1. Nalley, Catlin

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How can oncologists address treatment resistance in brain cancer?

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"This is one of the key questions the cancer research community is currently trying to solve," noted Damian A. Almiron Bonnin, MD-PhD candidate at the Geisel School of Medicine at Dartmouth. "High-grade gliomas are the most common and aggressive primary brain tumors in adults, and unfortunately, current medical therapies are largely ineffective against this type of tumor."


Initially, targeted therapy with receptor tyrosine kinase (RTK) inhibitors appeared like a promising approach in this type of tumor, he explained. "However, despite abundant evidence implicating RTKs, including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma, the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance.


"Despite the initial responsiveness of high-grade gliomas to these state-of-the-art therapies, these tumors virtually always become resistant and eventually recur," Almiron Bonnin continued. "This is one of the reasons why [high-grade gliomas] have one of the worst survival rates (less than 2 years)."


Mechanisms of Resistance

Researchers at Dartmouth's Norris Cotton Cancer Center, along with Almiron Bonnin, are looking for new approaches to prevent brain tumors from becoming resistant to anti-tumor drug treatment Almiron Bonnin and his team found that "insulin signaling functions as a 'tumor-growth signal' in brain cancer cells that have been treated with a targeted therapy, which allows the tumor to grow despite continued treatment (Mol Cancer Ther 2017;16(4):705-716).


"In this study, we have successfully identified a pathway that mediates the resistance of the most aggressive brain tumors, glioblastoma multiforme, to targeted anti-tumor drugs," Almiron Bonnin noted. "Importantly, there are drugs currently available that can block this pathway to resistance."


In order to study the mechanism of resistance to RTK inhibition in high-grade gliomas, researchers utilized a "mouse model of glioma that we develop in our lab to produce proneural glioblastomas as a direct result of inappropriate PDGF/PDGFR activation in glial cells," Almiron Bonnin explained. "We engineered this mouse model so that the PDGF/PDGFR could be turned on or off at the discretion of the investigator to mimic important aspects of the therapeutic activity of RTK inhibitors.


"We analyzed the response of these tumors to RTK inhibition utilizing different biomolecular techniques such as immunoblotting arrays, microarrays, western blotting, RT-PCR, cell culture, and immunohistochemical techniques," he elaborated. "To dissect large datasets produced by these experiments, we used several bioinformatics approaches. With the insights and knowledge we gained from these computational studies, we queried the cancer genome atlas database which contains clinical and genomic data of large cohorts of glioblastoma multiforme patients."


This study, according to Almiron Bonnin, "will lead to a better understanding of cancer mechanisms of drug resistance that will hopefully translate into improved clinical therapies for the treatment of high-grade gliomas."


The next step for researchers is to pursue a clinical trial to test the efficacy of this new approach on patients diagnosed with proneural glioblastoma with PDGF/PDGFR alterations.


"An important concept this study highlights was that when signaling from a specific secreted factor is blocked (such as PDGF), an alternative secreted factor can maintain the oncogenic functions of the secreted factor that was blocked (such as insulin and IGF1)," Almiron Bonnin added. "Multiple studies suggest that the capacity of cancer cells to secrete a wide range of soluble factors with redundant functions significantly limits the efficacy of current antineoplastic treatments including targeted therapies.


"Therefore, targeting the secretory mechanisms of cancer cells could potentially simultaneously reduce the levels of multiple pro-oncogenic secreted factors and, consequently, diminish cancer drug resistance and increase patient survival."


Glioma Stem Cells

The cancer stem cells within glioblastoma multiforme tumors are thought to be important drivers of resistance and recurrence.


"To put it simply, if you eliminate most of the tumor with standard treatments, but leave even one cancer stem cell behind, that cell could, in theory, give rise to an entire new tumor," explained Almiron Bonnin. "Therefore, making sure these cells are being effectively targeted is an important goal of cancer research."


According to Osuka, et al (J Clin Invest 2017;127(2):415-426), "certain glioma stem cell (GSC) populations display higher intrinsic chemo- and radioresistance than non-GSCs, indicating that a fraction of the primary tumor GSC population can survive the initial therapy and initiate recurrent tumor formation. GSCs can overcome the damage induced by chemotherapy and radiotherapy not only through innate properties (e.g., genetic heterogeneity), but also through adaptive resistance pathways.


"Because of their tumor-sustaining capacity and resistance to conventional therapies, GSCs represent an important target in the quest to find more effective therapies for GBM."


Almiron Bonnin's team recently uncovered a therapeutic approach that targets aggressive brain cancer stem cells (Oncogene 2018;37(8):1107-1118). "The presence of glioma stem cells within high-grade gliomas is one of the reasons they are so difficult to treat," noted Almiron Bonnin, in a statement. "In this study, we have successfully identified a secretion-mediated pathway that is essential for the survival of glioma stem cells within aggressive brain tumors."


"Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew," study authors wrote. "We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1[alpha] (HIF-1[alpha]) transcription factor and the JAK1/2-STAT3 axis to enhance the self-renewal of glioma stem-like cells."


Pharmacological blockade of the identified pathway leads to a noticeable reduction in tumor growth, according to Almiron Bonnin. "Being able to target the cancer stem cells within these tumors, like we did here, could potentially improve response to current chemotherapies and prevent recurrences, which would translate into an increase in patient survival rates."


Looking forward, the team is finalizing the preclinical experiments needed to initiate the clinical trial that will test drugs targeting glioma stem cells of patients diagnosed with this type of tumor.


Ongoing Research

The oncology community continues its efforts to unlock a better understanding of treatment resistance in brain cancer and new ways to combat it.


"Studies like ours demonstrate that it is not enough to target primary drivers of tumorigenesis such as PDGFR in proneural glioblastomas, for example," Almiron Bonnin concluded. "Effective anticancer therapies will have to be thoughtfully designed to also target the appropriate mechanisms of resistance, which vary depending on specific tumor types and therapeutic agent utilized."


Catlin Nalley is associate editor.