Value of correlative biomarkers in understanding tumor biology
We appreciate the insightful review of our article Batchelor et al. “Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation” by Dr. Burt Nabors (1,2). In his commentary, he skillfully highlights the initial enthusiasm followed by more measured interest for anti-angiogenic agents in glioblastoma (GBM) (1). Based on the robust angiogenesis that characterizes GBM, there exists a strong biological rationale for targeting tumor blood vessels and, fundamentally, blood flow and nutrient delivery are essential to tumor survival. The therapeutic challenge with this class of agents has been identifying those patients likely to benefit and achieve a durable response both clinically and radiographically.
In our study of newly diagnosed GBM patients treated with radiation, temozolomide, and cediranib, an oral VEGFR inhibitor, we incorporated both blood and imaging markers to track changes in vascular structure and function. The goal was to better understand the physiological impact of anti-angiogenic therapy. As Dr. Nabors pointed out, we found that those patients with increased perfusion to the tumor had improved tissue oxygenation and lived longer-likely because of better delivery of temozolomide and oxygen (necessary for radiation efficacy) to the tumor resulting in improved tumor cell kill. Furthermore, we identified that blood biomarkers, specifically PlGF and sVEGFR2, were useful pharmacodynamic biomarkers of response whereas Il-8 and sVEGFR1 were biomarkers of relapse.
Critically, the imaging and blood biomarkers we explored are noninvasive and can be performed serially to track changes in the tumor over time. A particular challenge with brain tumors is the limited access to serial tissue biopsies to shed light on how the tumor and its microenvironment evolves in response to therapeutic pressures. Having a tool such as MRI where signal changes reflect physical processes in the brain is essential to interpret responses and help guide therapeutic decisions or potential combination therapies (3). MRI also has the benefit of capturing known tumor heterogeneity since the entire volume of an individual tumor is visualized as well as separate tumors in the same patient. Consequently, a crucial step to improving the care of brain tumor patients is to optimize correlative biomarkers that shed light on biological changes and use the human as the experimental model so we can learn as much as possible about the effects of drugs being developed for this challenging disease. The more we learn from our patients, the better we can design the next wave of therapies (4).
Acknowledgments
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Hongcheng Zhu, MD, PhD (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2016.03.10). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Batchelor TT, Gerstner ER, Emblem KE, et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A 2013;110:19059-64. [Crossref] [PubMed]
- Nabors B. Identification of the hidden survival advantage for anti-angiogenic therapy in glioblastoma. Transl Cancer Res 2016;5:72-4.
- Kalpathy-Cramer J, Gerstner ER, Emblem KE, et al. Advanced magnetic resonance imaging of the physical processes in human glioblastoma. Cancer Res 2014;74:4622-37. [Crossref] [PubMed]
- Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 2014;26:605-22. [Crossref] [PubMed]
