Anaplastic Thyroid Carcinoma (ATC) stands out as one of the rarest and most aggressive forms of cancer on the planet. It’s a type of endocrine cancer—a cancer which affects glands that secrete hormones—and is the product of genetic mutations in two specific signaling pathways (Cleveland Clinic, n.d; Rashid et al., 2019). In this case, ATC affects the thyroid, a gland located at the base of the neck that controls the rate at which your metabolism works (Cleveland Clinic, n.d). Thyroid cancers typically have high levels of survival; however, ATC has a mortality rate of almost 100%, with its treatment proven to be completely insufficient and ineffective. However, recent research exploring the fusion of targeted therapy and immunotherapy shows much promise, cultivating a new hope in improving survival rates in ATC patients.
Typical treatments for cancer usually involve chemotherapy or radiation therapy, which can be harmful to healthy cells. However, with regard to ATC, studies have shown that these methods are not enough to successfully stop the cancer's progression. Instead, doctors have turned to other methods, such as targeted therapy. Targeted therapy is the specific targeting of cancerous cells, a treatment that alleviates the damage caused to healthy cells. It’s been shown to be one of the most effective treatments for ATC, helping to improve treatment effects and patients’ quality of life (Gao et al., 2023). Through targeted therapy, we can attack specific signaling pathways in ATC in order to block the activity needed for continued cancer growth and development. One such pathway is the Mitogen-activated protein kinase (MAPK) pathway, which plays an important role in ATC development (Gao et al., 2023).
Using targeted therapy, medications such as Sorafenib can be used to block the activity of the MAPK pathway to prevent further cancer growth (Bhullar et al., 2018). Sorafenib binds to the receptor site in the pathway to target BRAF, a specific mutation in this pathway (Gao et al., 2023), meaning that it blocks a ligand—a molecule used for signal transmission—from connecting or binding to a receptor site—a protein meant to receive its signal. Sorafenib showed success in blocking pathway activity as patients on the medication showed a 35% disease control rate, which is defined as patients that reached either partial remission, complete remission, or saw no change in the cancer's progression. Other inhibiting medications such as Imatinib showed similar rates of success, with 25% demonstrating partial remission and 50% demonstrating no change in progression. With BRAF being the most common gene mutation of the MAPK pathway, medications such as Sorafenib have high potential for being efficient treatments for ATC, as well as others that target ATC’s pathways and gene mutations similarly (Rashid et al., 2019; Guerra et al., 2013).
Immunotherapy treatment in ATC works similarly to targeted therapy in that we use medication to inhibit a specific pathway, except that here we refer to immunosuppressive pathways that regulate immune response. One example is programmed death receptor 1 (PD-1), which is an inhibitory receptor on immune cells. Its ligand PD-L1 is highly found in ATC and promotes tumor cell growth, predicting poor prognosis in patients with high expressions of it. Spartalizumab is a genetically engineered antibody that targets PD-1 and has shown good clinical results. Overall treatment showed a 19% remission rate with 3 patients in complete remission (Gao et al., 2023).
Monotherapy alone has shown successful rates of efficiency in various studies. However, combinations of treatments have proven to be similarly or even more effective. For instance, in a study conducted on a 62 year old male ATC patient that tested positive for the BRAF mutation and PD-1, a combination of targeted therapy and immunotherapy led to a decrease in cancerous cells and eventually complete remission after 20 months of treatment. Results such as these are miraculous when we consider that ATC typically has a life expectancy of approximately 6 months with 1 in 5 patients alive after a year (American Thyroid Association, 2020). Additionally, another medication, pembrolizumab, used in combination with kinase inhibitor treatment—a type of targeted therapy—has shown to enhance the use of the inhibitors, improving their efficiency (Gao et al, 2023).
Overall, combinations of immunotherapy and targeted therapy appear to be much more effective than singular treatment. As cancerous cells mutate, the effects of targeted therapy and immunotherapy can be negligent as mutations cause resistance and evasion of their targeted effects. But together, the two treatments have complementary effects in cancer treatment that can increase therapeutic effects (Ma et al., 2022). Ultimately, with a cancer as malevolent and rapidly progressive as ATC, these combinations of therapy are more effective than individual approaches. And as more clinical experiments are pursued, we can continue to understand the full potential that combination therapy has in treating ATC.
References
Guerra, A., Di Crescenzo, V. G., Garzi, A., Cinelli, M., Carlomagno, C., Tonacchera, M., Zeppa, P., & Vitale, M. (2013). Genetic mutations in the treatment of anaplastic thyroid cancer: a systematic review. BMC Surgery, 13(S2). https://doi.org/10.1186/1471-2482-13-s2-s44
Professional, C. C. M. (n.d.). Thyroid. Cleveland Clinic. https://my.clevelandclinic.org/health/body/23188-thyroid
Professional, C. C. M. (n.d.-a). Anaplastic thyroid Cancer (ATC). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/23539-anaplastic-thyroid-cancer-atc
American Thyroid Association. (2020, June 8). Anaplastic thyroid Cancer | American Thyroid Association. https://www.thyroid.org/anaplastic-thyroid-cancer/
Rashid, M. R. A., Agarwal, A., Pradhan, R., George, N., Kumari, N., Mayilvaganan, S., Chand, G., Mishra, A., Agarwal, G., & Mishra, S. K. (2019). Genetic alterations in anaplastic thyroid carcinoma. Indian Journal of Endocrinology and Metabolism, 23(4), 480. https://doi.org/10.4103/ijem.ijem_321_19
Bhullar, K. S., Lagarón, N. O., McGowan, E., Parmar, I., Jha, A., Hubbard, B. P., & Rupasinghe, H. V. (2018). Kinase-targeted cancer therapies: progress, challenges and future directions. Molecular Cancer, 17(1). https://doi.org/10.1186/s12943-018-0804-2
Gao, X., Hong, C., Xie, Y., & Zeng, X. (2023). Immunotherapy or targeted therapy: What will be the future treatment for anaplastic thyroid carcinoma? Frontiers in Oncology, 13. https://doi.org/10.3389/fonc.2023.1103147
Ma, D., Ding, X., Zhang, C., & Shi, P. (2022). Combined targeted therapy and immunotherapy in anaplastic thyroid carcinoma with distant metastasis: A case report. World Journal of Clinical Cases, 10(12), 3849–3855. https://doi.org/10.12998/wjcc.v10.i12.3849