Anaplastic Thyroid Cancer (ATC) is a rare yet highly aggressive subtype of thyroid carcinoma, distinguished by its undifferentiated nature and rapid progression. Protheragen is committed to combating this devastating disease by offering comprehensive preclinical development services that encompass both diagnostics and therapeutics.
Overview of Anaplastic Thyroid Cancer (ATC)
Anaplastic Thyroid Cancer (ATC) is an uncommon yet extremely aggressive thyroid malignancy, marked by rapid onset, extensive local invasion, and early distant metastasis. This disease predominantly impacts older individuals, with the vast majority of cases diagnosed in patients over the age of 60. ATC is particularly notorious for its grim prognosis; the median overall survival (OS) typically ranges from just 4 to 10 months following diagnosis. Although rare, ATC is one of the most lethal forms of thyroid cancer due to its swift progression and resistance to conventional therapies.
Fig.1 Molecular and therapeutic landscape of anaplastic thyroid cancer (ATC). (Jannin A.,
et al., 2022)
Pathogenesis of Anaplastic Thyroid Cancer (ATC)
The development of Anaplastic Thyroid Cancer (ATC) is driven by a complex interplay of genetic and molecular alterations. It is frequently viewed as a transformation from differentiated thyroid cancer (DTC) to an undifferentiated state. Common molecular alterations in ATC include mutations in the TERT promoter, TP53, BRAF, RAS, PIK3CA, EIF1AX, and PTEN genes. These mutations collectively drive tumor progression and contribute to the aggressive behavior of ATC. For example, the TERT promoter mutation is detected in up to 75% of ATC cases, while TP53 mutations are identified in approximately 63% of cases. Additionally, the presence of tumor-associated macrophages (TAMs) in the tumor microenvironment plays a significant role in promoting tumor growth and therapeutic resistance. These macrophages can account for up to 70% of the total tumor mass and contribute to an immunosuppressive environment.
Diagnostics Development for Anaplastic Thyroid Cancer (ATC)
Molecular Diagnostics
Molecular diagnostics play a critical role in the early detection and characterization of ATC. Next-generation sequencing (NGS) technologies enable the identification of specific genetic alterations, such as BRAF V600E mutations, which are present in approximately 40-45% of ATC cases. These mutations not only aid in diagnosis but also guide targeted therapy selection. For instance, the combination of dabrafenib and trametinib has shown significant efficacy in BRAF V600E-mutated ATC cases.
Histopathological Examination
Histopathological evaluation is essential for confirming the diagnosis of ATC. Pathologists examine biopsy samples under a microscope to identify the characteristic undifferentiated cells. Immunohistochemical markers such as thyroglobulin, TTF1, cytokeratins AE1/AE3, and PAX8 are used to support the diagnosis. For instance, PAX8 immunohistochemistry is often positive in thyroid tumors, helping differentiate ATC from other malignancies.
Therapeutics Development for Anaplastic Thyroid Cancer (ATC)
- Targeted Therapies
Targeted therapies are designed to exploit specific genetic alterations in ATC. For instance, the combination of dabrafenib and trametinib has shown promise in patients with BRAF V600E mutations. This combination has led to improved overall survival and response rates in clinical trials.
- Immunotherapies
Immunotherapies, particularly immune checkpoint inhibitors, have demonstrated encouraging results in ATC. For example, the anti-PD-1 antibody spartalizumab has shown a response rate of 19% in ATC cases, with a median overall survival of 5.9 months. These therapies aim to enhance the immune system's ability to recognize and attack cancer cells.
- Chemotherapies
Chemotherapies such as doxorubicin, paclitaxel, and cisplatin are commonly used in the therapeutics of ATC. These agents have shown some efficacy in controlling tumor growth and improving survival rates. For example, a combination of doxorubicin and cisplatin has been used in various regimens with reported median overall survival rates ranging from 6 to 12 months.
Table 1. Ongoing clinical trials in anaplastic thyroid cancer (ATC). (Jannin A., et al., 2022)
| Clinical Trials Gov. Identifier |
Therapeutics/Interventions (Settings) |
Phase |
Status |
| NCT03565536 |
Sorafenib (Neoadjuvant therapeutic of ATC) |
Phase 2 |
Unknown |
| NCT02688608 |
Pembrolizumab (Advanced ATC) |
Phase 2 |
Unknown |
| NCT02244463 |
MLN0128 (Advanced ATC) |
Phase 2 |
Active, not recruiting |
| NCT04739566 |
Dabrafenib + Trametinib (Neoadjuvant Strategy in ATC with BRAF mutation) |
Phase 2 |
Recruiting |
| NCT01236547 |
IMRT + Paclitaxel with or without Pazopanib Hydrochloride (Advanced ATC) |
Phase 2 |
Active, not recruiting |
| NCT02152137 |
Efatutazone + Paclitaxel (Advanced ATC) |
Phase 2 |
Active, not recruiting |
| NCT04552769 |
Abemaciclib (CDK4 + CDK6 inhibitor) (Advanced ATC) |
Phase 2 |
Recruiting |
| NCT04675710 |
Pembrolizumab + Dabrafenib + Trametinib (Neoadjuvant BRAF-Mutated ATC) |
Phase 2 |
Recruiting |
| NCT04238624 |
Cemiplimab + Dabrafenib + Trametinib (Advanced ATC) |
Phase 2 |
Recruiting |
| NCT03449108 |
LN-145/LN-145-S1 (Autologous Centrally Manufactured Tumor Infiltrating Lymphocytes) (Advanced ATC) |
Phase 2 |
Recruiting |
| NCT03181100 |
Cohort I (BRAF mutation): Vemurafenib + Cobimetinib + Atezolizumab. |
Phase 2 |
Recruiting |
| Cohort II (RAS, NF1 or NF2 mutations): Cobimetinib + Atezolizumab |
| Cohort III (non-BRAF or RAS mutation): Bevacizumab + Atezolizumab |
| Cohort IV: Nab-paclitaxel + Atezolizumab |
| NCT03246958 |
Nivolumab + Ipilimumab (Advanced ATC) |
Phase 2 |
Active non-recruiting |
| NCT04400474 |
Cabozantinib + Atezolizumab (Advanced ATC) |
Phase 2 |
Recruiting |
| NCT04759911 |
Selpercatinib (Neoadjuvant ATC with RET alterations) |
Phase 2 |
Recruiting |
| NCT04579757 |
Surufatinib + Tislelizumab (Advanced ATC) |
Phase 1/2 |
Recruiting |
| NCT05102292 |
HLX208 (Advanced ATC with BRAFV600 mutation) |
Phase 1b/2 |
Recruiting |
| NCT03122496 |
Durvalumab + Tremelimumab + Stereotactic Body Radiotherapy (Advanced ATC) |
Phase 1 |
Active, not recruiting |
| NCT04420754 |
AIC100 Chimeric Antigen Receptor T-cells (Relapsed/Refractory Thyroid Cancer) |
Phase 1 |
Recruiting |
| NCT03975231 |
Dabrafenib + Trametinib + IMRT in (Advanced BRAF Mutated ATC) |
Phase 1 |
Recruiting |
| NCT04592484 |
CDK-002 (exoSTING) (Advanced/Metastatic, Recurrent, Injectable ATC) |
Phase 1 |
Recruiting |
| NCT03085056 |
Trametinib + Paclitaxel (Advanced ATC) |
Early Phase 1 |
Recruiting |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen's customized services are designed to provide tailored solutions for each client. We offer a range of diagnostic and therapeutic options, including targeted therapies, immunotherapies, and chemotherapies. Our team works closely with clients to develop customized therapeutic plans that address the unique characteristics of their condition.
Disease Models
- RET/PTC1 +;Trp53 −/− Models
- Kras G12D;Trp53 −/−− Models
- Thrb PV/PV; Kras G12D Models
- Braf CA/+;Trp53 R270H/+ Models
- Braf CA/+;Pik3ca Lat/+ Models
- Pten −/−;Trp53 −/−Models
- Thrb PV/PV;Pten +/− Models
Protheragen is committed to advancing the field of ATC diagnostics and therapeutics through our comprehensive preclinical development services. By leveraging cutting-edge technologies and a team of experts, we strive to accelerate the discovery and development of novel therapeutics for this devastating disease. If you are interested in our services, please feel free to contact us.
Reference
- Jannin, Arnaud, et al. "Anaplastic thyroid carcinoma: an update." Cancers 14.4 (2022): 1061.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
