The Signal Transduction Pathways leading to Melanoma

and its effective inhibitors by Isabelle Sena

Abstract

Proliferation of melanocytes furthermore leads to the widespread investigation for certain therapeutic treatment. Melanoma cells lack the proper signal transduction pathways of normal skin cells and trace back to where the signal starts, which is in the stroma. Mutations can be observed within the malfunctions of the MAPK pathway that signals for mitosis. Without such processes, cell proliferation would easily take over, allowing for the growth of melanoma cells that can further on metastasize into the malignancies that relocate to other sites of the body. Treatment for metastatic melanoma is proven to be most effective during the combination of such therapies that utilize the inhibitors of the proteins involved within the pathways.

Introduction

Melanoma is a skin cancer associated with melanocytes — cells that are responsible for the production of melanin, a specific protein that gives the overall product and appearance of skin pigmentation. The three layers of skin consecutively consist of the epidermis, dermis, and subcutaneous fat starting from the surface and progresses inwards. Due to the constricted space in the epidermis layer alone, melanoma progression is highly likely to metastasize elsewhere. The melanocytes lie among the basal cells, the barrier that separates the rest of the epidermis from the dermis layer, allowing a mass of cells to easily relocate.

The development of melanoma cells occurs due to the uncontrolled proliferation of the melanocytes. This can be seen by the “seed and soil” hypothesis — an analogy that Dr. Stephen Paget created to describe the severity of metastasis. The crucial aspect and characteristics of cancerous growths tie back to the special localization of these cells in the human body. In this analogy, the stroma (the soil) of the evolutionary metastatic process.

Most importantly, mutations that occur within the signal transduction pathways, specifically the mitogen-activated protein kinase (MAPK) cascade tie back to the induced alterations of the healthy skin cell. “Mitogen” signals for mitosis — leading to the transcription of signals that promote healthy cell division as well as apoptosis. Without such processes, the death of cancerous cells is inhibited, and will continue its growth as the events allow that passage of viable tumor cells into the lymphatic and blood vessels. Such metastasis will maintain its viability as the growth reaches another suitable site that allows for proliferation. Mitosis cannot occur properly and efficiently without having passed through the stroma of the cell, which is why the earliest signs of cancerous growths are traced back to the “soil.” Such a hypothesis was determined by the tumor cell’s plasticity, demonstrating how the soil could alter the seed, thus establishing potential interdependence. This draws attention to the interdependence of the malignant cell to its stroma, where the cancer begins to grow.

Literature Review

Several ways of treatment are proposed by Magdalena Olbryt, with a PhD as a doctor of medicinal sciences at the Maria Sklodowska-Curie National Research Center. In her own research of therapeutic implications of melanoma development and progression, she suggests numerous ways of treatment that are determined by mutations that are present in an individual’s signal transduction pathways. Stanley P. L. Leong, Martin C. Mihm, Jr., George F. Murphy, Dave S. B. Hoon, Mohammed Kashani-Sabet, Sanjiv S. Agarwala, Jonathan S. Zager, Axel Hauschild, Vernon K. Sondak, Valerie Guild, and John M. Kirkwood: a group of credible researchers, and practitioners of medicine claim in their own research paper regarding the implications for treatment suggest that early diagnosis as well as surgical treatment is the most effective treatment as well as genetic profiling before the mass would begin to spread throughout the body and apply such knowledge to their surgical strategies in removing cancerous growths.

Objective

By the means of through research, the goal of writing this paper is to analyze the effectiveness of suggested therapies for adjuvant melanoma treatment.

In regards to the MAPK pathway, the occurrence of the BRAF mutation is present in 70% of melanoma cases as of 2019. Within this specific data set, 80% of the observed BRAF mutations involve a single mutation of the substitution of glutamate for valine (also known as V600E) — a mutation that is closely correlated to the rates of sun-exposed epidermis.

Proposed Methodology

From an outward perspective looking into the means of treatment for melanoma, the most successful treatment is early diagnosis and surgical treatment before its dissemination. New methods have recently revolutionized melanoma diagnosis and treatment. For a more precise subgrouping of patients, genomic profiling and sequencing would form a pillar for molecular taxonomy.

Radiation therapy, re-resection, and regional perfusion with chemotherapeutic agents have been attempted with minimal success. The toxicity and relative lack of effectiveness of most systemic agents in such patients have been a barrier to the use of intensive remedies, as described by Sanjiv S. Agarwala.

When it comes down to the treatment of BRAF mutations, the suggested treatments include oral inhibitors of the pathway — relatively specific to the V600E mutant form of the protein. Such inhibitors include vemurafenib (Zelfvoraf®, Genentech, South San Francisco, CA). Vemurafenib was approved in 2011 by the FDA and 2012 by the EMA in Europe for the treatment of unresectable, BRAF-mutated metastatic melanoma. The use of dabrafenib (GSK 2218436) chemotherapy, a single agent that is licensed and widely used and has given progression-free survival in BRAF mutated patients, is another targeted therapy technique. Current trials surround the idea of the MEK inhibitors, another factor of the MAPK pathway, such as trametinib (GSK1120212). Such inhibitors are useful within the genomic levels of cancer, with consideration that it tackles the mutations within the V600 codon.

Results and Observations

The effectiveness of these inhibitors come into play based on the data results from patients. The approved or recommended therapies for adjuvant or advanced melanoma treatment was apparent as ASCO 2011 provided exciting data on the use of a combination of inhibitors. In almost all treated patients, the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (GSK1120212) has demonstrated clinical benefit with as high of a response rate as 80%. Combining the use of vemurafenib and cobimetinib, another type of MEK inhibitor, created a response rate of 70%. By observations of the data set, the combination for such inhibitors is proven to be significantly effective rather than the use of one inhibitor alone. Results show that the singular use of inhibitors of vemurafenib, dabrafenib (GSK 2218436), and trametinib (GSK1120212) yields a response rate of 57%, 10–15%, and 25% respectively.

Interpretation of Results

In tumor biopsies, BRAF-MEK inhibitors modulate the immune microenvironment. In regards to the combined use of vemurafenib and cobimetinib, a response rate of 70% does not appear to be higher than expected from BRAF-MEK inhibitor therapy alone, future data on the longevity of these responses, along with overall survival, will help decide how effective the combination of targeted therapy and immunotherapy might be. This comes into consideration as the knowledge and data that was found and presented only depicts a response rate but not a rate of curation in the patient population. But the relatively quick response seen in the treatment of BRAF-MEK inhibitor therapy makes it an appropriate first option for BRAF-mutant melanoma patients with rapid disease progression in kinetics.

Conclusion

Circulating back to the seed and soil hypothesis, a malfunction in the soil’s properties that carry out the nurtured environment of the seed can easily transform into a malignancy. Malfunctions that occur within the stroma directly affect the signal that is delivered as transcription factors, furthermore leading to the proliferation of melanocytes, the inhibition of apoptosis and metastasis of the melanoma. Methods of treatment that involve malfunctions within an individual’s genomic sequences have an 80% chance of being correlated to the MAPK pathway. An inhibitor of each protein within the cascade allows for a greater rate of reaction rather than the use of a single therapeutic inhibitor of a singular protein on its own. Combining the workforce of inhibitors of the MAPK cascade is proven to be more effective than the use of a singular inhibitor of only one protein in the signal transduction pathway.

References

Lopez-Bergami, P., Fitchman, B., & Ronai, Z. (2008). Understanding signaling cascades in melanoma. Retrieved November 02, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874067/

Davis, C. P. (2016, July 22). Understanding Cancer: Metastasis, Stages of Cancer, and More. Retrieved November 02, 2020, from https://www.onhealth.com/content/1/cancer_types_treatments

Geggel, L. (2017, June 23). Melanoma: Symptoms, Treatment and Prevention. Retrieved November 02, 2020, from https://www.livescience.com/34783-uv-rays-increase-melanoma-skin-cancer-risk.html

NCI Dictionary of Cancer Terms. (n.d.). Retrieved November 02, 2020, from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/melanocyte

Olbryt, M. (2019, June 14). Molecular background of skin melanoma development and progression: Therapeutic implications. Retrieved November 30, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627250/

Leong, S., Mihm, M., Murphy, G., Hoon, D., Kashani-Sabet, M., Agarwala, S., . . . Kirkwood, J. (2012, August 15). Progression of cutaneous melanoma: Implications for treatment. Retrieved November 30, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311146/

Soh, U., Dores, M., Chen, B., & Trejo, J. (2010, May 18). Signal transduction by protease-activated receptors. Retrieved November 30, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874842/

Genentech: Zelboraf® (vemurafenib) — Information for Patients. (2017, November 6). Retrieved November 30, 2020, from https://www.gene.com/patients/medicines/zelboraf

Smalley, K., Eroglu, Z., & Sondak, V. (2017, April 1). Combination Therapies for Melanoma: A New Standard of Care? Retrieved December 01, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805442/