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July 2018 Volume 2 Issue 4

IN-DEPTH REVIEW

Current Therapy for Advanced Melanoma and a Look at Future Signaling
Pathways to Target

Peter Chow BS

a
, Pablo Angulo DO

b
, Kasie Kudrewicz Adkins DO

a
University of Kansas School of Medicine, Wichita, KS

b
Children’s Specialty Center of Nevada, Las Vegas, NV

c
Group Health TriHealth Physician Partners, Cincinnati, OH

Melanoma is a deadly skin cancer arising
from melanocytes, the cells in the basal
layer of the epidermis responsible for
forming the pigment in our skin, hair and
eyes. Melanoma’s incidence has
continuously increased throughout the
years.

1
Due to public awareness and

advancements in diagnostic methods, cases
of melanoma frequently are diagnosed
earlier through surgical excision, and thus
carry a good prognosis and 5-year survival
rate.

2
However, advanced metastatic stages

of melanoma (III and IV) have proven to be
difficult to treat, with traditional
chemotherapeutic drugs like dacarbazine

(DTIC) proving ineffective. In more recent
years, targeted therapy, most famously,
vemurafenib, a drug that targets melanomas
harboring a V600E mutation, have shown
improvement and promise in treating
metastatic melanoma.

1
Even still, metastatic

melanoma has proven resilient to new
treatments with its unique, heterogenous
resistance mechanisms, requiring new
approaches to bypass resistance.

ABSTRACT

Metastatic melanoma is a heterogeneous tumor of the skin derived from melanocytes
notorious for its resistance to various forms of systemic therapy. Many different types of
monotherapies and combination therapies have been developed in recent years, each with
their own setbacks, and drawbacks. This review article will provide an overview of current
FDA approved drug therapies for stage III and IV metastatic melanoma, key signaling
pathways they target, and mechanisms of drug resistance. This paper will then look at
future therapy for metastatic melanoma with a particular focus on targeted therapy on
embryonic and evolutionarily conserved pathways in metastatic melanoma, including notch,
wnt, hippo, hedgehog signaling, among others.

INTRODUCTION

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July 2018 Volume 2 Issue 4

Interferon alpha-2b
Traditional therapy for melanoma includes
surgery, radiation and systemic therapy, the
latter a category which encompasses
chemotherapy and immunotherapy.

Immunotherapy enhances the body’s
immune function to combat tumors. FDA
approved management options for resected
stage III melanoma immunotherapy includes
interferon alpha-2b. Interferon alpha-2b has
multiple actions in the body, including
binding to cell receptors and subsequently
initiating increased phagocytic activity of
macrophages and increased cytotoxicity of
lymphocytes. Interferon alpha-2b has shown
benefit in relapse-free survival benefit (1.72
vs 0.98 years), but no significant difference
in overall survival (OS).

Interleukin-2
FDA approved immunotherapy options for
stage IV melanoma includes interleukin-2
(IL-2). IL-2 is a T-cell growth factor.
Treatment with IL-2 carries only a 16%
overall response rate with a 6% complete
response.

Anti-CTLA-4 Antibody
More recent research has focused on
activating adaptive and innate immune
responses against tumor antigens.
Ipilimumab is an FDA-approved
immunotherapy for stage IV melanoma.

7
It is

a monoclonal antibody that blocks cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-
4), which normally acts as an immune
checkpoint in the body that inhibits T cell
activation. Therefore, by targeting CTLA-4,
ipilimumab enhances T cell activation and
cytokine production. In a phase 3
randomized controlled study, ipilimumab

significantly improved overall survival in
metastatic melanoma.

Data suggested a 28% to 34% decrease in
mortality rates in advanced melanoma
patients who were treated with ipilimumab
and a significant improvement in overall
survival.

7
However, drawbacks can include a

potential vast and dangerous array of
autoimmune side effects, including but not
limited to: enterocolitis, hypophysitis,
pancreatitis, leukopenia, hepatitis, and these
drug toxicities can be treatment-limiting and
life threatening.

8,9

PD-1 and PD-L1 Inhibitors
Programmed cell death protein 1 (PD-1) is a
receptor expressed on lymphocytes that
binds its ligand PD-L1 expressed on tumor
cells. The PD-1/PD-L1 is an immune
checkpoint interaction that ultimately leads
to T cell exhaustion and tumor cell
evasion.

10
Nivolumab is a monoclonal

antibody developed to target PD-1, inhibiting
its interaction with PD-L1, and potentiating
immune responses against tumor cells.

Clinical trials have shown promising results
of nivolumab compared to other therapies

11
,

and the efficacy of nivolumab combined with
ipilimumab in a phase 3 clinical trial has
shown significant regression when the two
immune checkpoint blockers were combined
when compared to either drug alone.

Chemotherapy
Dacarbazine (DTIC) is the only FDA
approved chemotherapy drug for the
treatment of advanced melanoma. DTIC is
believed to be an alkylating agent that adds
methyl adducts onto DNA, inducing cytotoxic
and antitumor effects.

12
However, responses

to it are low at 5-12%, the responses to the
treatment themselves do not last long, and it
has not been proven to prolong overall
survival.

13,14

CURRENT FDA APPROVED
IMMUNOTHERAPY AND CHEMOTHERAPY

FOR STAGE III AND IV MELANOMA

(Table 1)

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Table 1. Overview of currently available immunotherapy and chemotherapy options for advanced melanoma

FDA approved immunotherapy and chemotherapy for stage III and IV melanoma

Drug Mechanism of Action Common Side Effects

Interferon alpha-
2b

Increases macrophage
phagocytosis, increases cytotoxicity
of lymphocytes, and blocks
oncogene expression

Flu-like symptoms, elevated transaminases, nausea, vomiting, diarrhea,
neutropenia, leukopenia, thrombocytopenia

Interleukin-2 T cell growth factor Flu-like symptoms, hypotension, arrhythmias, nausea, vomiting, diarrhea, oliguria

Ipilimumab Blocks CTLA-4 immune checkpoint
inhibition, causing enhanced T cell
activation and cytokine production.

Rash, nausea, diarrhea, fatigue, weight loss

Nivolumab Blocks PD-1 and PD-L1 immune
checkpoint interaction between
tumor and T lymphocyte, ultimately
preventing tumor cell evasion.

Fatigue, malaise, hyperglycemia, hypertriglyceridemia, hyponatremia,
lymphocytopenia.

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BRAF Inhibitors
The BRAFV600 somatic missense mutation
is in approximately 66% of malignant
melanomas.

15
The mutation entails a

constitutively active RAS-RAF-mitogen-
activated protein kinase (MAPK) pathway, a
pathway that is in charge of cell growth and
proliferation. BRAF inhibitors that are FDA
approved for unresectable stage III
melanoma and stage IV melanoma
harboring a BRAFV600 mutation include
vemurafenib and dabrafenib. Vemurafenib’s
initial efficacy and low toxicity profile were
documented in a 2011 phase 3 randomized
clinical trial by Chapman et al comparing
vemurafenib to DTIC in patients harboring a
BRAFV600 mutation. In the study, the
overall survival of patients receiving
vemurafenib compared to dacarbazine was
84% at 6 months with a relative risk of death
reduction of 63%.

16
Another BRAF inhibitor,

dabrafenib, was approved in 2013, and it
showed similar results to vemurafenib.

Due to mechanisms of resistance, the
longevity of efficacy of a BRAF inhibitor has
been called into question. The response
duration to treatment ranges from 2 months
to more than 18 months.

18
Researchers

have shown that melanoma has a diverse
array of mechanisms of resistance to
escape BRAF inhibitor drug therapy. In a
study by Shi et al examining acquired
resistance to melanoma BRAF inhibitor
therapy, multiple mechanisms of resistance
were detected from tumor samples from
patients: an estimated 52% of melanomas
escaped via MAPK reactivating
mechanisms, 4% escaped via the

phosphatidylinositol 3’-kinase (PI3K)-PTEN-
AKT pathway, 18% escaped via both core
pathways, and 26% of melanomas escaped
in an unknown fashion. Additionally, when
they were able to take samples from multiple
tumors in the same patient, they discovered
81% (13/16) patients harbored multiple
mechanisms of resistance.

MEK + BRAF Combination Inhibitors
In order to further improve survival rates in
melanoma patients harboring a BRAFV600
mutation, combination therapy targeting
other aspects of the RAS-RAF-MAPK
pathways have been believed to be a
potential method to overcome escape
pathways of melanoma cells to BRAF
inhibitor monotherapy. Trametinib is an FDA
approved targeted therapy option for
patients who carry the BRAFV600E who
have unresectable stage III melanoma or
stage IV melanoma. Trametinib targets
MEK, a protein downstream of BRAF. A
phase 3 clinical trial showed the benefits of
combining a BRAF inhibitor (dabrafenib)
with the MEK inhibitor, trametinib. Robert et
al’s results show that combining dabrafenib
with trametinib compared to vemurafenib
alone yielded positive outcomes: overall
survival rate at 12 months was 72% in
combination treatment compared to 65% in
vemurafenib alone.

20
There are still patients

who fail combination therapy though, and
when they do fail they form a more
aggressive, metastatic melanoma.

Additionally, in many cases of combined
MEK-BRAF inhibitor treatment,
approximately 30% of patients still have
signs of progressive disease at 6 months.

CURRENT FDA APPROVED TARGETED
DRUG TREATMENTS FOR MELANOMA

(Table 2)

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Table 2. Overview of currently available targeted therapy for advanced melanoma

FDA approved targeted therapy for stage III and IV melanoma

Drug Mechanism of Action Common Side Effects

Vemurafenib Targets BRAFV600 mutation in MAPK
pathway

Fatigue, prolonged Q-T interval, hypertension, peripheral neuropathy, rash,
alopecia, skin photosensitivity, arthralgia, keratoacanthoma,

Dabrafenib Targets BRAFV600 mutation in MAPK
pathway

Hyperglycemia, skin rash, fatigue, headache, lymphocytopenia, arthralgia

Trametinib Targets MEK in patients with a
BRAFV600 mutation, a protein
downstream to BRAF in the MAPK
pathway

Rash, hypoalbuminemia, diarrhea, anemia, elevated transaminases

Table 3. Important melanoma signaling pathways

Signaling pathways that are potential targets for future melanoma therapies

Pathway Involvement in Melanoma

KIT A receptor that can be targeted upstream of the MAPK pathway

PI3K/AKT A pathway involved in tumor angiogenesis and invasion.

Notch Embryonic cell pathway that possibly promotes tumor chemoresistance, tumorigenesis and progression

WNT Related to melanoma tumor formation and metastasis

Hippo A pathway thought to contribute to melanoma invasion and metastasis.

Hedgehog Involved in spatiotemporal development in embryos as well as melanoma cell proliferation and metastasis.

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KIT Inhibitors
KIT is a transmembrane receptor tyrosine
kinase upstream of the RAS-BRAF-MAPK
pathway, and is in charge of cell survival
and proliferation in melanocytes.

23
Many

melanomas on mucosal, acral, and sun
damaged sites harbor KIT mutations.

Thus, KIT inhibitors like imatinib can be a
possible drug therapy. Guo et al’s phase 2
trial of imatinib on KIT mutations in
metastatic melanoma showed that imatinib
demonstrated significant activity against
patients with a KIT mutation.

25
However,

they do note imatinib’s overall response rate
(23.3%) is much lower than that of
vemurafenib, which had an 81% response
rate in BRAF patients, indicating the KIT
inhibitor has a lower specificity. In another
study of imatinib treatment of metastatic
melanoma, challenges in identifying
appropriate patients for KIT inhibition
treatment was highlighted. Compared to
BRAF mutations, KIT mutations can be
more widely distributed in the coding region,
providing patient identification challenges in
KIT inhibitor therapy.

24
Thus, although KIT

inhibitors have had meaningful treatment
outcomes in melanoma, more research is
required to enhance responsiveness to this
targeted therapy’s overall response rate.

PI3K/AKT Pathway
The PI3K (phosphatidylinositol 3 kinase)-
AKT-mTOR pathway is involved in cell
proliferation, invasion, metabolism, and
angiogenesis in normal and tumor cells.

26
It

is separate from the RAS-RAF-MAPK
pathway. There are studies now elucidating
the relationship between the MAPK and
PI3K pathways and mechanisms of tumor
resistance to targeted drug therapy. In
patient cell lines who were resistant to a
RAF or MEK inhibitor, the PI3K pathway

was found to be frequently upregulated or
persistent in response.

26
Thus, co-targeting

the PI3K and BRAF pathways can
potentially enhance metastatic melanoma
sensitivity and prevent drug resistance. So
far, co-targeting of MEK and PI3K/mTOR
pathways showed more effective inhibition
of BRAF mutant melanoma cell lines
compared to the BRAF and PI3K/mTOR co-
targeting inhibition.

27
More testing and in a

wider number and range of patients is
required to further elucidate the relationship.

Another protein involved in the PI3K
pathway is phosphatase and tensin homolog
deleted in from chromosome 10 (PTEN), a
tumor suppressor gene. PTEN is a PI3K
pathway inhibitor, and its loss has been
associated with tumor development in 30-
50% of melanomas.

28,29
In Stahl et al’s study

of mice models, PTEN loss was associated
with decreased apoptosis in melanoma cells
and PTEN expression associated with
increased apoptosis.

30
Furthermore, there

have been studies that show that BRAF
mutant melanoma cells actually utilize PTEN
loss in order to progress to metastatic
melanoma. The combination of BRAF
mutation and loss of PTEN is estimated in
approximately 20% of melanomas.

31
Thus, a

more intricate understanding of PTEN
expression, PI3K pathway, MAPK and their
role in melanoma tumorigenesis will be
useful for combating resistance.

Notch Pathway
The notch pathway is a new avenue in
battling melanoma which holds promise in
preventing chemoresistance. The notch
pathway is an evolutionarily conserved
embryonic cell pathway important for cell
fate and differentiation.

32
Studies have

suggested that dysregulated notch signaling
can prolong and confer life to cancer stem
cells, which are thought to be important in
tumor chemoresistance.

33
Other studies

THE PROMISING FUTURE OF

MELANOMA THERAPY (Table 3)

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July 2018 Volume 2 Issue 4

have shown that notch activation promotes
melanoma tumorigenesis and progression.

Thus, therapeutic benefit of targeting notch
signaling includes preventing tumor
angiogenesis, cancer stem cell depletion,
and cell death.

34
The notch receptor family

consists of four transmembrane receptors
(Notch 1-4).

35
Recent research on

melanoma cells correlate metastasis of
melanoma cells with expression of NOTCH4
gene, suggesting this protein and the notch
pathway can be a potential target of
melanoma therapy.

36
There is currently

research on drug therapy that can target
notch signaling in melanoma cells. Kaushik
et al have demonstrated that Honokiol (a
biphenolic organic compound) can target
notch signaling, confirmed with decreased
downstream effector target genes of notch:
Hes-1, and cyclin D1.

WNT Signaling Pathway
The WNT signaling pathway is important for
cell proliferation, differentiation, migration,
and many other processes of cell fate during
embryonic development.

37
Beta-catenin is a

downstream transcription factor of the WNT
pathway that can translocate to the nucleus
for target gene expression. Understanding of
the WNT signaling pathway in melanoma
progression may be critical-studies have
found canonical and noncanonical WNT
signaling effect different stages of tumor
progression, with canonical affecting
melanoma formation and noncanonical
affecting melanoma metastasis.

38
There

exists controversy in regards to the exact
involvement WNT signaling has on
melanoma behavior. One study showed loss
of nuclear beta-catenin staining was
associated with aggressive melanoma
behavior,

39
and another study showed that

elevated levels of nuclear beta-catenin was
associated with reduced proliferation of
melanoma cells.

40
Combined these findings

suggest that Wnt/beta-catenin signaling is

important for melanoma cell homeostasis,
and if dysregulated, can lead to
transformation of melanoma cells.

Hippo Signaling
While many drug therapies and studies are
focusing on the RAS-RAF-MAPK pathway in
melanoma, fewer studies are focusing on
targeting the invasive potential of melanoma
cells. The mechanisms underlying
melanoma invasion are presently poorly
understood. The Hippo pathway (the
Salvador-Warts-Hippo) is an evolutionarily
conserved mechanism in charge of tissue
and cell growth.

42
Downstream in the Hippo

pathway are YAP and TAZ effector proteins
which are amplified in many cancers and
promote epithelial-mesenchymal transition-a
frequent hallmark of metastasis.

43
In a

model of skin reconstruct, YAP
overexpression led to increased melanoma
cell invasiveness, and YAP knockdown led
to decreased metastasis potential.

43
Thus,

mutations in the Hippo pathway yield
increased activation of YAP and TAZ, which
promote metastasis regardless of BRAF
mutation status in melanomas.

42,44
Current

research is examining verteprofin,
44

a
molecule that inhibits YAP function and
whether or not it can successfully regulate
Hippo effector functions and subsequently
melanoma invasion.

Hedgehog Pathway
Another way to target cancer stem cells
involves the hedgehog signaling pathway.
This is an evolutionarily conserved pathway
in charge of spatiotemporal development in
embryos.

45
The pathway includes

Smoothened G-protein coupled receptor-like
receptor (SMO)

45
and downstream of SMO

include many transcription factors including
GLI1 and GLI2, both proven in recent years
to help melanoma cell proliferation and
metastasis.

46,47
Microarray gene expression

profiles of metastatic melanoma tumors

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July 2018 Volume 2 Issue 4

showed elevated SMO, which correlated
with overall decreased survival in melanoma
patients.

45
Promising studies have

demonstrated that by selectively blocking
SMO in the Hedgehog pathway with NVP-
LDE-225, melanoma growth is suppressed
in vitro and in vivo.

45,48

Melanoma is a heterogenous tumor capable
of resisting drugs through escape
mechanisms. Existing FDA approved
monotherapies have mostly been
unsuccessful in the treatment of metastatic
melanoma. Emerging research targeting
embryonically conserved pathways, among
others, are showing promising solutions to
beating this cancer.

Conflict of Interest Disclosures: None

Funding: None

Corresponding Author:
Peter Chow, BS
University of Kansas, School of Medicine
1010 N Kansas Street, Wichita, KS
pchow@kumc.edu

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