MedicalResearch.com Interview with:
Rakesh K. Jain, Ph.D.
A.W.Cook Professor of Radiation Oncology (Tumor Biology)
Director, E.L. Steele Laboratory
Department of Radiation Oncology
Harvard Medical School and
Massachusetts General Hospital
Boston, MA 02114
MedicalResearch.com: What is glioblastoma and why is it difficult to treat?
Dr. Jain: Glioblastoma (GBM) is the most common malignant tumor of the brain, and remains highly lethal. The standard treatment consists of surgical removal followed by chemo-radiation and anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) antibody. Unfortunately, glioblastoma cells invade the brain far from the original tumor mass. Hence, even with the best surgical techniques it is not possible to remove all tumor cells, as they are embedded in vital parts of the brain at the time of the surgery. As a result, even after multimodal therapies, most glioblastoma patients succumb to their disease within 2 years. New approaches are desperately needed.
MedicalResearch.com: What is anti-angiogenic therapy and why is it used for glioblastoma?
Dr. Jain: One key feature ofglioblastomas is their highly abnormal, leaky and ineffective vasculature. This leads to brain swelling around the tumor and poor tumor blood perfusion, which in turn can render the tumors more aggressive. These vascular abnormalities are due to the uncontrolled overproduction in GBMs of angiogenic factors such as VEGF. Anti-angiogenic therapies using anti-VEGF agents can transiently “normalize” the GBM vasculature structure and function and reduce brain swelling, increase blood perfusion, and impact morbidity and survival. Unfortunately, even when this therapy is added to the standard therapy with surgery and chemo-radiation, GBM patients typically do not survive on average more than 1.5 years.
MedicalResearch.com: Can you identify patients who benefit more from anti-angiogenic therapies than others?
Dr. Jain: Clinical studies indicated that some patients might benefit more than others after anti-VEGF therapies. As mentioned above, anti-VEGF therapy can restore the blood perfusion in glioblastomas. In imaging studies, we found that GBM patients who responded to anti-VEGF therapy with an increase in tumor blood perfusion lived longer compared to patients in which perfusion in the tumors did not increase. These studies show that it is possible to predict which glioblastoma patients will benefit the most from anti-angiogenic therapy.
MedicalResearch.com: Why is adding Angiopoietin-2 blockade a promising strategy for the therapy of Glioblastoma?
Dr. Jain: We previously found in clinical studies that glioblastoma patients treated with anti-VEGF agents experienced a decrease in Angiopoietin-2 (Ang-2) in their bloodstream, which rebounded simultaneously with disease progression. Since Ang-2 is an angiogenic factor with differential activity compared to VEGF, we hypothesized that Ang-2 can mediate anti-VEGF treatment resistance. Moreover, analysis of gene expression patterns in publicly available databases showed that Ang-2 is expressed across all types of GBMs, similar to VEGF. Thus, we designed studies to test whether dual inhibition of these angiogenic targets could overcome the resistance to single anti-VEGF therapy.
MedicalResearch.com: How did you test the effect of targeting both VEGF and Angiopoietin-2?
Dr. Jain: We tested two different yet complementary strategies targeting VEGF and Ang-2. Both approaches used clinically relevant agents. In one approach, to target VEGF pathway, we used a small molecule inhibitor targeting VEGF receptors in combination with anti-Angiopoietin-2 antibody. In the other, we used a bispecific antibody that neutralizes both VEGF and Ang-2. We tested these two approaches independently, using tumor models representing different types of glioblastoma. With this experimental setup, we were able to investigate therapy effects in a broad spectrum of GBMs, vascular pathophysiology, and immunological aspects.
MedicalResearch.com: What are the primary findings of the studies and why are they important?
Dr. Jain: These companion papers offer a potential solution to addressing glioblastoma escape from anti-VEGF therapy through activation of alternative vessel growth factor pathways such as Ang-2. We found that dual inhibition of VEGF and Ang-2 is a potentially efficacious strategy to overcome resistance to anti-VEGF therapy. In our back-to-back papers we not only provide proof-of-the-principle data that the dual treatment strategies slow glioblastoma tumor growth and survival but also reveal the underlying mechanisms for these benefits. One such mechanism reported in the article by Peterson et al. is that the dual anti-VEGF/Ang-2 therapy could normalize tumor blood vessels to a greater extent than anti-VEGF therapy alone. This is important, since mending pathological leaky blood vessels can alleviate dangerous swelling of the brain around the tumor (edema), and improve the delivery of other therapeutics. Another mechanism, described in the paper by Kloepper et al., is that dual therapy could modify malfunctioning, tumor-promoting immune cells toward an anti-tumor state. Importantly, this mechanism was apparent even in a GBM type in which the tumor blood vessels were not abnormal (in which vascular normalization was not the mechanism of benefit). This means that the beneficial effects on the immune system in the tumor may be observed in a wide range of glioblastoma types in patients. The importance of this mechanism was demonstrated in the Peterson et al. report through experiments showing that depletion of these immune cells dramatically reduced the therapeutic benefits.
MedicalResearch.com: Why is Angiopoietin-2 inhibition a timely new therapeutic strategy in glioblastoma?
Dr. Jain: The efficacy of current therapies for GBM is limited by the rapid development of treatment resistance. A prominent example is the use of the drug bevacizumab (an anti-VEGF antibody). This drug helps GBM patients live longer without disease progression, but unfortunately does not extend their overall survival. Our studies indicate that dual targeting of VEGF/Ang-2 could overcome some of the shortcomings and increase the survival benefit from anti-VEGF therapies for GBM patients. Importantly, clinically accessible agents are available for this dual targeting strategies.
In addition, our studies are timely because they show that dual anti-VEGF/Ang-2 therapy can also improve anti-tumor immune responses irrespective of its effect on blood vessels. Given the rapid development of new immunotherapies, our results open new avenues of research on combinations of these approaches with dual anti-VEGF/Ang-2 blockers, to obtain more durable responses in this devastating disease.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Jain: In our work we show how the inhibition of both Ang-2 and VEGF is effective against glioblastoma in preclinical models. This may translate into improved outcomes for patients. Our results could encourage clinicians to initiate clinical trials in patients who may benefit from dual anti-angiogenic therapy. Informed patients may seek to participate in clinical trials to test this novel therapy regimen for glioblastoma.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Jain: Future research in this area should focus on the combination of immunotherapies and anti-angiogenic therapy. There is a strong indication that modulating the patient’s own immune system could unleash powerful anti-tumor responses against this disease. Since our data showed an anti-tumor response that was partially based on changes in immune cells (macrophages and microglia), we think that additional stimulation of other immune cells such as T-cells may impart even greater benefits.
Peterson et al. (Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages) and Kloepper et al. (Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival)
Rakesh K. Jain, Ph.D. (2016). Dual Treatment Strategies Can Slow Glioblastoma Tumor Growth MedicalResearch.com