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MESSAGE FROM THE CO-DIRECTORS: 
Dear Friends and Colleagues,
 

Welcome to the UC Cancer Center May Newsletter as we focus on skin cancer.  UC has a rich history in the prevention, diagnosis and treatment of the various skin cancers.  Featured in this issue are descriptions of current research initiatives by Dr. Zalfa Abdel-Malek, the evolution of sentinel lymph node biopsy by Dr. Sameer Patel and Dr. Reka Chaudhary discusses advances in systemic therapy for melanoma. 
 
Dr. Mary Bell at UC had been integral in the understanding of Merkel cells as neuroendocrine cells contributing to touch reception.  Merkel cell carcinomas are uncommon and the discovery that they are caused by Polyomavirus was made at the University of Pittsburgh in 2008.
 
The first medical use of lasers was at the University of Cincinnati by Dr. Leon Goldman in the Department of Dermatology.  Lasers were first developed in 1960 and Dr. Goldman began medical applications in 1961 and founded the American Society of Laser Medicine.  He pioneered wide applications, significantly influencing many medical specialties.  Dr. Goldman worked closely with Dr. Charles Fixler who recently retired after a 60 year Dermatology career in Cincinnati.  Dr. Fixler began his career in California where he befriended his next door neighbor’s kids, often playing his trumpet with them in their garage as they forged their new band.  They became the Beach Boys.  Fifteen years ago the Beach Boys played at Riverbend and their encore, Barbara Ann, featured Dr. Charles Fixler on trumpet.
 
We hope you enjoy this edition.

 


Sincerely,
Syed A. Ahmad, MD, FACS
Professor of Surgery
The Hayden Family Endowed Chair for Cancer Research
Co-Director, UC Cancer Center
William Barrett, MD
Professor & Chairman of Radiation Oncology
Co-Director, UC Cancer Center
SKIN CANCER AWARENESS MONTH
In the past, advanced melanoma was one of the most aggressive cancers with a poor prognosis.  Because of recent advances in checkpoint inhibitors, although advanced melanoma is still very aggressive, the prognosis has changed markedly. The Checkmate 067 study was published in the New England Journal of Medicine  with 5-year survival rates in patients with advanced melanoma approaching 60%.  This is a true victory for cancer care givers everywhere.  Despite this victory, patients often feel a lack of control during cancer treatment and feel that treatments are always being "done to them."  In many studies, this lack of control has been shown to be associated with poor outcomes and depressive symptoms in these patients. There has been some exciting science in 2020, however,  that may help patients take the fight against melanoma into their own hands.
 
In 2018, Gopalkrishnan published an elegant paper in Science documenting the effects of the gut microbiome on melanoma treatment responses.  The stool of patients receiving immunotherapy was tested.  Patients with increased alpha diversity of the stool seemed to have increased responses to immunotherapy.  These patients' stool was then "transplanted" into germ-free mice.  The mice were implanted with melanoma in their rump and given immunotherapy just as their human stool donors had received.  The mice that received stool from humans whose melanoma had responded to the immunotherapy, responded to the immunotherapy.  The opposite was true as well. The mice who received stool from non-responder humans, did not respond to immunotherapy.  The only difference in the mice (Remember, they were germ free!) was the stool received. In Feburary 2021, Baruch et al published similar work except this time the stool transplant was human donor to human recipient.  Recipients of the transplant had melanoma not responding to immunotherapy. After receiving stool from a donor (melanoma patient) who was responding to immunotherapy, the recipients began to have responses.  This is very exciting news for patients because perhaps changing one's diet can impact your stool microbiome and your response to immunotherapy.  Alpha diversity seems to be increased with a high-fiber plant-based diet but more studies are needed on interventions needed to increase a patient's response to immunotherapy with diet and stool modulation.  Still, it is a fantastic start to putting cancer treatment back into the patients' hands.  

 
Rekha Chaudhary, MD
Adjunct Associate Professor of Medicine, Division of Hematology Oncology
Adjunct Associate Professor of Neurology
University of Cincinnati 

 
MELANOMA PREVENTION STRATEGY RESEARCH
Melanoma prevention strategy based on Targeting the melanocortin 1 receptor on melanocytes by analogs of its agonist α-melanocyte stimulating hormone
 
For almost two and a half decades, research in my laboratory has focused on understanding how pigmentation can affect an individual’s response to sun exposure and determine the risk for melanoma. Skin pigmentation and the ability to tan upon sun exposure are important determinant of the risk for skin cancers, including melanoma. α-Melanocyte stimulating hormone (α-melanocortin; α-MSH) is the main physiological regulator of pigmentation in vertebrate species. We were among the first to demonstrate that α-MSH stimulates pigmentation in human pigment cells, the melanocytes, by binding to a specific receptor, the melanocortin 1 receptor (MC1R), predominantly expressed on these cells. Activation of the MC1R by α-MSH binding increases the synthesis of the dark pigment eumelanin, which provides protection from the carcinogenic effects of ultraviolet rays (UV) from the sun. Epidemiological studies from various countries and continents showed that the MC1R gene is highly polymorphic, with over 100 variants of the gene expressed in different human populations, making it a central regulator of the diversity of human pigmentation. The wild type form of the gene is predominantly expressed in equatorial countries, where dark skin pigmentation is needed for protection from the adverse effects of excessive sun exposure.  A few MC1R variants are strongly associated with red hair phenotype and light skin color, and poor tanning capacity, a phenotype known to be associated with increased risk for skin cancers, including melanoma. We found that these red-hair color MC1R variants are loss of function alleles (forms) of the gene, which disrupt the signaling of the receptor when bound by α-MSH, thereby inhibiting the synthesis of eumelanin, allowing only for the synthesis of the red-yellow pigment pheomelanin. In contrast to eumelanin, which is photoprotective,  pheomelanin can contribute to the oncogenic effects of solar ultraviolet radiation (UV) by causing oxidative stress that can result in malignant transformation of melanocytes to melanoma. Importantly, we discovered that in addition to regulating pigmentation, activation of MC1R activates the DNA repair pathways in melanocytes, thereby reduces the extent of UV-induced DNA damage, which if not repaired, would result in mutations, the underlying cause of melanoma. These findings explain why the human MC1R gene functions as a melanoma susceptibility gene, and why loss of function variants of MC1R increase the risk for melanoma, by reducing skin pigmentation due to inhibition of eumelanin synthesis, and also by diminishing the DNA repair capacity of melanocytes. Furthermore, co-expression of loss of function variants of MC1R with mutations in other melanoma predisposition genes, primarily CDKN2A, which is the mostly mutated locus in familial melanoma kindreds, exacerbate the risk for melanoma.
 
Given the significance of α-MSH in regulating human pigmentation and DNA repair capacity, and reducing the risk of melanoma via activation of MC1R, we have developed very small analogs, consisting of 6-9 or 6-8 amino acids of the full length 13 amino acid peptide α-MSH, with different N-capping groups.  All these analogs have the same effects of α-MSH on cultured human melanocytes, stimulating pigmentation and enhancing repair of UV-induced DNA damage, as well as increasing pigmentation of cultured human skin substitutes. The 4 amino acid analogs proved to be 10-fold more potent, and the 3 amino acid analogs are only slightly less potent than α-MSH. These analogs are the smallest reported analogs of α-MSH, with most selectivity for MC1R, which reduces off target side effects. These analogs are covered by 3 international patents, and are currently being developed as topical agents that can be used for protection from the deleterious effects of UV, thereby preventing melanoma formation. Future commercialization of these analogs will have a huge impact on a large population with a high risk for melanoma, particularly those heterozygous  for a loss of function MC1R  variant (i.e. expressing one loss of function MC1R variant), who represent 50% of all whites in the U.S.A., and those with mutations in other melanoma susceptibility genes.
 
Research in my lab has been funded by federal grants from NIH (NCI and NIEHS), Department of Defense, and currently by a VA Merit Award. My laboratory has also received substantial university  funding from the Center for Environmental Genetics, the Cancer Center, and Venture Lab, as well as from the State of Ohio Third Frontier TVSF, and donations from Melanoma Know More.

Zalfa Abdel-Malek, Ph.D.
Professor, Department of Dermatology
University of Cincinnati
SENTINEL LYMPH NODE BIOPSY TECHNIQUE
The History and Importance of Sentinel Lymph Node Biopsy in Melanoma

The treatment of cutaneous melanoma has changed dramatically over the last several decades, with advancements in both medical and surgical treatments. One of the most important discoveries in the field of surgical oncology has been development of the sentinel lymph node biopsy (SLNB) technique.   
 
Historically, for patients that present with melanoma, treatment would entail wide local excision of the primary lesion and prophylactic removal of all regional lymph nodes (complete lymph node dissection), even in the absence of palpable nodal disease. However, in patients with intermediate thickness melanomas, only 20% will have metastases to regional lymph nodes.1 Therefore, 80% of patients are undergoing a procedure that is associated with morbidity without gaining any potential staging or survival benefit.2 This is especially important when considering that approximately 106,110 new cases of melanoma will be diagnosed in the US  in 2021.3  In order to resolve this dilemma, the technique of SLNB was born.

Dr. Donald L. Morton and colleagues were credited for refining SLNB in melanoma. Their work began in 1977 by developing a technique of mapping lymphatic drainage pathways (lymphoscintigraphy) by injecting the primary lesion with radioactive colloid.4 This was particularly helpful in identifying the regional lymph node basin involved for melanomas on the trunk, where drainage can vary. While examining the drainage pattern, they noticed that the colloid first went into a primary node and then into

secondary nodes, in an orderly pattern. This primary or “sentinel” node was theoretically the node at greatest risk of having melanoma metastasize to and knowing the status of this node, would reflect the status of the entire nodal basin. Following this, in 1992, they published their technique of SLNB using radiocolloid and intradermal injections of blue dye to identify sentinel lymph node(s). These patients also underwent complete lymph node dissection, but when they compared the non-sentinel node to the sentinel node, only 1% (2/194) of the non-sentinel nodes had metastases. These data verified that the sentinel node was the first node involved in melanoma lymph node metastases and could give an accurate assessment of the entire nodal basin.

In 2006, they published findings from The Multicenter Selective Lymphadenectomy Trial‑1 (MSLT‑I).1 This was a groundbreaking randomized control trial of patients with intermediate thickness cutaneous melanoma who were assigned to undergo wide local excision with either SLNB or observation of the regional nodal basin. If patients had a positive sentinel lymph node, they would then undergo immediate complete lymph node dissection. In the observation arm, if patients later developed clinically detectable nodes, they would undergo complete lymph node dissection. They found that the overall rate of positive nodes was ~20% (16.0% in the SLNB arm and 4.8% in the observation arm). Although there were no differences in 10 year melanoma-specific survival (81.4% versus 78.3%, p = 0.56), the study was not powered to detect such a difference given that ~80% of patients without a positive sentinel lymph node were included in the analysis.5 However, when only patients with positive lymph nodes were examined, there was indeed an improvement in melanoma specific survival in the group that underwent SLNB (85.1% versus 62.1%). On multivariate analysis, the status of the sentinel lymph node was the most important prognostic factor for recurrence and melanoma-specific survival.

This data not only solidified the role of SLNB in clinical practice but also transformed the treatment algorithm for cutaneous melanoma.
 
Sameer Patel
, MD

Assistant Professor, Division of Surgical Oncology
University of Cincinnati


References
1.           Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. The New England journal of medicine. 2006;355(13):1307-1317.
2.           Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Archives of surgery (Chicago, Ill : 1960). 1992;127(4):392-399.
3.           Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA: a cancer journal for clinicians. 2021;71(1):7-33.
4.           Holmes EC, Moseley HS, Morton DL, Clark W, Robinson D, Urist MM. A rational approach to the surgical management of melanoma. Annals of surgery. 1977;186(4):481-490.
5.           Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. The New England journal of medicine. 2014;370(7):599-609.
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