Pursuing the Unconventional in Glioblastoma
The AACR Judah Folkman Career Development Award for Angiogenesis Research represents a joint effort to encourage and support a junior faculty researcher to conduct tumor angiogenesis research and to establish a successful career path in this field.
2016 AACR Judah Folkman Award recipient, Yi Fan, MD, PhD, of the University of Pennsylvania, discussed the ongoing impact of this award on his research group’s glioblastoma research initiatives:
July 22 is Glioblastoma Awareness Day. What has inspired you to focus on glioblastoma research?
Many years ago when I was a medical student in Shanghai, I witnessed the cruelty by which cancer destroys entire families. I can still remember a lovely young kid who suffered sorely from a brain tumor and the frustrating I felt because there was barely anything I could do. Since then, I have made a life-time commitment to the battle of fighting cancer. I later enrolled in a graduate program with Dr. Paul Fox in Cleveland where I met Dr. Jeremy Rich. Their visionary work inspired me to purse an academic career and conduct cancer research with a focus on glioblastoma, the most lethal type of brain cancers.
What has been the impact of your AACR Judah Folkman Career Development Award on your career (for example, additional funding, researchers interested in collaboration/working in your laboratory, etc.)?
The AACR Judah Folkman Career Development Award offered me exciting opportunities to develop my scientific career. The initial results generated from this awarded project were published in JCI, Nature Communications, Science Translational Medicine, and Nature Cancer, and led to additional funding including two NIH R01 grants and several other foundation awards. In addition, this award enhanced the visibility of our research and helped me recruit several talented graduate students and postdoc fellows.
How important to you, at that stage of your career, was the award? Did it allow you to do things you might not otherwise have done?
I was honored to receive the Judah Folkman Award from AACR as a junior faculty member because Dr. Folkman had been my hero — a pioneer of angiogenesis research. This award provided flexible funding that allowed me to explore an unconventional angle of anti-vascular therapy; namely, targeting genetic endothelial transformation, in contrast to conventional studies focusing on angiogenic factors. It is hard for a junior scientist to acquire traditional funds for a high risk, but potentially impactful, research project. The Judah Folkman Award provided me a unique avenue to pursue this research idea.
What do you consider the most important scientific advance(s) made, at least in part, because of your AACR Judah Folkman Career Development Award grant?
The Judah Folkman Award incredibly helped us develop a new therapeutic concept, namely, vascular detransformation, to combat cancer (Fan, Trends in Cancer, 2019). The central idea is that tumor-associated endothelial cells acquire plasticity-mediated genetic reprogramming, leading to aberrant vascularity (Huang et al, JCI 2016), tumor immunosuppression (Wang et al., Nature Communications 2018), and tumor resistance to anti-VEGF treatment (Liu et al., Nature Communications 2018) and chemotherapy (Huang et al., Science Translational Medicine 2020). We hope that, compared to conventional anti-vascular therapy that targets angiogenic factors, vascular detransformation may serve as a next-generation strategy as either monotherapy or in combination with chemoradiation or immunotherapy for cancer treatment.
How do you foresee the findings from your AACR Career Development Award impacting patients in the near and long-term future?
Built on the key findings from my Judah Folkman Award, we have screened the whole kinome and genome to identify therapeutic targets for vascular detransfromation. One of these targets is Pak4, which reprograms the tumor vascular microenvironment and drives glioblastoma resistance to immunotherapy (Ma et al., Nature Cancer 2021). We plan to initiate related clinical trials for human patients with glioblastoma and expect that Pak4 inhibition will improve T cell-based immunotherapy (such as chimeric antigen receptor (CAR) T cell therapy). In the long-term future, we will test more of the identified targets and develop small- or big-molecule drugs to target vascular transformation and translate the findings into human clinic.
Since 1993, the AACR grants program has contributed to the development of new and improved approaches to cancer treatment and cure. What is your vision for the future of glioblastoma research? What areas of glioblastoma research remain underfunded?
I appreciate the tremendous effort made by the AACR to support cancer research, which has enormously supported many research programs for early-stage scientists. As for glioblastoma research, future success may rely on the deep understanding of tumor complexity, plasticity, and immunity and their spatiotemporal regulation, which will ensure we develop integrated, effective therapeutic approaches. I think that the multidimensional interaction between tumor stroma, immune cells, and neoplastic cells is central to tumorigenesis and immune escape, representing a potentially key node for clinical intervention, which is, however, an underfunded field. Finally, as glioblastoma is one of most deadly human cancer types, the findings from glioblastoma research will provide important clues that can also contribute to treatment advances in a variety of solid tumors, particularly those immunological cold tumors such as pancreatic and prostate cancers.