Exploiting drug repositioning and the brain microenvironment to treat brain metastases

It is well known that malignant tumors growing in the brain, whether primary tumors such as glioblastoma or metastases associated with the progression of cancers such as non-small-cell lung cancer, breast cancer, and malignant melanoma, carry a dismal prognosis, as they are notoriously difficult to treat. Ironically, the problem of treating patients with brain metastases, if anything, is growing in magnitude because of advances in treating and controlling systemic metastatic disease, thus prolonging survival and increasing the risk of relapse with difficult-to-treat brain metastases.1 The lack of success in treating tumors growing in the brain with systemic therapies is often attributed to the impact of the blood–brain barrier (BBB), and yet the blood vessels in such tumors are often dysfunctional and highly leaky, especially larger lesions.2,3 So, what other factors might contribute to the resistance of tumors growing in the brain, including metastases? Is there something about the nature of the brain microenvironment beyond or in addition to the BBB that contributes to drug resistance which can be identified as well as exploited to improve therapeutic outcomes? In this issue of Neuro-Oncology, the group of Fidler and colleagues (Lee et al)4 report the latest in a series of preclinical results implicating brain astrocytes and endothelial cells as cellular “shields” to promote the survival and, hence, resistance to therapy—in this case chemotherapy—of breast or lung cancer brain metastases, a process mediated by endothelins (ETs) and endothelin receptors (ETRs).4 Moreover, treatment of brain metastases with a dual targeting ETR antagonist (macitentan), already approved for pulmonary arterial hypertension,5 is shown to be successful against brain metastases when combined with a conventional chemotherapeutic agent, paclitaxel. Previous studies by Fidler's group showed that several prosurvival (anti-apoptotic) genes in tumor cells, including BCL2L1 Twist 1 and GSTA5 (glutathione S-transferase alpha 5), are upregulated by direct contact in culture with astrocytes through gap junctions.6 Subsequent in vitro studies also implicated brain endothelial cells, in addition to astrocytes, as promoters of tumor cell survival, and this effect was mediated by increased production of one of the 3 endothelial ligands, ET-1 by astrocytes or endothelial cells, and elevated ETR expression by cancer cells.7 The cell-to-cell ET-1/ETR interaction caused activation of Akt/mitogen-activated protein kinase signaling leading to the upregulation of the aforementioned anti-apoptotic genes, resulting in reduced sensitivity of the cancer cells in vitro to paclitaxel. Importantly, a dual receptor ET antagonist blocking the 2 major ETRs—endothelin receptor A (ETAR) and endothelin receptor B (ETBR)—was required to reverse this protective effect.7 These in vitro studies led to the next logical experimental steps—evaluating the in vivo therapeutic impact of single versus dual ETR blockade on chemosensitivity of tumors growing in the brain. A recent prior study in Neuro-Oncology by Fidler's group evaluated macitentan in combination with temozolomide in several primary orthotopic glioblastoma models, including 2 lines selected for acquired resistance to temozolomide.8 Whereas antagonists selective for either ETAR or ETBR were found to be ineffective, macitentan was highly efficacious, provided it was combined with temozolomide.8 In the present brain metastasis study by Lee et al,4 similar results were obtained and, along with the glioblastoma studies, are remarkable in several respects. First, neither macitentan nor paclitaxel chemotherapy was effective, but the 2 drugs administered concurrently caused potent efficacy: complete tumor responses in 35 of 35 mice with established breast or lung cancer–derived metastases that were generated by intravenous injection of the tumor cells.4 In the prior glioblastoma study,8 46 of 48 mice treated with the macitentan + temozolomide combination showed no evidence of disease. Both studies provided evidence of antitumor as well as antivascular effects, which included downregulation of the aforementioned prosurvival-related proteins expressed in both cancer and brain endothelial cells.4 Taken together, the results suggest the exciting possibility of dual ETR antagonism in combination with chemotherapy as a new strategy to treat primary brain tumors or brain metastases. Some comment is necessary to put these results in perspective. First, using drugs originally developed for non-oncologic indications, such as pulmonary arterial hypertension or other (cardio)vascular indications, would appear to be a promising example of “drug repositioning” or “drug repurposing” in oncology.9,10 Second, there has been decades-long interest in targeting the ET-ETR axis as a potential cancer treatment,11–13 particularly for certain indications such as prostate and ovarian cancer.13 In addition to reports documenting ET-ETR interactions contributing to tumor cell survival and drug resistance, other critical biologic properties can be affected as well, including tumor cell proliferation, cancer stem cell survival, invasion, metastasis, and angiogenesis, as summarized in Fig. 1 and detailed by Kandalaft et al.13 Blockade of ETR function would therefore be expected to cause therapeutic benefits in potentially multiple ways, and indeed many previous preclinical studies have demonstrated this, but mostly using ETAR-specific antagonists. These findings helped lead to advanced clinical trials in advanced hormone-resistant prostate cancer. This included a randomized phase III trial which, unfortunately, failed to reach its primary endpoint when testing a specific ETAR antagonist.14 This leads to an important aspect of the macitentan-paclitaxel brain metastatic therapy results of Lee et al4: the necessity and benefits of using a dual ETAR/ETBR antagonist. There are a number of possible reasons for this, including the heterogeneous expression of ETAR and ETBR in tumor cells noted in the studies by Fidler's group: some cells express ETAR only, others ETBR only, and some both.4,7 Another possibility was hypothesized by Kandalaft et al of the Coukos group.13 Blocking ETBR function can have a stimulatory effect on the immune system in cancer by promoting T-cell homing to tumors.15 Consequently, selectively blocking only ETAR function may result in stimulation of ETBR and hence suppression of T-cell mediated antitumor immunity, potentially counteracting some of the beneficial tumor cell and vascular targeting effects of ETAR blockade.13 This can be avoided by dual ETR antagonism, although it should be noted that the study by Fidler's group involved human tumor xenografts grown in immune-suppressed mice lacking T cells. Summary of the main ways that the ET-ETR axis can promote tumor growth and malignancy. Some of the functions are mediated by ETBR, such as blockade of immune T-cell trafficking/recruitment into tumors, whereas others are mainly mediated by ETAR function, as summarized by Kandalaft et al.13 Thus, dual ETR blockade is likely necessary to exploit the full therapeutic potential of blocking ET function in cancer biology and optimizing treatment benefit. Putting all this information together would seem to make a powerful case for clinically evaluating dual ETR antagonists with chemotherapy (or immune checkpoint inhibitors) to treat metastatic disease, particularly when it involves the brain—a devastating condition currently affecting up to 1/3 or more of all cancer patients with advanced disease.16 But will financial considerations of evaluating drugs developed and successfully marketed for non-oncologic conditions prevent their assessment in oncology clinical trials because of fears that toxicities will emerge that may have nothing to do with treatment? Let us hope not. Dr. Kerbel's research programs are supported by grants from the Canadian Institute for Health Research (CIHR), the Canadian Breast Cancer Foundation (CBCF), World Wide Cancer Research (WWCR), and the Israel Cancer Research Fund (ICRF). Conflict of interest statement. Dr. Kerbel declares no competing financial interests for this article.

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