PRECISION MEDICINE
Jun
2014
Vol. 33. No. 2
Introduction
The implementation of diagnostic, therapeutic, and monitoring
strategies precisely tailored for each individual patient is increasingly
common, perhaps most notably in oncology. Such
“precision medicine,” ultimately guided by a molecular taxonomy
of disease, as well as detailed molecular knowledge of disease
course and therapeutic response, has been articulated as a vital goal
for the future of medicine.1 The unprecedented pace of scientific
progress and technologies for the deep molecular interrogation of
biological samples has arguably outpaced the ability to translate
this data into useful patient interventions. Nevertheless, there are
emerging areas in which such data has been successfully used to
create, implement, and monitor therapies.
In this issue, we explore the state-of-the-art in precision
medicine across a wide spectrum of dermatologic disease, including
nonmelanoma skin cancers, Merkel cell carcinoma,
melanoma, psoriasis, inherited structural diseases, and the skin
microbiome.
The existence of dominant driver pathways in both melanoma
and basal cell carcinoma has resulted in the rapid development of
specific inhibitors of ERK2,3 and Hedgehog signaling,4,5, respectively
with substantial clinical benefit. Despite the fact that such
targets have not been identified for squamous cell carcinoma or
Merkel cell carcinoma, intense research efforts are now aimed
at identifying appropriate targets. Immunotherapies that induce
checkpoint blockade against PD1 or CTLA4 signaling have shown
great promise, particularly in melanoma.6,7 It is possible that this
type of immunomodulation will eventually have a role in the treatment
of squamous cell carcinoma and Merkel cell carcinoma.
The identification of specific genetic defects in inherited disorders
of basement membrane presents a different problem. Many
targets are known, but the delivery of gene replacement has proven
to be difficult. It is unclear which technologies are most likely to
be effective and result in stable expression of components in the
appropriate cell types and contexts.
Molecularly targeted therapies are not limited to cancer. The
advent of biologicals for the treatment of psoriasis has not only
validated the targeting of numerous cytokines and their cognate
receptors, but has resulted in dramatic and sustained responses.8
However, the complexity of evaluating clinical response, predicting
response and managing adverse effects presents numerous
challenges in the optimal assessment and management of moderate
to severe psoriasis.
Finally, the microbiome has emerged as an exciting new frontier
of skin biology.9 The finding that bacterial diversity and composition
on skin differ by location and in disease states, suggests critical
roles for heretofore unappreciated skin-immune interactions
and novel therapeutic approaches for inflammatory disorders.
These articles are authored by leaders at the forefront of their respective
fields of expertise. The diversity of dermatologic disease
and the effective translation of deep biological understanding to
enable effective therapy pose significant challenges; however, the
enormous progress that has been made bodes well for continued
future success.
Current status and future directions of molecularly targeted therapies and immunotherapies for melanoma
Key molecular and immunological insights over the past
decade have radically changed the face of therapy in
melanoma. Whereas 5 years ago, treatment for advanced
melanoma was restricted to the alkylating agent dacarbazine
and the immunostimulants interleukin-2 and
interferon-a-2b, today the therapeutic menu includes precise
therapies that target key determinants in oncogenic
pathways and immune checkpoints. In this chapter, we will
review the current status and future directions of targeted
therapies for melanoma directed at mitogen-activated
pathways and immune checkpoints.
Semin Cutan Med Surg 33:60-67 © 2014 Frontline Medical
Communications
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Gene therapies for inherited skin disorders
Skin is an amenable organ for gene replacement and
gene editing therapeutics. Its accessibility makes it wellsuited
for direct topical gene delivery, grafting of genetically
corrected cells, and monitoring of possible adverse
events. Monogenic recessive disorders with a clinically
severe or life-threatening phenotype provide the best
candidate diseases for the introduction of a single normal
copy of the gene into the target cell, usually keratinocytes.
Preclinical studies have shown impressive results in terms
of gene correction using both in vivo and ex vivo approaches.
The clinical application of gene replacement
or genomic editing as potential therapies for inherited
skin disorders, however, has been held back by the inadequacy
of delivery vectors and concerns from regulatory
agencies regarding safety; thus translation to clinical trials
has been slow. Over the past 15 years, cell culture and
animal models have shown efficient gene correction techniques
as preludes to treat inherited skin disorders such as
junctional epidermolysis bullosa, dystrophic epidermolysis
bullosa, xeroderma pigmentosum, lamellar ichthyosis and
Netherton syndrome, but so far only one patient has been
treated in a clinical trial. This article reviews the current
status of gene therapies for patients with inherited skin
diseases and explores future perspectives.
Semin Cutan Med Surg 33:83-90 © 2014 Frontline Medical
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Merkel cell carcinoma: current status of targeted and future potential for immunotherapies
Merkel cell carcinoma is an aggressive neuroendocrine
tumor with a high incidence of local recurrence, regional
nodal and distant metastasis, and a high mortality rate. It
has been linked to a polyomavirus in addition to immune
suppression. Traditionally, treatment options have been limited
to surgery and radiation therapy. Better understanding
of the molecular pathways of infection and carcinogenesis
has provided potential molecular targets and potential
immunotherapies which are discussed in this review.
Semin Cutan Med Surg 33:76-82 © 2014 Frontline Medical
Communications
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Precision medicine and precision therapeutics: Hedgehog signaling pathway, basal cell carcinoma and beyond
Precision medicine and precision therapeutics is currently
in its infancy with tremendous potential to improve patient
care by better identifying individuals at risk for skin cancer
and predict tumor responses to treatment. This review
focuses on the Hedgehog signaling pathway, its critical
role in the pathogenesis of basal cell carcinoma, and the
emergence of targeted treatments for advanced basal
cell carcinoma. Opportunities to utilize precision medicine
are outlined, such as molecular profiling to predict
basal cell carcinoma response to targeted therapy and to
inform therapeutic decisions.
Semin Cutan Med Surg 33:68-71 © 2014 Frontline Medical
Communications
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Prospects for personalized targeted therapies for cutaneous squamous cell carcinoma
Targeted therapies for cutaneous squamous cell carcinoma
(cSCC) remain limited. Extensive genetic heterogeneity
complicates a robust molecular characterization
of the evolution of cSCC. Nonetheless, potential targeted
therapies for this cancer are under investigation, including
the inhibition of epidermal growth factor receptor
(EGFR), which may yield promising results. In addition, the
emergence of immune checkpoint blockade therapy
and vaccine-based methods may provide novel treatment
strategies for cSCC that are tailored to the individual
patient. Ultimately, a combination of such methods may
yield a multi-pronged targeted approach to personalize
the treatment of cSCC.
Semin Cutan Med Surg 33:72-75 © 2014 Frontline Medical
Communications
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