richarderickast@gmail.com
ORCID 0000-0002-7876-0400
16 June 2020
ABSTRACT
In the effort to improve treatment effectiveness in glioblastoma, this
short note reviewed collected data on the pathophysiology of
glioblastoma with particular reference to intersections with the
pharmacology of perphenazine. That study identified five areas of
potentially beneficial intersection. Data showed seemingly 5 independent
perphenazine attributes of benefit to glioblastoma treatment - i)
blocking dopamine receptor 2, ii) reducing centrifugal migration of
subventricular zone cells by blocking dopamine receptor 3, iii) blocking
serotonin receptor 7, iv) activation of protein phosphatase 2, and v)
nausea reduction. Perphenazine is fully compatible with current
chemoirradiation protocols and with the commonly used ancillary
medicines used in clinical practice during the course of glioblastoma.
All these attributes argue for a trial of perphenazine’s addition to
current standard treatment with temozolomide and irradiation. The
subventricular zone seeds the brain with mutated cells that become
recurrent glioblastoma after centrifugal migration. The current paper
shows how perphenazine might reduce that contribution. Perphenazine is
an old, generic, cheap, phenothiazine antipsychotic drug that has been
in continuous clinical use worldwide since the 1950’s. Clinical
experience and research data over these decades have shown perphenazine
to be well-tolerated in psychiatric populations, in normals, and in
non-psychiatric, medically ill populations for whom perphenazine is used
to reduce nausea. For now (Summer, 2020) the nature of glioblastoma
requires a polypharmacy approach until/unless a core feature and means
to address it can be identified in the future. Conclusions: Perphenazine
possesses a remarkable constellation of attributes that recommend its
use in GB treatment.
Keywords: dopamine; glioblastoma; perphenazine; protein phosphatase 2A;
serotonin; subventricular zone;
Abbreviations: dopamine receptor 2 (D2); glioblastoma (GB); serotonin or
serotonergic (5-HT); trimeric protein phosphatase 2A (PP2A);
1. Introduction:
There has been little progress in treating glioblastoma (GB) since the
introduction circa 2005 of temozolomide to the, then standard, resection
and irradiation. This paper addresses the rationale for adding
perphenazine to current GB treatment. By reviewing recent data on the
pathophysiology of GB with specific reference to intersections with the
pharmacodynamic attributes of perphenazine, this paper identified five
areas of potentially beneficial intersection. Strong empirical evidence
for perphenazine’s, and related D2 blocking drugs’, ability to reduce GB
growth is also presented.
Perphenazine is a 404 Da brain-penetrant, cheap, generic drug, approved
for use in humans worldwide. It has been in continuous use since the
1950’s to treat psychotic states and conditions [1, 2]. Perphenazine
is also used to reduce nausea [3], or to calm people who are in an
acutely disorganized agitated state. It also has adjunctive use in
treating depression. Basic pharmacologic parameters of perphenazine are
listed in Table 1.
Its antipsychotic properties are thought to be due to blockage of, or
inducing reduced activity of, signaling at the dopamine receptor 2 (D2).
Perphenazine also exerts inhibitory activity at selected serotonergic
(5-HT) receptors that contribute to its adjunctive effects in treating
depression. Table 2. lists the currently FDA/EMA approved and marketed
D2 blocking drugs used to treat psychosis that, remarkably, all also
happen to have a clinical or preclinical research database showing
activity in inhibiting glioma growth. The potential for clinical benefit
of D2 blockade with approved and marketed anti-psychotic drugs as part
of treatment of GB was recently reviewed by four different groups
[4-7].
This short paper examined published data on areas of intersection
between the documented pharmacodynamic attributes of perphenazine and
other marketed D2 blocking drugs generally and what we know about the
pathophysiology of GB growth and GB’s treatment resistance.
2. GB and dopamine:
Human GB biopsy tissue has increased D2 mRNA and protein expression
compared to normal brain tissue. The four recent reviews mentioned above
discussed in detail many of the pathways by which D2 blocking
antipsychotic medicines act to inhibit GB growth [4-7]. D2 blocking
also has been discussed as a potential treatment in cancer generally
[8-10].
Dopamine signals via 5 different receptors, D1 to D5. Although they each
have distinct attributes, they also share certain commonalities. Human
GB cells synthesize and secrete dopamine [5]. Signaling at D2
increases GB stem attributes, stimulates growth, and increases their
reliance on glycolysis [5]. Perphenazine inhibits both D2 and D3
receptors.
3. GB and need for polypharmacy:
3.1. GB cells use a variety of metabolic energy generation paths that to
varying degrees cross-cover for each other [11, 12]. Drug
repurposing allows use of well-known older drugs that, while not
cytotoxic in themselves, are able to block GB survival and growth
pathways. GB cells after all, like other cancers, use normal,
physiologic growth signals to thrive, albeit abnormally applied.
3.2. GB like other treatment resistant cancers is a community of
mutually supporting subclones [13]. Horizontal communication of
resistance exists via double minutes, exosomes, cell fusions, and other
means. Disrupting that mutually supporting communication between the
subclones, is required for “proper functioning” of the tumor subclones
for optimal growth. Thus inhibiting that communication is one path for
tumor control.
3.3. GB’s extreme temporal and spatial heterogeneity with multiple
cross-covering, growth-driving systems, combined with a uniquely robust
motility with consequent wide tissue invasion [14-16] all must be
simultaneously blocked - and kept blocked over time - to retard or stop
GB growth.
3.4. Growth driving systems in GB are moving targets, evolving over time
and responding to our treatment interventions [17, 18]. Also stem
cells within a cancer likewise are not a stable clonally related
population [19]. Stemness is an attribute that can be lost in
daughter cells of stem cells, or gained by daughter cells of stem-marker
negative cells [19]. Stemness is a fluid attribute. For these
reasons - and the failure over the last 40 years of several hundred
clinical GB studies of various cytotoxic drugs or drugs that blocked
single growth driving systems - we believe a polypharmacy approach is
needed. D2 blocking will be an important part of that polypharmacy for
GB.
3.5. A guiding principle behind the development of more effective GB
treatment is the concept used in military planning of clearly
identifying and individually addressing the different requirements for
A) a main operation, and B) shaping operations (note pleural). The main
operation commonly is aimed at destruction of enemy forces. In our case
- killing GB cells. Supporting operations are all activities directed at
matters peripheral to the main effort, but that are designed to help the
main effort succeed. A military example would be destroying a bridge
enemy forces might use to bring in reinforcements to where the main
operation is occurring.
In GB treatment this concept must be applied in crafting our treatment
regimen. This paper shows how adding perphenazine has five attributes
that would qualify it as a worthwhile shaping operation to current main
operations of surgery, temozolomide and irradiation.
3.6. Let the 2011 study in recurrent GB of Hegi et al serve as example
of need for shaping operations: In accord with others, they found that
60% of GB had EGFR gene amplification and that agonist stimulation
(phosphorylation) of EGFR in vitro resulted downstream phosphorylation
of RAS/MAPK and PI3K/AKT pathways. Gefitinib achieved ~
10 to 20 times higher GB tissue concentrations compared to serum, and
effectively prevented EGFR activation (phosphorylation) but had no
effect on reducing RAS/MAPK and PI3K/AKT pathways’ activation in
clinical samples or in a xenograft model. Crucially for our research
planning however, they did find effective blocking of downstream
RAS/MAPK and PI3K/AKT signaling after in vitro gefitinib exposure
[20]. Conclusion from Helgi et al: In vitro GB cell coping paths are
not reflective of human disease processes and polypharmacy required to
defeat GB’s as things now stand.
Elmaci and Altinoz reviewed past data on an old, still-in-use
antipsychotic drug, pimozide, and drew the conclusion that it may show
GB growth inhibition [21]. Pimozide has similar receptor binding
profile as does perphenazine. Pimozide has tighter inhibitory affinity
to D2, D3, and calmodulin, but regulatory restrictions in some
jurisdictions and risks of QTc prolongation with pimozide would
complicate its use in GB. Thus perphenazine.
In addition to the above reasoning, that a polypharmacy approach will be
required, we are planning on adding perphenazine to GB treatment based
on fully five perphenazine attributes: i) D2 antagonism, ii) D3
antagonism, iii) 5-HT7 inhibition, iv) de-inhibition (i.e. activation)
of trimeric protein phosphatase 2A (PP2A), v) nausea reduction. Details
on these mechanisms of action and how they therapeutically beneficially
interact with GB pathophysiology, with references, follow below:
4. The findings- GB and D2 antagonism.
Perphenazine has empirical evidence for anti-GB effects. EC50 of
perphenazine to GB cells in vitro was 0.98 μmol [22]. However, this
is unlikely to be a relevant mechanism of action though, given the nmol
range of clinically achievable levels.
We find the data of Table 2 to be remarkable in that 16 structurally
different, marketed, clinically used D2 antagonists should each have
evidence of anti-glioma effects. In addition to the autocrine growth
loop, the existence of which is suggested by GB’s expression of both D2
receptors and dopamine [5] we see strong cytotoxic synergy between
temozolomide and D2 blockade [23]. That single empirical evidence
alone should be enough to warrant a clinical trial of perphenazine. In
addition to the 16 marketed anti-psychotic medicines of Table 2, several
experimental, not-yet-marketed D2, D3, and D4 antagonists like Lcc-09
and ONC201 also have demonstrated GB cell killing effects and are being
actively pursued for GB treatment [24-26].
Psychosis is one of the most common major malfunctions of humans in all
societies worldwide. Because of this, and the general applicability of
D2 antagonism in stopping overt psychosis, we have ~ 20
antipsychotic, D2 inhibiting medicines currently marketed in most
jurisdictions.
GB spheroid growth in vitro is inhibited by several clinically used D2
antagonists and stimulated by specific D2 agonists [30]. Paths by
which D2 antagonism augments temozolomide and other common cancer
chemotherapeutic drugs was recently reviewed by Shaw et al, and
demonstrated specifically for temozolomide in GB by Liu et al. [31,
23].
The experimental D2 antagonist, ONC201, has just completed a phase 1
clinical trial in recurrent GB with evidence of good tolerability but
little general activity as single agent, although there was one durable
remission in an H3K27 mutated case [26].
5. The Findings- D3 antagonism and the SVZ.
Yoon et al early in 2020 distinguished a clear distinction between
post-resection GB as originating from centrifugally migrating
subventricular zone cells (SVZ) versus recurrences from already present
residual cells within brain tissue that had migrated - invaded - brain
from the original tumor mass [17]. Collected data below indicate
that perphenazine will reduce centrifugal migration of SVZ cells,
malignant or non-malignant.
SVZ cells line the lateral ventricles in a ribbon just distal to the
hypocellular gap [32]. These SVZ cells are one of the very few areas
of the adult brain that give rise to new neurons. Robust data show that
SVZ contributes to GB growth, with strong indications that indeed adult
GB tends to originate from a malignantly transformed SVZ cell or cell
group [17, 33-42]. Indeed, recent evidence indicates that malignant
transformation of nonmalignant cells of the SVZ is the primary
initiating event from which the cell of origin many human GBs migrate
[17, 43, 44]. Such cells are particularly resistant to TMZ and
irradiation due to an abundance of anti-apoptotic Bcl-2 and Mcl-1
[45]. Normal, non-malignant neural stem cells residing in the SVZ
are highly motile, and exhibit normal migratory patterns reminiscent of
Scherer’s structures in GB [46]. Contact with the SVZ is a poor
prognosis sign independent of the molecular GB subtype [34, 47].
The SVZ neurons or neuron-like cells replicate throughout life. They
also centrifugally migrate throughout life. Both normal SVZ cells and
malignant transformed SVZ GB cells proliferate and centrifugally migrate
in response to dopaminergic signals, and particularly, specifically,
dopaminergic signals at the D3 receptor [33-38, 40, 48]. Hence
perphenazine to inhibit D3 driven contributions to GB from the SVZ.
6. The Findings- blocking 5-HT7.
5-HT is remarkable in that all Animalia studied use 5-HT in similar or
analogous ways. In both invertebrates and vertebrates, 5-HT tends to
potentiate or mitigate neuronal activity rather than to start, stop or
trigger a specific behavior [49]. 5-HT tends to exert a behavioral
fine-tuning effect from crabs to primates.
Of the dozen or so 5-HT receptors currently recognized, 5-HT receptor 7
(5-HT7) is expressed on GB cells where agonism enhances growth
[50-52]. This same finding of growth drive stimulation via 5-HT7 is
also found in non-small cell lung adenocarcinoma where 5-HT7 agonism
drives proliferation, migration, and invasion [53]. Similar growth
stimulation by 5-HT7 was seen in neuroendocrine tumors [54],
hepatocellular carcinoma [55], and triple negative breast cancer
[56, 57]
7. The Findings- De-inhibition of PP2A.
PP2A is a trimeric serine-threonine phosphorylase, with a scaffolding
subunit , a catalytic subunit , and a regulatory subunit with multiple
subunits isoforms, resulting in over 60 combinations [58, 59]. Half
a dozen inhibitory peptides are recognized. PP2A dephosphorylates many
of the substrates phosphorylated by receptor kinases (examples: c-MYC,
AKT, Cdc25, Bax, and GSK3) active in driving cancers’ growth [58].
Phosphorylation of PP2A itself can inactivate it. Importantly for use in
GB, phenothiazines generally, and perphenazine specifically, activate
(de-inhibit) PP2A [59, 60].
So common a finding in various cancers is diminished PP2A activity that
subnormal PP2A has been termed “the broken off switch in cancer”
[61, 62, 63, 64]. PP2A, as a phosphatase, removes a phosphate from
phosphorylated kinases, many of which drive GB growth and many of which
become inactivated by such dephosphorylation [65, 66]. Advantages of
activating (de-inhibiting) PP2A during cancer treatment with kinase
inhibitors was recently reviewed by Westermarck et al [67, 68].
Multiple cell surface receptor kinases phosphorylate PIP2 to PIP3. PTEN
reverses that process, dephosphorylating PIP3 to PIP2.
PIP3 phosphorylates AKT, which itself then becomes an active kinase.
Higher level phosphorylated AKT correlates with shorter survival in GB.
Upregulation of PI3K/AKT pathway has also been documented in GM stem
cells. AKT phosphorylates several growth promoting cytosol targets in
GB, thus forming a growth driving signaling node contributing to
multiple malignant behaviors of GB [27, 28, 29]. As an important
example, PP2A dephosphorylates AKT, inactivating it in glioma cells
[69, 70]. AKT phosphorylation is a central signaling hub in
phosphorylation chains upon which growth signals from several receptors
converge that are required for GB mitosis entry [71].
PTEN and AKT are so fundamental to the normal functioning of all
nucleated cells that straight inhibition of AKT seems less promising
than simply calming it down, moderating it, reducing the hyperactivation
seen in GB.
Because so many outer cell membrane signaling receptors converge on AKT,
effect of blocking one or two of them can leave other receptors to cross
cover for the blocked ones (our Nile Distributary Problem).
PP2A dephosphorylates proto-oncogene basic helix-loop-helix
transcription factor (MYC) resulting in a more rapid degradation of MYC
leaving less time for it to act [72]. MYC is often overactive in
driving GB growth [73, 74].
PP2A also dephosphorylates Bax, enhancing its pro apoptosis function
[75]. Inhibition of PP2A is required for increasing phosphorylation
of Wee1, Myt1, and Cdc25, which are in turn required for mitosis entry
[59]. We reason that since perphenazine is widely used around the
world to treat psychosis, without evidence of mitosis prevention, that
the disinhibition of PP2A it exerts must be only partial or at least
partially circumventable.
PP2A dephosphorylation of MYC might also be of interest in immunotherapy
of GB and other cancers in that MYC transactivates PD-1 ligand [60].
Dephosphorylated MYC is rapidly degraded so lowering MYC dwell time
might thereby lower PD-1 immunoinhibitory function.
Perphenazine has demonstrated tumor growth retarding effects via PP2A
activation in lymphoma [76], acute lymphocytic leukemia [77],
acute myeloid leukemia [78]. Importance of activating PP2A during GB
treatment was recently reviewed [62]. PP2A activating perphenazine
derivatives are in active development to treat several cancers and have
demonstrated preclinical activity [79, 80].
8. The Findings- Anti-nausea effects of perphenazine.
Nausea is common during treatment of GB. Although standard current
treatment with irradiation and temozolomide is not highly emetogenic,
nausea does occur and does shorten progression free survival when it
occurs [81, 82]. Perphenazine reduces nausea and has a long history
of use for that purpose, dating from the 1960’s [83-88].
Perphenazine is used as one of several drugs in modern anti-nausea
regimens during chemotherapy particularly when one is aiming for “zero
tolerance” [87]. Perphenazine and other D2 inhibiting drugs are
non-inferior to the more modern drugs of the ‘setron group (like
ondansetron, granisetron, etc) [3, 88]. Anti-nausea effects of
perphenazine are additive with 5-HT3 antagonists, NK-1 antagonists and
steroids. Given the distress of even grade 1 or 2 nausea or vomiting,
perphenazine’s good tolerability, and the multiple potential areas of
anti-GB growth effects, a trial of perphenazine 8 mg x 1 at h.s. added
to standard Stupp chemoirradiation right from day 1 of treatment is
warranted.
9. Potential risks of perphenazine.
Side effects from perphenazine tend to be dose related and are not
common below 6 mg/day. Parkinsonian signs or symptoms (bradykinesia,
akinesia, tremor, diminished motor fluidity), or daytime sedation are
progressively more frequently seen as dose exceeds 8-12 mg/day but are
fully and rapidly reversible upon dose lowering.
More serious but also readily reversible with medical treatment followed
by dose reduction are neuroleptic malignant syndrome (NMS) and serotonin
syndrome. Serotonin syndrome is characterized by confusion, autonomic
nervous system instability, neurologic manifestations, and hyperthermia.
NMS is estimated to occur in three patients per 10,000 patients treated
with D2 blocking medicines [89]. NMS is characterized by a similar
clinical picture as serotonin syndrome with elevations of creatine
kinase, lactate dehydrogenase, aspartate transaminase), and leukocyte
count. These two nominal entities can overlap [90-93]. Formes
frustes are far more common than the fully blown, classically defined
syndromes. Left untreated these can be fatal but when recognized early,
treatment with cessation of the offending drug and supportive measures
are commonly enough for rapid resolution, although more active reversal
medical treatments are available [94].
Tardive dyskinesia is a late adverse effect seen occasionally after
decades of any D2 inhibitor’s use. Tardive dyskinesia tends to be
treatable but irreversible. Perphenazine is one of the four commonly
used D2 blocking drugs for which routine drug level monitoring is
recommended, so blood level testing is widely available [95].
10. Conclusions.
GB has been an intractable cancer with short survival after diagnosis
despite current standard treatment efforts. It seems polypharmacy will
be required for long-term control of GB growth until we find a core core
feature of GB growth and the means to address that core feature.
Perphenazine is an old, generic, and well-studied drug. Most clinicians
around the world regardless of their specialty are familiar with it.
This article assembled data on five areas where the biochemical and
physiological attributes of perphenazine intersected with those of GB in
ways that might be expected to impede GB’s resistance to current
treatment.
Acknowledgements:
There are no conflicts of interest in any matter related to this work.
There was no funding for this work.
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Table 1. Basic pharmacological parameters of perphenazine.