SPECTRUM OF THERAPIES
Melanoma accounts for less than 1% of skin cancer cases yet causes the vast majority of skin cancer deaths. If detected early enough, melanoma is almost always curable. If not, its ability to metastasize makes it difficult to treat.
Melanoma is more common in young adults than many other types of cancer, with 25% of new cases occurring in people under age 45. Its prevalence is growing — the number of new cases per year relative to the total population has doubled since 1973. In 2023, there will be an estimated 97,610 new cases of melanoma in the U.S. and 79,90 melanoma-related deaths, according to the American Cancer Society. Let’s review the basics and find out the latest treatments in the battle against melanoma.
Melanoma is the uncontrolled growth of melanocytes, the pigment-producing cells located in the bottom layer of the skin’s outermost layer (the epidermis). In skin cancer, a tumor initially grows and spreads within the epidermis due to DNA damage, which is usually caused by ultraviolet (UV) radiation.
If melanoma is detected during the epidermal level growth stage, it can often be surgically removed. Penetrating the deeper layers of the skin as it grows, it will eventually come into contact with lymph and blood vessels — which act as a cancer highway. When melanoma spreads to other parts of the body, it is known as metastatic melanoma.
Lighter-skinned people are at higher risk for melanoma because the increased skin pigmentation found in darker skin tones helps to block UV rays from penetrating and damaging skin cell DNA. However, darker-skinned people can and do get skin cancer. Another general risk factor for melanoma is atypical moles, or moles with irregular shape, color, or size. Moles are clusters of melanocytes, so sudden changes in them may be an early warning sign of melanoma.
GENETIC FACTORS: P53 & BRAF
Although most cases of skin cancer are traceable to excessive UV radiation from sun exposure, about 10% are likely due to genetic factors. The gene most commonly mutated in familial melanoma is p53. p53 is a “tumor suppressor” — it detects DNA damage in cells and triggers either DNA repair pathways or activates cell death if the damage cannot be repaired. Another gene, known as the BRAF gene, regulates cell growth and is mutated in inherited forms of melanoma. About half of all genetically-based melanomas have the BRAF mutation.
Let’s take a closer look at BRAF. BRAF codes for a protein required for the transmission of a growth signal from a cell surface receptor to the cell nucleus (growth signal transduction). A growth factor binding initiates growth signaling to its receptor. This binding transmits a signal through the membrane, causing the internal portion of the receptor to interact with and activate a protein inside the cell. This activation is then transferred to the next protein in the pathway, and so on, until the signal reaches the last protein in the pathway. When this protein is activated, it enters the nucleus, turning on specific genes that make proteins that initiate cell division. BRAF is one of the proteins in this pathway. In BRAF-associated melanoma, the mutated BRAF is always turned on even when no growth factor is present.
The small molecule drugs Zelboraf (Genentech; South San Francisco, CA) and Tafinlar (Novartis; Basel, Switzerland) inhibit overactive BRAF and are approved for the treatment of late-stage melanoma.
IMMUNOTHERAPIES IN THE FIGHT
A few different checkpoint inhibitor therapies are on the market for metastatic melanoma. These therapies enable killer T-cells – immune system cells that recognize and kill threats such as cancer cells – to become fully activated and able to kill tumor cells. Keytruda (Merck, Kenilworth, NJ) and Opdivo (Bristol-Myers Squibb, New York, NY) both target PD-1, an inhibitory protein on the surface of T-cells; Yervoy (Bristol-Myers Squibb) targets a second inhibitory protein, CTLA-4. Both PD-1 and CTLA4 essentially act as “off switches” for killer T-cells. By inhibiting these off switches, the killer T-cells become fully activated and able to kill melanoma cells.
A second type of immunotherapy approved for melanoma is Amgen’s (Thousand Oaks, CA) oncolytic virus therapy, talimogene laherparepvec (T-VEC). An oncolytic virus is a virus that infects and kills cancer cells. The cancer cells are killed through cell lysis: as the virus multiplies inside the cells, it causes them to burst open. This, in turn, releases new infectious particles that can target remaining tumor cells. In addition to killing cancer via lysis, the presence of an actively replicating virus triggers the immune response to target the tumor. T-VEC was designed to infect and kill melanoma cells and is so far the only FDA-approved oncolytic virus.
Incyte (Alapocas, Delaware) has a new type of small molecule immunotherapy in Phase III called Epacadostat – it inhibits the enzyme IDO1. IDO1 helps regulatory T-cells to develop and become activated. Regulatory T-cells suppress the immune response and help cancer cells escape immune surveillance. Inhibiting IDO1 should suppress the development of regulatory T-cells, bolstering the immune response against melanoma.
THE IMPLICATIONS OF MICRORNA
Researchers at Tel Aviv University (Tel Aviv, Israel) examined how melanoma metastasized in an article in 2016: the melanoma cells release tiny vesicles containing microRNA, a type of regulatory RNA produced by all cells.
The microRNA-filled vesicles induce changes in the layer of skin just below the epidermis, where melanoma originates. That lower layer of skin, known as the dermis, contains blood vessels that cancer cells are able to access. The Tel Aviv team is identifying drug candidates that may interfere with this process, preventing the metastasis that makes melanoma so deadly.
An increased understanding of the molecular pathways that contribute to melanoma’s development and spread will provide additional tools to fight metastatic melanoma cases that will inevitably continue to arise.
Melanoma, although accounting for a small fraction of skin cancer cases, poses a significant threat due to its high mortality rate and propensity to metastasize. The landscape of melanoma treatment is evolving, with advances ranging from targeted therapies like Zelboraf and Tafinlar that focus on genetic mutations to immunotherapies like Keytruda and Opdivo that activate the body’s own defense mechanisms. Emerging treatments, such as Incyte’s Epacadostat and oncolytic virus therapies, are also showing promise in clinical trials. As our understanding of melanoma’s genetic and molecular mechanisms deepens, including the role of microRNA in metastasis, the hope is that these insights will lead to even more effective therapies and preventive measures, especially as the incidence of this deadly disease continues to rise.
FREQUENTLY ASKED QUESTIONS
1. What makes melanoma so deadly compared to other skin cancers?
Melanoma’s ability to metastasize or spread to other parts of the body makes it particularly dangerous. Once it reaches this stage, it becomes much more challenging to treat effectively.
2. Are younger adults more susceptible to melanoma?
Yes, melanoma is more common in young adults than many other types of cancer, with 25% of new cases occurring in people under age 45.
3. What are some of the latest treatments for melanoma?
Some of the latest treatments include targeted therapies like Zelboraf and Tafinlar, which inhibit overactive BRAF. Immunotherapies like Keytruda and Opdivo are also making strides in treating metastatic melanoma.
4. How do genetic factors contribute to melanoma?
About 10% of melanoma cases are likely due to genetic factors. The most commonly mutated gene in familial melanoma is p53, followed by the BRAF gene. These mutations can make individuals more susceptible to developing melanoma.
5. What is the role of microRNA in melanoma?
Researchers have found that melanoma cells release vesicles containing microRNA, which induce changes in the layer of skin just below the epidermis. This facilitates the cancer cells’ access to blood vessels, aiding in metastasis.
6. Are there any preventive measures for melanoma?
Early detection is crucial. Regular skin checks and monitoring for changes in moles can be early warning signs. Protecting your skin from excessive UV radiation by using sunscreen and avoiding prolonged sun exposure can help reduce the risk.