- Hypoxia is recognized as a major factor contributing to radioresistance, and in prostate cancer, hypoxia is directly associated with poor prognosis in patients treated with radiotherapy.
- Targeting tumor hypoxia has been shown to improve the efficacy of
- Identifying patients with hypoxic tumors using a hypoxia biomarker in routine clinical practice has the potential to improve the management and treatment of high-risk prostate cancer.
Rapidly growing tumors with poorly formed vasculature have low oxygen levels, and limited oxygen availability results in a hypoxic microenvironment. Cells respond to the low levels of oxygen through the hypoxia-inducible factor (HIF) signaling pathway, which facilitates cellular adaptation to the hypoxic tumor microenvironment. In the absence of oxygen, the cytoplasmic HIF-1a protein is stabilized and translocates to the nucleus to function as a transcription factor. Hundreds of genes are regulated by HIF-1a in response to the hypoxic tumor microenvironment, and these genes are involved in a vast range of cellular pathways such as angiogenesis, cellular metabolism, and invasion.
Androgen signaling, which is key in prostate cancer biology, is known to overlap and interact with hypoxia-driven signaling pathways. The link between hypoxia and androgen resistance is complex; evidence suggests that crosstalk between the hypoxia and androgen receptor (AR) signaling pathways contributes to tumor progression and the development of hormone-resistant prostate cancer.1,2 Dihydrotestosterone has been shown to stabilize HIF-1a,3 and androgen suppression has been shown to increase survival after radiotherapy,4 demonstrating the interdependency of the signaling pathways. Dual targeting of the HIF and AR pathways with HIF-1a inhibitors and the hormone therapy enzalutamide has been shown to synergistically inhibit prostate cancer cell growth.5 Furthermore, the current clinical practice is to diagnose prostate cancer recurrence through changes in PSA, which is itself an AR- and hypoxia-regulated gene.6
In prostate tumors, hypoxia is associated with increased metastatic spread, resistance to treatment, and shorter times to biochemical failure.7 Current international guidelines recommend surgery or radical radiotherapy combined with androgen deprivation therapy for high-risk locally advanced prostate cancer.8 Patients with high-risk locally advanced disease are treated with curative intent, but despite radical treatment with surgery or radiotherapy, one in three patients will have disease that relapses within 5 years. Patients with high levels of tumor hypoxia have a significantly worse prognosis than patients with low levels. Targeting tumor hypoxia in the treatment of prostate cancer has the potential to improve patient response to treatment and overall survival.
Hypoxia and Radiotherapy
Hypoxia is recognized as a major factor contributing to radioresistance, and in prostate cancer, hypoxia is directly associated with poor prognosis in patients treated with radiotherapy. Intratumoral hypoxia induces physiologic and molecular alterations in the tumor microenvironment that promote resistance to radiotherapy. Radiotherapy causes DNA damage, which is stabilized in the presence of oxygen, and unrepaired DNA breaks lead to cell death. Under hypoxia, radiation treatment induces less DNA damage, thereby preventing irreparable damage and subsequent cell death. Furthermore, HIF-1a independently upregulates survival pathways and allows cells to evade cell death after ionizing radiation.9 Hypoxia-modifying therapies, such as nimorazole or carbogen and nicotinamide, can increase tumor oxygenation levels. When combined with radiotherapy, these treatments have the potential to enhance tumor radiosensitivity and improve patient response to therapy.10 The current phase II PROCON trial aims to evaluate the addition of carbogen and nicotinamide to radiotherapy for patients with high-risk prostate cancer.11
Hypoxia and Chemotherapy
The STAMPEDE trial aimed to improve outcomes in metastatic prostate cancer by adding docetaxel and zoledronic acid to hormone therapy. Zoledronic acid did not provide a significant survival benefit to patients; however, docetaxel did improve survival and delayed treatment failure. Docetaxel is known to retain its cytotoxic action in hypoxic conditions.12 It activates proteasomal degradation of HIF-1a,13 whereas zoledronic acid has been shown to reduce the transcription of HIF-1a in breast cancer.14 As HIF-1a activity is regulated at the protein level, one could hypothesize that the suppression of HIF-1a transcription by zoledronic acid was not sufficient to deplete the pool of HIF-1a protein in the timeframe required, whereas the direct proteasomal degradation of the HIF-1a protein by docetaxel produced a rapid and sustained reduction in HIF-1a protein levels. One lesson from this is that any potential systemic treatment should be considered for its action in a hypoxic microenvironment.
Hypoxia and Immunotherapy
There is a great deal of interest in immunotherapy for prostate cancer. The efficacy of immunotherapies targeting CTLA-4 (ipilimumab) and PD-L1 (nivolumab) depend on the pre-existing activity of the target molecules and the presence of T cells. These immunotherapies promote the activity of the host immune response through T-cell activation. At the time of treatment, the CTLA-4 or PD-L1 pathways must be active within the tumor, and T-cell numbers must be sufficient for these immunotherapies to enhance immune destruction of cancer cells. Hypoxia suppresses the infiltration of T cells and evokes an immunosuppressive phenotype,15 reducing the efficacy of immunotherapy. Targeting tumor hypoxia has been shown to improve the efficacy of immunotherapy. In vivo administration of the hypoxia-specific pro-drug evofosfamide in combination with CTLA-4 or PD-L1 inhibitors has been reported to overcome hypoxia-driven immune suppression and sensitize tumors to immunotherapy.16 Combining radiotherapy and immunotherapy is an alternative approach because the administration of radiotherapy initiates an immune response that can subsequently be capitalized on with immunotherapy.17 The scheduling of combined therapies is critical to achieve maximum tumor cell killing.
Hypoxia Biomarkers for Patient Stratification
Patients with hypoxic tumors benefit most from hypoxia-modifying therapies and hypoxia-targeted drugs.18 Selecting patients with hypoxic tumors in a pretreatment setting would identify patients most likely to benefit from hypoxia-targeted therapies.
Tumor hypoxia can be assessed in situ using oxygen electrodes or PET imaging with markers of hypoxia such as 18F-fluoromisonidazole.19 Alternatively, hypoxia can be indirectly assessed in tumor biopsies with protein or gene biomarkers. In prostate cancer, identifying patients with hypoxic tumors in a pretreatment setting would support clinical decisions for treatments. Hypoxia protein biomarkers can also be assessed in the formalin-fixed, paraffin-embedded (FFPE) needle core biopsies; however, immunohistochemistry is a subjective and semiquantitative technique that can be operator dependent and is, therefore, difficult to translate into routine clinical practice. Hypoxia gene signature biomarkers are a more favored approach because not only can they be measured in the FFPE needle core biopsies that are routinely used for pathologic diagnosis, but they also include a large number of genes that can be measured and quantified using a fast and reproducible protocol. In other cancers, such as head and neck cancer, hypoxia gene signatures are advancing toward inclusion in routine clinical practice.20 Lalonde et al. demonstrated that it was possible to identify those patients at risk of biochemical recurrence following radiotherapy or prostatectomy by using a hypoxia signature.21 Addition of a measure of genomic instability, which is thought to be driven by hypoxia, resulted in a further refinement of patient stratification.
Clinical trials testing hypoxia-related therapies in prostate and other cancer types have not selected patients with hypoxic tumors as part of the trial design. This lack of stratification in patient selection may have resulted in an underestimation of the clinical benefits of hypoxia-modifying therapy.22 Selecting the most appropriate group of patients for inclusion in clinical trials is essential to robustly test the potential clinical benefit of new treatments. Identifying patients with hypoxic tumors using a hypoxia biomarker in routine clinical practice has the potential to improve the management and treatment of high-risk prostate cancer.
About the Authors: Dr. Bibby is a postdoctoral researcher at the University of Manchester, UK. Dr. Roberts is a postdoctoral researcher at the University of Manchester, UK. Dr. Choudhury is a consultant and honorary clinical reader in clinical oncology at the University of Manchester, UK.