Chordoma

Statistical analysis using Fisher's exact test revealed significant P-values for LC3A/B (P=0.048), AMBRA-1 (P=0.033), Ki-67 (P=0.048) and surgical treatment (P=0.048). Consequently, a negative prognostic role for these two ATGs may be hypothesized in the development of CHs.

We revised 2 initial AT/RT diagnoses as poorly differentiated chordoma based on the morphology, brachyury expression, topographical features, and methylation profile. Differentiating poorly differentiated chordoma from AT/RT could be challenging; brachyury expression can be useful in diagnosing poorly differentiated chordoma over AT/RT in suitable clinical and radiological settings.

Given the rarity of this diagnosis, molecular testing was performed which revealed a unique SMARCB1 molecular profile with a single-nucleotide variant in addition to the commonly reported loss of chromosome 22q. This report of an ultra-rare sarcoma in an uncommon anatomic site highlights multiple potential pitfalls in the diagnosis of poorly differentiated chordoma, emphasizes the importance of brachyury immunohistochemistry in rendering a correct interpretation, and underscores an opportunity for further molecular analysis to better define the molecular profile of this entity.

P2, N=19, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

The aim of this review is to summarize novel chordoma treatments in immune-targeted therapies. The current merits, trial outcomes, and toxicities of these novel immune and targeted therapies, including those targeting vascular endothelial growth factor receptor (VEGFR) targets and the epidermal growth factor receptor (EGFR), will be discussed.

Thorough clinical and radiological follow-up is mandatory as local recurrences are to be expected due to the infiltrative behavior. In case of a loco regional recurrence the fusion with FGFR2 may represent a therapeutic option for a targeted therapy on molecular level.

This study illustrates the dynamics between chordoma cells and TAMs in promoting chordoma invasion and suggests that IL-6/STAT3 pathway is a potential therapeutic target to reduce TAM-induced chordoma invasion.

The present case study helps in creating an awareness and attempts to expand our knowledge in relation to the spectrum of chordoma (clinico-histological) and its immunohistochemical profile.

P1/2, N=27, Not yet recruiting, University of Florida

P=N/A, N=60, Recruiting, Mayo Clinic | N=180 --> 60

P1/2, N=86, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2025 --> Jun 2026 | Trial primary completion date: Sep 2025 --> Jun 2026

P2, N=45, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Oct 2024 --> Jun 2025

Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.

Our initial findings distinguish recurrent chordomas from their primary counterparts based on cancer gene expression changes that encourage growth and proliferation, remodel the bone matrix environment, and evade the immune system. Continued investigation is needed to assemble a broader patient sample. Examining the pathways and genetic mutations across the chordoma disease progression may reveal novel therapeutic avenues for recurrent chordomas.

Clinically, a significant correlation of high IER2/ITGB1 expression with tumor aggressive phenotype and poor patient survival is observed. Collectively, the findings suggest that ERS-CAF regulates SPP1+ macrophage to aggravate chordoma progression via the IER2/GMFG/ITGB1 axis, which may be targeted therapeutically in future.

Among all the considered clinicopathological features related to patient survival, only tumor location in the sacrococcygeal region and adequate surgical margins positively impacted DFS. In conclusion, partial SMARCB1/INI1 loss, mostly due to 22q deletion, was detected in a significant number of patients with conventional spinal chordomas and was correlated with mobile spine location and inadequate surgical margins.

P=N/A, N=35, Recruiting, CNAO National Center of Oncological Hadrontherapy | Trial primary completion date: Feb 2024 --> Aug 2025 | Trial completion date: Apr 2025 --> Aug 2025

P2, N=15, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2024 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2026

After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96-96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77-105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.

Additionally, IL-7 modulated favorable subpopulations of cultured CAR-T cells, diminished immune checkpoint expression on T-cell surfaces, and enhanced T-cell functionality. The incorporation of IL-7 molecules into the B7-H3 CAR structure augmented CAR-T-cell function and improved CAR-T-cell efficacy, thus providing a novel dual therapeutic strategy for chordoma treatment.

P=N/A, N=35, Not yet recruiting, Hospices Civils de Lyon

P=N/A, N=40, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

P2, N=818, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2033 --> May 2026 | Trial primary completion date: May 2033 --> May 2026

P2, N=818, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> May 2033 | Trial primary completion date: May 2026 --> May 2033

In patients with a history of testicular mixed germ cell tumors, comparison of histomorphology using HE and Brachyury staining of lung and testicular tumors, and analyzing isochromosome 12p and 12p amplification in lung tumors using FISH is pivotal for the diagnosis of rare lung chordomas.

Most patients received immunotherapy targeting the PD-1/PD-L1 interaction, and two patients received therapy targeting this interaction along with the tyrosine kinase inhibitor pazopanib...Despite challenges in patient accrual, future directions in chordoma immunotherapy may lie in vaccine-based therapies and immune checkpoint inhibitors. Understanding chordoma heterogeneity and microenvironment will likely elucidate important chordoma features that will inform future clinical trial design.

P=N/A, N=40, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

To our knowledge, this is the first report of a chordoma with RICTOR amplification, which was co-amplified with FGF10 on chromosome 5p13. RICTOR amplification may represent a clinically significant alteration in chordoma and predict response to targeted therapy with RICTOR/mTORC2 inhibitors.

Currently, there are several CDK9 inhibitors in preclinical and clinical investigations. This review aims to highlight the recent discovery and results on the transcriptional role and therapeutic potential of CDK9 in sarcoma.

P1, N=21, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2024 --> Apr 2024

CDK7 and CDK9 inhibition was lately identified as being effective in reducing viability in four chordoma cell lines, most likely due to a reduction in brachyury levels. In this study, we determined the capability of the CDK7 inhibitor THZ1 and the CDK1/2/5/9 inhibitor dinaciclib to reduce TBXT expression at mRNA and protein levels in a broad range of nine cell lines that are models of primary, recurrent, and metastasised chordoma of the clivus and the sacrum.

P2, N=24, Completed, NantCell, Inc. | Unknown status --> Completed | N=55 --> 24

Similarly, potential immunotherapeutic targets on CSCs, including B7H6, MICA-B, ULBP1, EGFR, and HER2 are overexpressed across cell lines. Targeting these markers may have a preferential role in combating CSCs, an aggressive subpopulation likely consequential to chordoma's high recurrence rate.

No abstract available

We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

Then they discuss completed and ongoing clinical trials of MTTs, including several tyrosine kinase inhibitors used as monotherapy or in combination, such as imatinib, sorafenib, dasatinib, and lapatinib, among others, as well as mammalian target of rapamycin inhibitors such as everolimus and rapamycin. Additionally, they provide a brief overview of novel systemic strategies such as adoptive cell transfer (CAR-T and NK cells), oncolytic viruses, epigenetic targeting (KDM6, HDAC, and EZH2 inhibitors), and several promising preclinical studies with high translational potential. Finally, the authors present their institutional multidisciplinary protocol for the incorporation of systemic therapy for both newly diagnosed and recurrent chordomas based on molecular studies including upfront enrollment in MTT trials in patients with epidermal growth factor receptor upregulation or INI-1 deficiency or enrollment in ICI clinical trials for patients with high tumor mutational burden or high PD-L1 expression on tumor cells or in the tumor microenvironment.

These findings indicate that EP300 functions as an oncogene in chordoma. Targeting EP300 offers a novel approach to the development and clinical treatment of chordoma.

The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that of the adult cohort (p=0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (p<5.9e-07 and p<0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations appear important for chordoma genesis, especially in pediatric chordoma.

KIF15 promotes chordoma development and progression through the activation of the PI3K-AKT signalling pathway. Thus, targeting KIF15 might be a promising therapeutic strategy for treating chordomas.

P2, N=267, Completed, Epizyme, Inc. | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Feb 2024

In this study, the role of m6A-modified circTEAD1 in chordoma was identified. The findings offer novel insights into the potential molecular targets for chordoma therapy, shedding light on the intricate interplay between circRNAs, m6A modification and Yap1 mRNA in chordoma pathogenesis.

In chordoma, we propose that in addition to conventional bone resorption by osteoclasts, chordoma cells possess bone-dissolving activity at the tumor-bone boundary. Furthermore, bone destruction and tumor expansion may occur in a positive feedback loop.