Chordoma is a rare type of bone cancer that develops from the remains of the notochord, a structure that exists during the early stages of development. At Protheragen, we offer in-depth research services to speed up the creation of diagnostics and therapeutics for chordoma. Our capabilities cover the complete preclinical pipeline, starting from target validation and including all the way to drug screening.
Overview of Chordoma
Chordoma is an uncommon, low-grade malignant tumor that arises from the remnants of the notochord, most commonly found around the cranial base, mobile spine, and in the sacrum region. Though the growth of chordoma is slow, it is marked by a propensity for local recurrence and invasion of adjacent neurovascular structures, leading to considerable morbidity and mortality. The approximate incidence of chordoma is 0.08 per 100,000, with males more commonly affected, and a peak age of 50 to 60 years. Due to its indolent growth, chordoma is often discovered in the form of a substantial tumor mass, which further complicates therapeutics.
Fig.1 Diagram showing some of the molecular pathways implicated in chordoma pathophysiology. (Barber S. M.,
et al., 2021)
Pathogenesis of Chordoma
The pathogenesis of chordoma is multifactorial, involving genetic and molecular alterations that drive tumor development and progression. Key molecular pathways implicated in chordoma include:
- Brachyury Overexpression: Brachyury, a transcription factor necessary for notochord development, is known to be overexpressed in all cases of chordomas. This overexpression is believed to contribute to the development of chordoma, supported by studies that show that suppressing brachyury expression can reduce the growth of chordoma cells.
- Receptor Tyrosine Kinases (RTKs): In chordomas, PDGFR, EGFR, and c-Met RTKs are often overexpressed. These receptors activate signaling cascades associated with cellular growth and apoptosis evasion.
- PI3K/Akt/mTOR Pathway: This pathway, as relates to RTKs, is frequently hyperactive in chordomas and, as a result, drives malignancy.
- FGF/MEK/ERK Pathway: This signaling cascade facilitates brachyury expression and signaling, thereby brachyury pathologizing it further brachyury implying its involvement in the pathogenesis of chordoma.
Diagnostics Development for Chordoma
- Imaging Techniques
Modern imaging techniques are foundational in the detection and therapeutics of chordoma. Technologies like Magnetic resonance imaging and computed tomography are important in visualizing the tumor and understanding its characteristics both qualitatively and quantitatively. MRI, especially, gives details of the tumor, including its size, location, and its relationship with nearby structures.
- Molecular Markers
Molecular diagnostics pertain to the detection of specific genetic and protein markers that are characteristic of chordoma. For example, immunohistochemistry enables the detection of the markers brachyury, S100 protein, pan-keratin, and EMA. In addition to these, some genomic studies have noted the presence of chromosomal alterations, particularly the loss of 1p36 and 9p, which are associated with more aggressive behavior.
Therapeutics Development for Chordoma
Targeted Therapies
Targeted therapies focus on inhibiting specific molecular pathways that are overactive in chordoma. Examples include:
- Imatinib: A PDGFR inhibitor that has shown efficacy in PDGFR-positive chordomas.
- Erlotinib: An EGFR inhibitor that has demonstrated some clinical benefit in small studies.
- Palbociclib: A CDK4/6 inhibitor that has shown promise in preclinical studies and early clinical trials.
Immunotherapies
- Immunotherapies aim to enhance the immune system's ability to recognize and attack chordoma cells. Examples include:
- Monoclonal Antibodies: Anti-PD-1 antibodies such as nivolumab and pembrolizumab are being explored for their potential to enhance antitumor immune responses.
- Vaccines: Brachyury-targeting vaccines, such as GI-6301 and MVA poxviral vaccines, are under investigation for their ability to induce specific immune responses against chordoma cells.
Table 1. Therapeutics of Chordoma. (Chen S., et al., 2023)
| Therapeutics |
Subcategory |
Primary Outcome Measures |
Phase |
| α-PD-1 mAb |
1. FAZ053
2. Atezolizumab
3. Nivolumab
4. Pembrolizumab |
1. Assess whether α-tumor activity increases when combined with PDR001 (α-PD-1 mAb)
2. Assess efficacy when combined with Tiragolumab (α-TIGIT mAb)
3. Determine PFS, ORR, MTD, DLT, and safety when administered in combination with other drug and radiation therapies
4. Evaluate therapy response and ORR for unresectable metastatic CH |
Phase I
Phase I + II
Phase II |
| α-EGFR mAb |
Cetuximab |
Assess efficacy by measuring ORR |
Phase II |
| TKIs |
1. Nilotinib
2. Lapatinib
3. Afatinib
4. Imatinib
5. Sorafenib, Regorafenib |
1. Assess synergistic effect of concurrent RT via measuring DLT and above MTD
2. Assess efficacy (EGFR-expressing and HER2Neu+ advanced CH via ORR)
3. Assess efficacy (EGFR- and/or HER2- expressing CH via PFS and ORR)
4. Assess efficacy (in combination with RAD001 (cell cycle inhibitor) on PDGFRβ+ CH
5. Assess α-tumor activity and its effect on PDGFRβ+ CH |
Phase I
Phase II |
| EZH2 inhibitors |
Tazemetostat |
Assess safety and tolerability with monotherapy vs. combination with Nivolumab & Ipilimumab
Evaluate efficacy in EZH2 GOF mutation and INI1-negative tumors |
Phase I
Phase II |
| CDK inhibitors |
Palbociclib |
Assess efficacy (LA or metastatic CH via DCR and PFS) |
Phase II |
| KB-0742 |
Assess safety and tolerability of relapsed or refractory CH via AE, MTD, and RP2D |
Phase I |
| Brachyury vaccines |
BN-Brachyury |
Assess vaccine radiographic ORR in CH in combination with radiation therapy |
Phase II |
| TAEK-VAC-HerB |
Assess DLT & vaccine interaction with therapeutic HER2 antibodies |
Phase I |
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 offers comprehensive services for the development of diagnostics and therapeutics for chordoma. Our services include advanced imaging techniques, molecular diagnostics, and the development of targeted therapies and immunotherapies. We provide state-of-the-art facilities and expertise to support preclinical research and the development of innovative therapeutics for this challenging disease.
Protheragen's advantage lies in our ability to provide comprehensive, high-quality services that are tailored to meet the specific needs of our clients. Our commitment to scientific excellence, combined with our state-of-the-art facilities and experienced team, ensures that our clients receive the highest level of support. Whether you are developing a new diagnostic tool or exploring innovative therapeutic strategies, Protheragen is your partner of choice for chordoma research and development. If you are interested in our services, please feel free to contact us.
References
- Barber, Sean M., et al. "Chordoma—current understanding and modern treatment paradigms." Journal of clinical medicine 10.5 (2021): 1054.
- Chen, Sonja, et al. "Chordoma: a comprehensive systematic review of clinical trials." Cancers 15.24 (2023): 5800.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
