† These authors contributed equally.
Despite their differences, central nervous system (CNS) tumors and degenerative
diseases share important molecular mechanisms underlying their pathologies, due
to their common anatomy. Here we review the role of the renin-angiotensin system
(RAS) in CNS tumors and degenerative diseases, to highlight common molecular
features and examine the potential merits in repurposing drugs that inhibit the
RAS, its bypass loops, and converging signaling pathways. The RAS consists of key
components, including angiotensinogen, (pro)renin receptor (PRR),
angiotensin-converting enzyme 1 (ACE1), angiotensin-converting enzyme 2 (ACE2),
angiotensin I (ATI), angiotensin II (ATII), ATII receptor 1 (AT
In this review, we discuss the links between the renin-angiotensin system (RAS) and central nervous system (CNS) tumors and degenerative diseases, to highlight the potential role of the RAS in diseases of the CNS. While there is considerable literature on the relationship between the RAS and CNS disorders, there has been a recent resurgence in interest in the shared pathways between CNS tumors and degenerative diseases [1, 2], which suggest the RAS may play a larger role in both disease processes than previously thought.
The systemic role of the RAS in renal and cardiovascular physiology is well recognized, particularly for blood pressure, blood volume and electrolyte homeostasis [3, 4]. Angiotensin II (ATII)—the main effector the RAS, increases arterial pressure by causing vasoconstriction, retention of sodium, and release of the mineralocorticoid aldosterone by the zona glomerulosa of the adrenal cortex in the adrenal gland. RAS inhibitors (RASis) are used in the treatment of hypertension, cardiac failure, diabetic nephropathy, chronic kidney disease and several autoimmune diseases [5]. Despite the widespread use of RASis, the paracrine and autocrine functions of the RAS in organ systems including the CNS are not well understood. The observation that RASis are effective in patients with low or normal plasma renin activity may be explained by autocrine/paracrine RAS acting within the local tissue microenvironment of the CNS [5]. This article discusses the growing evidence demonstrating the universal role of certain components of the RAS in cellular homeostasis and disease pathogenesis [5] of CNS degenerative diseases (Table 1) and CNS tumors (Table 2). The review was undertaken utilizing the key words on the search platform PUBMED. The criteria for inclusion were to demonstrate potential molecular links of the RAS in CNS degenerative diseases including Parkinson’s disease and Alzheimer’s disease, and CNS tumors including glioblastoma (GB).
ATII is the main effector hormone produced by the RAS. It is formed by
sequential cleavage of angiotensinogen (AGT), which belongs to a family of serpin
A
Schematic diagram of the cellular RAS pathway in
neuroprotection, neuroinflammation, neurogenic hypertension and cellular
proliferation (see text). ACE1, angiotensin-converting enzyme 1; ACE2,
angiotensin-converting enzyme 2; ADAM-17, a member of the disintegrin and
metalloprotease adamalysin family; AGT, angiotensinogen; AKT, protein kinase B;
APA, aminopeptidase A; APC, adenomatosis polyposis coli; APN, aminopeptidase N;
AT1, angiotensin 1; ATII, angiotensin II; ATIII, angiotensin III; ATIV,
angiotensin IV; AngA, angiotensin A; Ang(1-7), angiotensin(1-7); Ang(1-9),
angiotensin(1-9); AT
Renin is an aspartyl protease. Its abundant precursor, preprorenin, is coded by
a gene located on chromosome 1 [10]. Renin is expressed in neurons, astrocytes,
oligodendrocytes and microglia in various regions of the brain [11]. Preprorenin
is cleaved to generate (pro)renin, which is then transferred to the Golgi
apparatus [12]. Most of the (pro)renin is then cleaved and packaged in dense core
secretory granules to be released via regulated exocytosis, with a small
proportion of (pro)renin released directly into the general circulation [13].
Brain (pro)renin has a higher affinity for PRR, compared to (pro)renin from other
sources, and it cleaves the 10-amino acids from the N-terminus of AGT, to form
inactive ATI [14] (Fig. 1). Physiologically, the macula densa (sensory cells) and
the renal juxtaglomerular cells within the juxtaglomerular apparatus (JGA), are
the primary sources of the PRR and renin in the blood circulation, respectively
[15]. Expression and secretion of renin are tightly regulated at the JGA by local
baroreceptors and by detection of chloride ion concentrations in the distal
tubule fluid by cells in the macula densa [16]. Activation of renin in
specialized extrarenal tissues requires binding to vacuolar (H
Angiotensin-converting enzyme 1 (ACE1; originally known as ACE), cleaves 2
amino-acids from the C-terminus of ATI, to form ATII (Fig. 1). ACE1 is a
dipeptidyl-carboxypeptidase found predominantly in lung endothelium [20]. ACE1 is
also expressed by endothelial cells in the intestine [21], placenta [22] and the
brush border membrane in the kidney [23]. It is also expressed in areas of the
brain that regulate blood pressure, and other areas that perform homeostatic
functions including the choroid plexus, organum vasculosum of the lamina
terminalis, subfornical organ, and area postrema [24]. In addition to the
C-terminus cleavage of ATI to form ATII (Fig. 1), ACE1 also degrades bradykinin
to an inactive form, which may impart secondary vasoactive effects by inhibiting
the vasodilatory and natriuretic properties of bradykinin [25]. ATII can be
converted to angiotensin III (ATIII), and then angiotensin IV (ATIV) by
aminopeptidases. ATIII binds to AT
ACE2, a monocarboxypeptidase, is a transmembrane protein found on cells in many tissues, including brain endothelium [27]. ACE2 preferentially cleaves ATII to form Ang(1-7) in the cerebrospinal fluid (CSF), a ligand for the MasR, where the ACE2/Ang(1-7)/MasR axis opposes the effect of ATII (Fig. 1), and is neuroprotective — an effect enhanced by vitamin D in hypertensive rats [28]. Conversely, ACE2 also acts in a minor manner on ATI, to release Ang(1-9), which can contribute to neurogenic hypertension with neuronal upregulation of ADAM-17 (Fig. 1), also known as tumor necrosis factor (TNF) converting enzyme, a member of the disintegrin and metalloprotease (ADAM) family. ADAM-17 cleaves the ectodomain of ACE2 resulting in its release from the plasma membrane, leading to RAS overactivity [29].
The end effects of ATII are mediated by its binding to AT
AT
AT
The recent spotlight on COVID-19 has also highlighted the role of ACE2 in
inflammation, as it also functions as a receptor for SARS-CoV-1 and SARS-CoV-2
[41]. The entry of SARS-CoV-2 into cells downregulates ACE2 receptors,
accentuating the adverse effects via the ATII/ACE1/AT
The neurogenic blood pressure response via the action of angiotensin on the CNS
was first discovered in 1961 [49]. Since then, cellular ATII has been recognized
to have both paracrine and autocrine actions with diverse physiological effects
including functional modification of the autonomic nervous system [50]. The
subsequent discovery of bypass loops of the RAS which include cathepsins B, D and
G, chymase, and aminopeptidases playing a supplementary role (Fig. 1), have been
demonstrated in the pineal and pituitary glands [51], human amniotic fluid and
kidney [52], human neutrophils [53], and in rat pituitary gland
cells [54]. Under physiological conditions, cathepsins B, D and G found in
neurons and glia and CSF, cleave neuropeptide Y (NPY), an abundant conserved
neuropeptide that partly modulates communication between the CNS and the immune
system [55]. NPY has been shown to inhibit microglial phagocytosis induced by
IL-1
Amongst the many functions of the CNS, the circumventricular organs (CVOs), which have a partial or absent BBB, may play pivotal roles in cardiovascular control, body fluid equilibrium, food intake, immune response, temperature regulation, energy metabolism, stress response and the vomiting reflex [58]. This is achieved by regulating the bioavailability of NPY by peptidases such as cathepsin D at the interface between the CNS and the periphery [58]. The sensory CVOs comprise the subfornical organ, organ vasculosum of the lamina terminalis and area postrema, and the neurosecretory CVOs comprise the neurohypophysis, median eminence, subcommisural organ and the pineal gland [59]. Tanycytes, specialized epithelial ependymal cells located in the CVOs, detect neuroendocrine signals from the circulating blood, CSF, and perivascular interstitial spaces, and convey signals through dendrites and axons in the median eminence [60] and the sensory CVOs [61]. Cathepsin D and NPY are localized in the CVOs, especially at the apex of the ependymal cells and tanycytes located at the floor of the third ventricle, above the median eminence [58]. Ordinarily, cathepsin D can cause lysosomal degradation of NPY, but the increased level or potency of cathepsin D results in a reduction of cellular and perivascular NPY, and neuroinflammation [58].
Cathepsin B is a lysosomal cysteine protease that catalyzes (pro)renin to form active renin [54, 62], which can therefore function in the absence of the PRR (Fig. 1). Cathepsin D is an aspartic lysosomal protease with some homology to renin that can convert AGT to ATI, in the absence of renin [63] (Fig. 1). Cathepsin G is a serine protease that catalyzes ATI to form ATII, and by adopting the role of ACE1, it can also convert AGT directly to ATII [64] (Fig. 1). The cathepsins are expressed in several diseases, including keloid disorder [65, 66], Dupuytren’s disease [67], vascular tumors [68], vascular malformations [69] and benign and malignant solid tumors including meningioma [70], GB [71], metastatic colon adenocarcinoma to the liver [72], and cutaneous [73] and oral cavity [74] squamous cell carcinoma (SCC). Similarly, chymase—a ubiquitous serine protease with a strong ability to catalyze the formation of ATII, is found in many disorders [75].
The role of the endocrine RAS in the CNS remains to be fully elucidated.
However, the existence of an intrinsic RAS within the brain, and its contribution
to neurogenic hypertension [76, 77] and CNS degenerative diseases, such as
Alzheimer’s disease and Parkinson’s disease [40], is now better recognized in the
neuroscience literature [78]. Although each component of the RAS has been
detected in the CNS, no single cell type within the brain contains all its
components. This suggests that localized synthesis is required given the
endocrine RAS can only access the brain via the CVOs with fenestrated capillaries
[79]. Loosely attached astrocytes and tanycytes in the CVOs can act as a
neuroendocrine bridge [80] between the brain and the endocrine RAS within the
circulation to access renin. Increased activity of neuronal AT
The demonstration of higher expression of components of the RAS by dopaminergic
neurons in the substantia nigra of monkeys and humans indicates a contributing
role in Parkinson’s disease [81]. AT
ATII via AT
ACE inhibitors and ARBs inhibit the ACE1/ATII/AT
The understanding of carcinogenesis has evolved markedly over the past two
decades due to advances in molecular and genetic profiling. The six hallmarks of
cancer first reported by Hanahan and Weinberg in 2000 [99] are less relevant
today, as the same authors revised the changes in 2011 to describe further
emerging hallmarks that enable characteristics of cancer cells, which are
features of a heterogenous tumor microenvironment [100]. Reprogramming of
cellular metabolism to support cell growth and proliferation and active evasion
of cancer cells from elimination by immune cells, underscore the complexity of
the genetic mutations, the role of cancer stem cells (CSCs) defined in the
concept of upstream limitless replicative potential, and the vast downstream
molecular interactions that contribute to neoplastic transformation and
plasticity [100]. In their landmark paper, Yamanaka et al. [101]
demonstrated that mouse embryonic and adult fibroblasts could be induced to form
pluripotent stem cells, with the supplementation of the essential core
transcription factors OCT4, SOX2, c-MYC and KLF4. These Yamanaka factors are
important pluripotency regulators linked to the regulation of cellular
reprogramming pathways with recognized connections to downstream signaling
pathways. These include Wnt/
GB is one of the most aggressive and lethal brain cancers, with a median overall survival of 14.6 months, despite the current standard of care involving surgery, radiotherapy and temozolomide [104]. The aggressive behavior and cellular pleomorphism in GB has various possible proposed mechanistic hierarchies. These multiple mechanisms include (1) the ability for GB CSC clones to show mesenchymal differentiation to generate chondrogenic cells associated with reduced growth rate [105], and (2) aberrant expression of EGFR, NF1 and PDGFRA/IDH1 genes in GB which define the classical, mesenchymal and proneural subtypes [106]. The proneural subtype shows the least benefit from aggressive therapies [106]. The mechanistic relevance of GB cell subpopulations that express OCT4 and SOX2 as being potentially more aggressive in GB carcinogenesis is yet to be proven [107, 108]. GB single cell RNA sequencing confirms the four distinct cellular states of GB with dynamic changes in the tumor microenvironment and plasticity [109]. Furthermore, endothelial cells in human GB have been shown to carry the same genomic alteration as tumor cells, suggesting the endothelial cells have a neoplastic origin. When these GB stem-like cells were injected subcutaneously into immunocompromised mice, the xenograft vessels were composed of human endothelial cells, properties highly suggestive of a plastic subpopulation of CSCs [110]. GB rarely present with distant metastasis, but the presence of circulating tumor cells [111] implicates a role for epithelial-to-mesenchymal transformation, and the necessity for a selective tumor microenvironmental niche that is essential for local tumor recurrence [112].
OCT4 is the master regulator for stem cell pluripotency [113], and the only
Yamanaka factor that cannot be replaced to generate induced pluripotent stem
cells (iPSCs). There is greater expression of OCT4 in higher grade gliomas [113, 114]. Similarly, SOX2 has also been recognized as a critical upstream
transcription factor which maintains self-renewal of GB CSCs. This is supported
by the observation that knockout of SOX2 inhibits GB cell proliferation [115].
Furthermore, SOX2 activity has been associated with the maintenance of glioma
stem cells and the ability to reprogram differentiated glioma cells into
stem-like cells which may contribute to chemoresistance and tumor recurrence
[116]. Recent studies have demonstrated the presence of cell populations
expressing primitive transcription markers in CNS tumors such as GB that exhibit
abundant expression of SOX2 [108], and components of the RAS: PRR, AT
SOX2 is known to be critical in lung development, and in promoting lung SCC as
an oncogene [118]. PRR is also essential in the development of the lung through
the Wnt/
PRR appears to play a role in the development of human glioma by aberrant
activation of the Wnt/
Components of the RAS: AGT, renin, ACE, ATI and ATII are synthesized and
expressed by human GB and GB cell cultures [127]. Renin has been detected in GB
cells, particularly in perivascular GB astrocytes [128]. The possible importance
of the RAS in GB may be highlighted by the demonstration of podocalyxin, a highly
glycosylated transmembrane protein present in hematopoietic stem cells,
endothelial cells, glomerular podocytes and some neural progenitors, in promoting
GB cellular proliferation and invasion. This occurs via elevation of soluble
Current evidence suggests the RAS plays a role in CNS diseases such as GB, but
mechanistic links have yet to be demonstrated. Underscoring the recent molecular
advances using the IDH mutation to classify gliomas [134], GB has the established
pathognomonic central necrosis, perivascular cellular palisading, endothelial
proliferation within the outer and inner margins of the active tumor bulk, and
vasogenic white matter edema at the growing front on the outer margin of the
tumor [135]. We speculate that the RAS may play a role in all these
characteristic features. This includes the neoplastic endothelium involved in
capillary breakdown at the BBB that results in vasogenic edema, and the formation
of tumor microvessels that feed the maturing tumor cells within the tumor bulk
before their resultant apoptosis and necrosis within the central region of the
active tumor. Many questions have arisen, especially since PRR is upregulated in
CVOs and tanycytes, such that there may be a progenitor subpopulation in the
areas of endothelial proliferation around the loose astrocytes and endothelium
closer to the outer margins of tumors that have upregulated PRR expression, and
co-express OCT4 and SOX2. Using the OCT4+ and/or SOX2+ cell subpopulations that
express components of the RAS, there may be distinct characteristics of
pluripotent cells identifiable by measuring single cell glutamate excitotoxicity
together with single cell RNA sequences at the penumbra of GB. Furthermore, given
podocalyxin promotes GB invasion and proliferation linked to upregulation of the
Wnt/
The role of RASis in degenerative neurological disorders remains unclear (Table 1, Ref. [137, 138, 139, 140, 141, 142, 143, 144, 145, 146]), although an early proof-of-concept double-blind placebo-controlled study shows perindopril, an ACE inhibitor, enhances the effect of levodopa without inducing dyskinesia [137]. Multiple review articles discuss the theoretical benefit of RASis for neurodegenerative diseases, but to date these drugs are not routinely used clinically for these disorders [40, 78, 82, 147, 148].
Authors and year | RASi used | Study type | Participant number | Neurodegenerative disease(s) | Outcome(s) |
Scotti et al. (2021) [138] | ACEis and ARBs | Meta-analysis of 15 studies | 3,307,532 | Any dementia, AD and VD | ARBs are associated with a significant decrease in risk for dementia (pRR 0.78, 95% CI: 0.70–0.87) and AD (pRR 0.73, 95% CI: 0.60–0.94). Compared to ACEis, ARBs reduce the risk of any dementia (pRR 0.86, 95% CI: 0.79–0.94) |
Harrison et al. (2021) [139] | Specific RASis studied not stated | Retrospective cohort | 181,495 | Dementia, AD, MD and PD | Compared to RASis, CCBs are associated with an increased likelihood of dementia (OR 1.24, 95% CI: 1.18–1.32), MDs (OR 1.21, 95% CI: 1.16–1.28). The OR for AD and PD both also have increased likelihood |
Oscanoa et al. (2020) [140] | ARBs | Meta-analysis of 10 studies | Patients were derived from 10 studies (1 RCT, 2 case-control and 7 cohort studies) | AD | ARBs are associated with a reduced risk of incident AD (HR 0.72, 95% CI: 0.58–0.88, p |
Dong et al. (2011) [141] | ACEi (perindopril) | In vivo experimental study on a mouse model of AD | N/A | Mouse model of AD | Prevented cognitive impairment and brain injury caused by glial activation and oxidative stress induced by A |
Li et al. (2010) [142] | ARBs and ACEis | Prospective cohort analysis | 819,491 | Dementia, including AD | The HR for incident dementia in the ARB group was 0.76 (95% CI: 0.69–0.84) compared with a cardiovascular comparator. Those taking ARBs with pre-existing AD have a significantly lower risk of admission to a nursing home (0.51, 95% CI: 0.36–0.72) and death (0.83, 95% CI: 0.71–0.97) |
ACEis were associated with a reduced risk of incident dementia (0.54, 95% CI: 0.51–0.57) and admission to a nursing home (0.33, 95% CI: 0.22–0.49) | |||||
Yamada et al. (2010) [143] | ACEi (perindopril) | In vivo experimental study on a mouse model of AD | N/A | Mouse model of AD | Reversal of cognitive impairment |
Stegbauer et al. (2009) [144] | Renin inhibitor (aliskiren), ACEi (enalapril), ARB (losartan) | In vivo experimental study | N/A | MOG-EAE, a model that mimics several aspects of MS | Significantly ameliorated course of MOG-EAE |
Ohrui et al. (2004) [145] | ACEi (perindopril) | Randomized, prospective, parallel group trial | 161 | AD | The mean 1-year decline in mini-mental state examination scores in the group taking a brain penetrating ACEi is lower than the 1-year decline in those taking non-brain penetrating ACEis or CCBs |
Iwasaki et al. (2003) [146] | ACEi (temocapril) | In vitro experimental study on organotypic spinal cord culture | N/A | Post-natal organotypic culture model of motor neuron degeneration, induced by glutamate | Temocapril prevents motor neuron death from glutamate-induced neurotoxicity |
Reardon et al. (2000) [137] | ACEi (perindopril) | Pilot study | 7 | PD | Enhances the effect of levodopa without inducing dyskinesia |
A |
The use of RASis in the treatment of cancer may mitigate adverse effects of
cytotoxic agents experienced by cancer patients, hence improving their overall
quality of life [149]. A meta-analysis of 17 observational studies by Shen
et al. [126] show RASis are associated with a reduced risk of cancer
[150]. A prospective population-based study also shows long-term (
A recent retrospective cohort study analyzed data from 810 patients enrolled in
two large multicenter studies to investigate the role of drugs targeting the RAS
in GB (Table 2). They challenge the rationale for performing future prospective
studies [157], given the paucity of data on multiple drug repurposing purely
targeting the RAS pathway. A recent clinical trial using multiple repurposed
drugs that target the RAS and converging signaling pathways, including captopril
and celecoxib in combination with temozolomide, shows promise as evidenced by the
observed maintenance of good quality of life for patients [158]. In addition,
RASis in combination with bevacizumab has been shown to improve survival in
patients with GB [159] (Table 2, Ref. [157, 158, 159, 160, 161, 162]), whereas there is no overall
survival benefit of this VEGF inhibitor as a monotherapy for de novo or
recurrent GB [163]. PRR may be a critical biomarker and therapeutic target for
the treatment of cancers including GB, as it influences the
Wnt/
Authors and year | RASis used | Study type | Participant number | CNS tumor | Outcomes |
Happold et al. (2018) [157] | ACEi and ARBs | Retrospective cohort study | 810 | Newly diagnosed GB | The OS for patients taking ACEis is 20.4 months versus 22.6 months for those taking the control (HR 1.25, 95% CI: 0.96–1.62, p = 0.10) |
The OS for patients taking ARBs is 21.7 versus 22.3 for those taking the control (HR 0.86, 95% CI: 0.61–1.21, p = 0.38) | |||||
There is no association between survival outcomes and RASi usage in patients with GB | |||||
Levin et al. (2017) [159] | RASis in patients receiving chemotherapy and/or bevacizumab | Retrospective study | 2 cohorts: 1186 glioma patients, and 181 patients with recurrent GB | WHO grade 2–4 glioma and recurrent GB | In glioma patients receiving chemotherapy, RASi exposure improves OS (HR 0.82; 95% CI: 0.71–0.93; p = 0.003) |
In patients with recurrent GB who receive bevacizumab in varying doses, RASis improve OS (0.649; 95% CI: 0.46–0.92; p= 0.0016) | |||||
Carpentier et al. (2016) [160] | ARBs | Cross sectional study | 11 ARB treated patients with 11 matched controls | GB patients treated with ARBs for hypertension, who had pre-operative MRI without steroids | Decreased volume of peri-tumoral hyper T2-FLAIR signal (vasogenic edema) |
Januel et al. (2015) [161] | ACEi and ARBs | Retrospective study | 81 | GB patients treated with RT and TMZ | The number of patients who remain functionally independent at 6 months after RT is higher in the patient group treated with ATII inhibitors, compared to those who were not (85% vs 56%, p = 0.01) |
Patients treated with ATII have a PFS of 8.7 months (vs. 7.2 months in other patients), and their OS is 16.7 months (vs. 12.9 months). The use of ATII inhibitors is a statistically significant prognostic factor for both PFS (p = 0.04) and OS (p = 0.04) | |||||
Kast et al. (2014) [158] | Captopril and celecoxib as part of the CUSP9 treatment protocol (apretitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine and sertraline combined with TMZ) | In vivo | N/A | Recurrent GB | Using CUSP9 with TMZ, 50% of patient-derived GB stem cells display high sensitivity to the drug combination, demonstrated by a decrease in percentage cell survival |
Decreased Wnt-activity | |||||
Carpentier et al. (2012) [162] | ACEi and ARB | Retrospective study | 87 | Glioma | Decrease in steroid dosage required |
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor
blocker; ATII, angiotensin II; CI, confidence interval; GB, glioblastoma; HR,
hazard ratio; RCT, randomized controlled trial; OS, overall-survival; PFS,
progression-free survival; RAS, renin-angiotensin system; RASi, RAS inhibitor;
RT, radiotherapy; T |
There is conflicting evidence on the efficacy of RASis in the treatment CNS
tumors, and other cancer types [165, 166] (Table 2), which is likely to be
multifactorial. The effects of RASis may depend on the cancer type, participant
baseline characteristics, the RASi used, study design, and publication bias.
Another possible contributing factor is differing levels of antagonism between
the pro-inflammatory ACE1/ATII/AT
The demonstration of components of the RAS in a spectrum of CNS diseases, such as Parkinson’s disease and GB, highlights the need for further research using well-developed experimental models. This includes functional experiments to elucidate the complex pathways linked to the RAS, and its potential role in the pathophysiology of CNS diseases. The recent technological breakthroughs in generating human cerebral organoids [167] from pluripotent cells, combined with genetic engineering [168], mass spectroscopic proteomics [169] and next generation gene sequencing tools [170], will allow more detailed studies to be conducted, to investigate the pathogenesis of CNS tumors and degenerative diseases. This may lead to the development of novel therapeutic approaches by targeting the RAS and its related pathways.
SH and EJK drafted the manuscript. PFD, SSS, TM, AHK, SRH, STT and ACW critically revised the manuscript. All authors commented on and approved the manuscript.
Not applicable.
Not applicable.
This research received no external funding.
PFD and STT are inventors of the patent Cancer Diagnosis and Therapy (United States Patent No. 10281472), provisional patents Cancer Diagnosis and Therapy (PCT/NZ2015/050108) and Cancer Therapeutic (PCT/NZ2018/050006), provisional patent application Novel Pharmaceutical Compositions for Cancer Therapy (US/62/711709). The authors declare that the review article was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors otherwise declare no conflict of interest.