Unraveling the genetic causes of skin cancer

Interplay between key gene and receptor

Date:January 14, 2019
Source:American University
Summary:Medical researchers are helping to identify the genetic factors that lead to squamous
cell carcinoma. In a new article, they show how the interaction between a cell signaling pathway
called MET and a gene, Tpl2, contributes to skin cancer progression.

Skin cancer is on the rise in the United States. Squamous cell carcinoma,
the second most common form of cancer in the U.S., has the highest
mortality rate of all non-melanoma skin cancers. In roughly two to five
percent of patients, the disease will metastasize and spread throughout the
body, making it difficult to treat.

American University Associate Professor of Biology Katie DeCicco-Skinner and her colleagues are
helping to identify the genetic factors that lead to squamous cell carcinoma. In a new paper, they
show how the interaction between a cell signaling pathway called MET and a gene, Tpl2,
contributes to skin cancer progression. Their findings indicate a potential target for therapies that
could help those suffering from advanced squamous cell carcinoma for whom treatments like
radiation and chemotherapy are not options.

"It's critical we obtain a better understanding of the biological mechanisms by which skin cancers
develop," DeCicco-Skinner said. "The incidence of all skin cancers has drastically increased over
the last several decades and yet much is still unknown about the genetic causes that lead to
development or progression of these cancers."

Using animal models, DeCicco-Skinner researches how skin cancers develop. In 2011 she and
her colleagues revealed how the loss of Tpl2 increased susceptibility to skin tumor development.
In that study, Tpl2 was deleted in mice. Without the gene, the mice developed a significantly higher
number of tumors and showed biomarkers of cancer, such as increased inflammation and skin
cells turning invasive and attacking healthy cells. Tpl2's role in cancer is far from clear, however.
It works as an oncogene for some cancers, and a tumor suppressor for others, depending on the
tissue in which the signal is altered, DeCicco-Skinner said. In squamous cell carcinoma, Tpl2 acts
as a tumor suppressor.

In the new paper, published in Oncogenesis, DeCicco-Skinner and her team dig deeper: what is it
about the loss of Tpl2 that's causing benign skin tumors to convert into squamous cell carcinoma?
Part of the answer, it turns out, is the cell signaling pathway MET. MET is known to play a role in
many cancers. Activation of MET contributes to many different aspects of skin cancer progression,
including survival, invasion, angiogenesis, and drug resistance.

In a controlled study, knockout mice (those mice without the gene Tpl2) were treated with
Capmatinib, a drug currently being tested in clinical trials to treat a variety of cancers, and which
blocks MET from activating. The study results showed a 60 percent reduction in tumors in the mice.
More importantly, the tumors stayed benign. Therefore, lack of the Tpl2 gene results in an
overexpression of MET, which is, in part, the cause of squamous cell carcinoma, the researchers
concluded.
As a receptor, MET activates a wide range of signal transduction pathways. If it gets activated, it
turns on proteins in a cascading effect. What results is cell dysregulation: the cell divides quicker,
is more invasive, and becomes more inflammatory.

While MET is a significant player in skin cancer progression, it's not the only one, DeCicco-Skinner
points out. Future studies will dive into the relationship between MET and other receptors to further
explore its aberrant signaling.

Cell signaling pathways are complicated. Patients with advanced cancer disease are often treated
with medicinal cocktails to keep cancer from spreading throughout the body. "But it can be like the
game of Whac-A-Mole," DeCicco-Skinner explains, "in that, when one protein gets knocked down,
sometimes compensation occurs and another one pops up. We need to understand the
interactions between different proteins, so we can identify how to most effectively target the
development and spread of cancers such as squamous cell carcinoma."
Novel atopic dermatitis cream shows promise in
phase 2 study

Publish date: January 12, 2019

By Heidi Splete
Dermatology News

FROM THE BRITISH JOURNAL OF DERMATOLOGY

Adults with mild to moderate atopic dermatitis showed significant improvement after 8
weeks of treatment with a novel topical cream, compared with a placebo group, based
on data from 194 patients.

“Transient receptor potential vanilloid subfamily, member 1 (TRPV1) is expressed not

only on sensory nerves, but also on keratinocytes, dendritic cells and sebocytes in the
skin,” wrote Y.W. Lee, MD, of Konkuk University, Seoul, South Korea, and colleagues.
Previous research suggests that TRPV1 may play a role in the inflammation and
itching associated with atopic dermatitis, but use of a TRPV antagonist as treatment
has not been well studied, the researchers said.

In a phase 2b trial published in the British Journal of Dermatology, the researchers

randomized 194 adults with atopic dermatitis to one of three concentrations of a topical
cream containing the selective TRPV1 antagonist PAC‐14028, or a placebo vehicle.
The patients had baseline scores of 2 or 3 (mild to moderate) on the Investigator’s
Global Assessment (IGA) scale. Patients were instructed to apply the cream twice
daily to AD-affected areas.

After 8 weeks, treatment success (defined as a score of 0 or 1 on the IGA) occurred

in 57% of patients given 1% cream, 38% of those given 0.3% cream, 43% of those
given 0.1% cream, and 15% of those given a placebo cream.

In addition, other measures of improvement including the Scoring of Atopic Dermatitis

(SCORAD) index, EASI 75/90, sleep disturbance score, and pruritus visual analogue
scale (VAS) trended toward improvement in patients who received the treatment
cream.

The mean change in the SCORAD index was significantly greater in the 0.1% and
1.0% groups, compared with the placebo group. Also of note, patients in the 1.0%
cream group showed significant improvements in both sleep disturbance and VAS
scores, compared with the placebo patients, the researchers said.

The incidence of adverse events was similar among the groups, and no treatment-
related serious adverse events were reported. A total of 18 patients discontinued the
study, but 193 received at least one dose of treatment cream.
The study findings were limited by several factors, including the small size and lack of
comparison to treatment with topical corticosteroids and topical calcineurin inhibitors,
the researchers noted.

However, the results support the safety and efficacy of PAC‐14028, they added. And
“based on these results, a phase III program is underway to assess the efficacy and
safety of PAC-14028 topical cream 10% in adolescent and adult patients with mild to
moderate AD,” they said.

AmorePacific funded the study. Dr. Lee disclosed relationships with AmorePacific, as
well as LG Household & Health Care and Medytox.
Control HIV by treating schistosomiasis, new study
suggests
Date:December 13, 2018
Source:PLOS
Summary:Of the 34 million people worldwide with HIV, and the 200 million with schistosomiasis,
the majority live in Africa -- where millions of people are simultaneously infected with both diseases.
Now, researchers have shown that schistosomiasis infections are associated with increased HIV
onward transmission, HIV acquisition in HIV negative women with urogenital schistosomiasis, and
progression to death in HIV positive women.

Of the 34 million people worldwide with HIV, and the 200 million with
schistosomiasis, the majority live in Africa -- where millions of people are
simultaneously infected with both diseases. Now, researchers reporting
in PLOS Neglected Tropical Diseases have shown that schistosomiasis
infections are associated with increased HIV onward transmission, HIV
acquisition in HIV negative women with urogenital schistosomiasis, and
progression to death in HIV positive women.

Schistosomiasis is caused by a parasitic worm and is second only to malaria in terms of parasitic
diseases with the most global health impact. Schistosomiasis may cause lesions in the genital tract
and has been shown -- in cross-sectional studies -- to be associated with HIV prevalence.

In the new work, Dr. Kristin Wall, of Emory University, USA, and colleagues retrospectively tested
the blood sera of 2,145 people enrolled in a cohort of HIV-discordant heterosexual couples in
Zambia. Each sample was measured for schistosome-specific antibody levels. In addition, health
information including HIV status over time and death was available for the cohort.

59% of all participants were positive for a schistotome-specific antibody response. Among men
and women positive for HIV, baseline response for schistosomiasis was associated with an
increased risk of transmitting HIV to their uninfected partner. In addition, among women,
schistosomiasis was associated with increased acquisition of HIV (in HIV negative women with
urogenital schistosomiasis) and increased progression to death (in HIV positive women).

"Since treatment of schistosome infections with praziquantel is inexpensive, effective, and safe,
schistosomiasis prevention and treatment strategies may be a cost-effective way to reduce not
only the symptoms associated with the infection, but also new cases of HIV and death among HIV+
persons," the researchers say.

Story Source:

Materials provided by PLOS. Note: Content may be edited for style and length.

Journal Reference:

Kristin M. Wall, William Kilembe, Bellington Vwalika, Cecile Dinh, Paul Livingston, Yeuk-Mui Lee,
Shabir Lakhi, Debi Boeras, Htee Khu Naw, Ilene Brill, Elwyn Chomba, Tyronza Sharkey, Rachel
Parker, Erin Shutes, Amanda Tichacek, W. Evan Secor, Susan Allen. Schistosomiasis is
associated with incident HIV transmission and death in Zambia. PLOS Neglected Tropical
Diseases, 2018; 12 (12): e0006902 DOI: 10.1371/journal.pntd.0006902
Speed up public health decisions on scabies by
skipping full-body exams

Date:December 27, 2018

Source:PLOS
Summary:For years, the diagnosis of scabies has relied on time-consuming and intrusive full-body
examinations. Now, researchers have found that an exam of just a patient's hands, feet and lower
legs may have the potential to catch more than 90 percent of all scabies cases, regardless of
severity. These speedier exams may be useful in public health assessments on the prevalence of
scabies.
For years, the diagnosis of scabies has relied on time-consuming and
intrusive full-body examinations. Now, researchers reporting in PLOS
Neglected Tropical Diseases have found that an exam of just a patient's
hands, feet and lower legs may have the potential to catch more than 90
percent of all scabies cases, regardless of severity. These speedier exams
may be useful in public health assessments on the prevalence of scabies.

Scabies, a skin condition caused by the microscopic mite Sarcoptes scabiei, is a major public
health problem in low- and middle-income tropical settings. There is no laboratory test for
infestation and diagnosis is almost always made with clinical examination. Scabies control relies
traditionally on diagnosing individual patients, however there is increasing use of mass drug
administration programs. For mass drug administration to be a viables approach surveys of
communities to gauge scabies prevalence will be needed.

In the new work, Michael Marks of the London School of Hygiene & Tropical Medicine and
colleagues analyzed data from three recent large population-based surveys of scabies in the
Solomon Islands and Fiji. In all three surveys, examinations of covered the arms, legs, face and
torso. If patients reported itching in the groin, buttocks or breasts, these areas were also examined.
Exams in children under 1 year covered the whole body. Reports of scabies in examined patients
included which of nine body regions lesions were found in.

Based on the information where lesions were found, the team concluded that exams of exposed
body regions -- the hands, feet and lower legs -- had close to 90 percent sensitivity for detecting
scabies compared to a whole-body exam. Further restricting exams limited sensitivity, however,
with a sensitivity of only 51.2 percent for exams of the hands alone.

"Our study adds valuable data to the development of a simplified diagnostic process for scabies
that may be applied to guide decisions about future public health interventions," the authors say.

Story Source:

Materials provided by PLOS. Note: Content may be edited for style and leng

Journal Reference:

Michael Marks, Daniel Engelman, Lucia Romani, Daniel Mason, Oliver Sokana, Mike Kama,
Margot Whitfeld, Andrew C. Steer, John Kaldor. Exploration of a simplified clinical examination
for scabies to support public health decision-making. PLOS Neglected Tropical Diseases,
2018; 12 (12): e0006996 DOI: 10.1371/journal.pntd.0006996
On the horizon: An acne vaccine
Date:August 29, 2018
Source:Elsevier
Summary:\A new study reports important steps that have been taken towards the development of
an acne vaccine. The investigators demonstrated for the first time that antibodies to a toxin
secreted from bacteria in acne vulgaris can reduce inflammation in human acne lesions.

A new study published in the Journal of Investigative Dermatology reports

important steps that have been taken towards the development of an acne
vaccine. The investigators demonstrated for the first time that antibodies to
a toxin secreted from bacteria in acne vulgaris can reduce inflammation in
human acne lesions.

"Once validated by a large-scale clinical trial, the potential impact of our findings is huge for the
hundreds of millions of individuals suffering from acne vulgaris," explained lead investigator Chun-
Ming Huang, PhD, Department of Dermatology, University of California, San Diego. La Jolla, CA,
USA, and Department of Biomedical Sciences and Engineering, National Central University,
Jhongli, Taiwan. "Current treatment options are often not effective or tolerable for many of the 85
percent of adolescents and more than 40 million adults in the United States who suffer from this
multi-factorial cutaneous inflammatory condition. New, safe, and efficient therapies are sorely
needed."

Even though acne is not a life-threatening disease, its psychological burden is high. It is difficult to
conceal and frequently impairs the self-esteem of affected individuals, especially during
adolescence -- a period of important physical, emotional, and social development. Acne lesions
and/or scars may persist in adults. Current medications are often insufficient and can cause
difficult-to-tolerate side effects ranging from skin dryness and irritation, to depression, suicidal
thoughts, and increased rates of birth defects. An acne vaccination could circumvent potential
adverse effects of topical or systemic retinoids and antibiotics, the current treatment options.

This vaccine would be the first to target bacteria already in human skin, instead of invading
pathogens. After first demonstrating that Christie-Atkins-Munch-Peterson (CAMP) factor, a toxin
secreted from the Propionibacterium acnes (P. acnes) bacteria, can induce inflammatory
responses, the investigators explored in mice and ex vivo in human skin cells whether they could
inhibit inflammation by employing antibodies to neutralize this virulence factor. Their findings show
that the application of monoclonal antibodies to CAMP 2 factor did indeed decrease the
inflammatory response.

Both the significance of the findings and the need for continuing research were expressed in an
accompanying commentary. "While addressing an unmet medical need and providing an
appealing approach, acne immunotherapies that target P. acnes-derived factors have to be
cautiously designed to avoid unwanted disturbance of the microbiome that guarantees skin
homeostasis. Whether or not CAMP factor-targeted vaccines will impact multiple P. acnes
subtypes and other commensals has to be determined, but acne immunotherapy presents an
interesting avenue to explore nonetheless," wrote Emmanuel Contassot, PhD, Dermatology
Department, University Hospital and Faculty of Medicine of the University of Zürich, Zürich,
Switzerland.

The choice of the antigen to be targeted is critical, not only as a determinant of the efficacy of the
vaccine, but also to minimize possible unintended effects or cross-reactivity impairing the microbial
equilibrium and skin barrier homeostasis. Future studies will address these factors and focus on
engineering a non-toxic chemical or targeted vaccine formulation for its human application.

The findings support P. acnes CAMP factor as a promising target for acne immunotherapy. This is
an important observation since CAMP factor had not been previously implicated in the
pathogenesis of acne vulgaris. The study also provided a human acne model using acne biopsies,
as there is not a fully satisfactory animal model for acne studies.

Story Source:

Materials provided by Elsevier. Note: Content may be edited for style and length.

Journal Reference:

Yanhan Wang, Tissa R. Hata, Yun Larry Tong, Ming-Shan Kao, Christos C. Zouboulis, Richard L.
Gallo, Chun-Ming Huang. The Anti-Inflammatory Activities of Propionibacterium acnes
CAMP Factor-Targeted Acne Vaccines. Journal of Investigative Dermatology, 2018;
DOI: 10.1016/j.jid.2018.05.032