the increased levels of autophagy, acting as a tumour survival mechanism [72].…”

Hypoxic Jumbo Spheroids On-A-Chip (HOnAChip): Insights into Treatment Efficacy

“…For example, soft tissue sarcomas (STSs) are prone to forming large and highly hypoxic tumors, leading to increased risk of metastasis [6,7]. Therefore, investigating combination therapies to target multiple molecular pathways involved in metastasis, such as hypoxia, could potentially improve patient prognosis [8]. The study of hypoxia and its implications on radioresistance have been a topic of interest in fundamental, pre-clinical and clinical research, culminating in 2019 with the Nobel Prize in Physiology or Medicine [9].…”