Tumor hypoxia is associated with poor response to radiotherapy (RT) and chemotherapy, and worse treatment outcome. Strategies to mitigate hypoxia-driven radiation resistance include administration of hypoxia cytotoxins, vasodilators and the breathing of high oxygen-content gas during RT. Although some clinical trials employing such strategies have yielded promising results, definite advancement has been limited by the lack of up-front patient selection.
Recently, inhibition of oxygen consumption has emerged as a novel strategy to reduce tumor hypoxia, allowing for enhanced oxygen diffusion from well-oxygenated tumor vessels [1]. Several agents with this mechanism of action have entered clinical trials based on promising preclinical results. We previously discovered that targeting mitochondrial oxygen consumption with metformin could improve oxygenation and RT response in several experimental tumor models [2]. Metformin targets mitochondrial complex I activity and is commonly prescribed as first-line treatment for type 2 diabetes. Metformin also has many other reported anti-cancer properties, including inhibition of cancer cell proliferation and stemness, promoting immune infiltration, and radiosensitization [3]. In line with this, numerous retrospective studies have found that metformin use is associated with better outcomes in cancer patients across multiple disease sites. Several prospective studies in non-diabetic cancer patients have also noted that metformin has positive effects on biomarkers such as tumor cell Ki67 (proliferation) or circulating leptin and insulin.
Despite these preclinical and retrospective data, metformin has not been found to be beneficial for outcome in a few recently completed prospective randomized trials carried out in non-diabetic populations. Phase 2 and phase 3 randomized trials of chemotherapy plus metformin or placebo in metastatic or early-stage breast cancer patients respectively, showed no effect on response rate, disease free survival or overall survival [4,5]. Two randomized phase 2 trials in locally advanced non-small cell lung cancer found no improvement in overall or progression free survival when patients received metformin in addition to concurrent chemoradiation [6,7]. However, these studies did not employ biomarkers for patient selection that would be expected to predict for benefit through a specific mechanism.
In contrast, we recently concluded a phase 2 trial in women with stage IB-IVA cervical cancer, where tumor hypoxia as detected by fluoroazomycin arabinoside (FAZA) positron emission tomography (PET) imaging was used for patient selection [8]. Only women with hypoxic tumors were randomized to receive metformin (or not) during chemoradiation. Using a second FAZA-PET scan, this study demonstrated that metformin could reduce tumor hypoxia. It also suggested improved progression free survival for patients in the metformin arm [8]. Retrospective analysis of RNA sequencing data from punch biopsies indicated that tumor expression levels of the multidrug and toxin extrusion protein MATE2 (SLC47A2) was negatively correlated with response to metformin. This result is also in line with our preclinical data demonstrating that MATE2 expression correlated with metformin resistance in a large panel of cell lines [9].
Taken together, these recent studies highlight the importance of biomarker driven patient selection for hypoxia intervention trials. They suggest that metformin may specifically benefit a subgroup of patients with hypoxic tumors accompanied by low MATE2 expression.
1 Ashton, T. M. et al. Clin Cancer Res 24, 2482-2490 (2018).
2 Zannella, V. E. et al. Clin Cancer Res 19, 6741-6750 (2013).
3 Koritzinsky, M. Int J Radiat Oncol Biol Phys 93, 454-464 (2015).
4 Pimentel, I. et al. Breast 48, 17-23 (2019).
5 Goodwin, P. J. et al. San Antonio Breast Cancer Symposium, doi:https://www.abstractsonline.com/pp8/#!/10462/presentation/2161 (2021).
6 Skinner, H. et al. JAMA Oncol 7, 1324-1332 (2021).
7 Tsakiridis, T. et al. JAMA Oncol 7, 1333-1341 (2021).
8 Han, K. et al. International Journal of Radiation Oncology, Biology, Physics 111, S19-S20 (2021).
9 Chowdhury, S. et al. PLoS One 11, e0165214 (2016).