Discovery of 4 subtypes of melanoma points to new treatment approachesApril 12, 2018
Melanoma, a relatively rare but deadly skin cancer, has been shown to switch differentiation states -- that is, to regress to an earlier stage of development -- which can lead it to become resistant to treatment. Now, UCLA researchers have found that melanomas can be divided into four distinct subtypes according to their stages of differentiation. Cell subtypes that de-differentiated -- meaning that they reverted back to a less-mature cell -- showed sensitivity to a type of self-inflicted cell death called ferroptosis.
The research also showed that certain subtypes of melanoma cells could be successfully treated using multiple cancer therapies in combination with ferroptosis-inducing drugs.
Melanoma arises from melanocytes, cells that produce pigments. Although targeted therapies and a greater understanding of cancer immunology have significantly improved survival, many patients either relapse or do not respond to treatment.
The UCLA team, led by Dr. Thomas Graeber, analyzed the gene expression of melanoma cells and compared them to information in public genetic databases to identify the four different subtypes of melanoma with different drug sensitivities. The team organized the melanoma cells according to characteristic patterns of genes turned on by the cells. Comparing the gene expression patterns to data from stem cells induced to differentiate into melanocytes, they found that melanomas can be categorized into four distinct differentiation states.
"This refined characterization improves our understanding of the progressive changes that occur in melanoma cells during dedifferentiation, which can help develop better strategies to target this form of therapy resistance," said Jennifer Tsoi, who was a member of the research team as a UCLA graduate student and now is a postdoctoral fellow at UCLA.
The investigators then searched pharmacogenomics databases for compounds that could best be used to treat melanomas characterized by the dedifferentiation expression pattern, either individually or in combination with other drugs.
The study introduces a new area of therapeutic possibilities for melanoma, because it is the first to link ferroptosis to melanoma differentiation states. It also more precisely defines different subtypes of melanoma, based on specific gene expression and metabolic profiles. Those subtypes characterize four steps along a trajectory taken by melanoma cells as they respond to exogenous stresses, such as drug treatments.
The approach for targeting dedifferentiated melanomas could complement existing standard-of-care therapies, since kinase inhibitors and immunotherapies are much more effective against differentiated cells than de-differentiated cells.
"Furthermore, these standard-of-care therapies can induce dedifferentiation, and thus in a co-treatment setting, ferroptosis induction can potentially block melanoma cells attempting to take this escape route," Graeber said.
Graeber is a professor of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA and a member of the UCLA Jonsson Comprehensive Cancer Center. Tsoi is the first author. Other authors, also of UCLA, are Dr. Lidia Robert, Kim Paraiso, Carlos Galvan, Katherine Sheu, Johnson Lay, Dr. Deborah Wong, Mohammad Atefi, Roksana Shirazi, Xiaoyan Wang, Daniel Braas, Catherine Grasso, Dr. Nicolaos Palaskas and Dr. Antoni Ribas.
The research is published online in Cancer Cell.
The research was supported by grants from the National Cancer Institute, the American Cancer Society, the Melanoma Research Alliance, the Concern Foundation, the Parker Institute for Cancer Immunotherapy, the Dr. Robert Vigen Memorial Fund, the Garcia-Corsini Family Fund, the Ressler Family Fund, and the Grimaldi Family Fund, the V Foundation-Gil Nickel Family Endowed Fellowship, and the Spanish Society of Medical Oncology for Translational Research in Reference Centers.
In collaboration with Dr. Graeber, UCLA Technology Development Group has filed a provisional application based on this work. For more information, please contact UCLA TDG at email@example.com
The UCLA Jonsson Comprehensive Cancer Center has more than 500 researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the UCLA Jonsson Comprehensive Cancer Center is dedicated to promoting research and translating basic science into leading-edge clinical studies.
University of California - Los Angeles Health Sciences
Related Melanoma Articles:
Researchers at Dartmouth's Norris Cotton Cancer Center find that unique immune cells, called resident memory T cells, do an outstanding job of preventing melanoma in patients who develop the autoimmune disease, vitiligo.
University of Iowa researchers have documented in continuous, real time how melanoma cells form tumors.
A University of Colorado Cancer Center study published March 15, 2017, in the journal Melanoma Research uses the unique resource of over 600 melanoma samples collected at the university to demonstrate, for the first time, novel mutations involved in mucosal melanoma, paving the way for therapies to treat this overlooked subtype.
Newly identified genes and genetic pathways in primary melanoma -- a type of skin cancer -- could give researchers new targets for developing new personalized treatments for melanoma, and potentially other cancers.
A QUT-driven project has identified the way in which melanoma cells spread, opening up new pathways to treatment via drugs to 'turn off' the invasive gene.
A new research letter published online by JAMA Dermatology updates information on trends in melanoma incidence and death in the United States since 2009.
In a paper published online Nov. 30, 2016, in Melanoma Management, Adam Riker, M.D., Professor of Surgery and Chief of Surgical Oncology at LSU Health New Orleans School of Medicine, reviews approaches to manage melanoma, including one tested at LSU Health New Orleans that provoked a complete response in a patient with a long history of the disease.
The latest study of the Melanoma Group at the Spanish National Cancer Research Centre describes the roles of CPEB4; a protein that is crucial for melanoma cell survival.
Changes in the genetic make-up of tissue samples can be detected quickly and easily using a new method based on nanotechnology.
Colorado State University Professor Jesse Wilson has received a one-year, $30,000 grant from the Colorado Clinical and Translational Sciences Institute to develop a new microscope that can distinguish between benign and malignant pigmented skin lesions, without the need for biopsy.
Related Melanoma Reading:
Beating Melanoma: A Five-Step Survival Guide (A Johns Hopkins Press Health Book)
by Steven Q. Wang MD (Author)
Dr. Steven Q. Wang, a world-renowned skin cancer expert, provides an essential guide for people with melanoma and their families.
The book’s unique, practical format approaches the disease in two phases, just as people with melanoma need to do. First comes a step-by-step guide for what Dr. Wang calls the "mad rush" phase―an intense and stressful period from diagnosis to completing initial treatment. Dr. Wang's calm guidance helps readers through this critical time, using an easy to understand plan for ensuring optimal treatment and survival outcomes. Once the mad rush phase is... View Details
Melanoma without a Cause: How the New Miracle Immunotherapy Drugs and My Own Immune System Helped Me Fight Stage Four Cancer
by Bryant Wieneke (Author)
Melanoma without a Cause: How the New Miracle Immunotherapy Drugs and My Own Immune System Helped Me Fight Stage Four Cancer is a tale of survival following a devastating diagnosis of metastatic melanoma. Fighting through some heavy side effects, the author is saved by a treatment not available even a few years ago. He is given immunotherapy drugs, which stimulate his immune system to target and destroy the cancer cells that have spread throughout his body. Melanoma with a Cause chronicles the author’s treatment and remarkable turnaround, but remission remains elusive. A blog has been... View Details
The Melanoma Book: A Complete Guide to Prevention and Treatment, Including theEarly DetectionSelf-Exam Body Map
by Howard L. Kaufman (Author)
Citing high rates of cures that can be achieved with early detection, a whole-life plan informs readers on how to best enable melanoma skin cancer's immediate detection and select the most compatible and effective treatment options. Original. View Details
Melanoma: It Started With a Freckle
by David L. Stanley (Author)
With "Melanoma: It Started with a Freckle", David L. Stanley invites you to join him on an inside tour of his cancer. You'll travel with Stanley from the dimly lit and elegantly decorated office of the dermatologist to the fluorescent glare of the operating room theater and back to the workplace as he faces up to melanoma, the only major cancer that has seen its incidence rise since 2000, with humor, humility, and a deep understanding of the disease borne of research and science. In a memoir that speaks to anyone who has bumped up against a major health scare, Stanley offers up an engaging... View Details
Melanoma- Not Just Skin Cancer
by Catherine M. Poole (Author)
All cancer diagnoses are terrifying, but a melanoma diagnosis is both frightening and confusing. When Catherine M. Poole learned she had melanoma twenty-five years ago, she found that most of the literature on melanoma focused on prevention. To add to her understandable alarm, she couldn’t find clear, concise information on treatment options. Poole wanted to be an informed patient, but she had no resources.
She survived melanoma and has become a dedicated activist for melanoma research and a staunch patient advocate. Her new book, Melanoma: Not Just Skin Cancer, is a... View Details
by Jonathan S. Zager (Editor), Vernon K. Sondak (Editor), Ragini Kudchadkar (Editor)
Melanoma is a concise handbook that identifies best-practice guidelines and presents the most current procedures for the diagnosis and management of melanoma in a succinct and easy-to-read manner. Chapters cover melanoma pathology, biopsy techniques, staging and risk stratification, surgical treatment of localized melanoma, immunotherapy, radiation therapy, and guidelines for resected melanoma, targeted therapy, cytotoxic chemotherapy, and management of brain metastases, mucosal and ocular melanoma, and pediatric melanoma patients. This handbook is a must-have tool for clinicians... View Details
Healing Melanoma - The Gerson Way
by Charlotte Gerson (Author)
This booklet introduces Dr. Max Gerson and the founding principal of the Gerson Therapy, that Melanoma and most chronic diseases are able to manifest in the body because of toxicity and nutritional deficiency. Charlotte Gerson gives an overview of the Gerson Therapy and reviews some of the methods used in the program. Also included are case histories of individuals confronted with Melanoma and how they overcame then using the Gerson Therapy.View Details
A Melanoma Patient's Survival Guide: Lemons Really Do Make Lemonade: You Just Have to Add a Little Sugar
by Sally Welsh (Author)
A Melanoma Patient’s Survival guide: Lemons Really Do Make Lemonade is an effort to bring awareness to the subject of melanoma. This insidious disease is being diagnosed in over 50,000 people a year in the United States alone. Melanoma will affect one in seventy-five people in California. That rate goes up each year. Melanoma can be a silent killer. This heart-warming book was written by a survivor of serious melanoma, Sally Welsh. Sally has shared her experience with thousands of people, and has prepared this book with the hope of making your journey a little easier. Her suggestions deal... View Details
What You Really Need to Know about Moles and Melanoma (A Johns Hopkins Press Health Book)
by Jill R. Schofield MD (Author), William A. Robinson MD PhD (Author)
Throughout the world, the incidence of malignant melanoma is increasing at an alarming rate. This dramatic rise is largely due to more frequent and prolonged exposure to intense sun, the result of major changes in clothing styles, recreation, and lifestyle (including widespread access to midwinter resort vacations). Significantly, recent scientific studies have shown an increased number of moles on, and a higher rate of melanoma in, people with the greatest sunscreen use, pointing out the mistaken belief that using sunscreen means getting a "safe" tan. The truth is that most... View Details
Melanoma (Cancer Treatment and Research)
by Howard L. Kaufman (Editor), Janice M. Mehnert (Editor)
Melanoma is one of the most types of cancer. When melanoma is detected at an early stage, treatment is highly successful, but outcomes can be poor when the disease is advanced. There has been significant progress in our understanding of the molecular biology, genetics, and immunology of melanoma over the past decade. This has been accompanied by rapid advances in therapeutic strategies for patients with melanoma. This book provides the clinician and the researcher with a broad understanding of the molecular and cellular pathogenesis of melanoma, explores the clinical characteristics and... View Details