TGFβ

TGFβ in Chordoma

Evidence suggests that the TGFβ signaling pathway acts upstream of brachyury (of known importance in chordoma) and plays a role in bone and cartilage development.³ TGFβ’s relationship with brachyury and growing body of evidence suggesting that genes involved in cartilage development are important in the development of chordoma⁴  have called attention to the pathway as a possible therapeutic target. While abnormalities involving genes of the pathway have been identified in chordomas, but the importance of TGFβ signaling in chordoma and the consequences of its inhibition have not been extensively explored.

• Molecular Evidence
• Clinical Evidence

Molecular Evidence

Copy Number Variation

• Chromosomal Aberrations: Partial gains of chromosome 19, where the gene TGFB1 resides, have been observed in many chordoma tumor samples.^{5 6 7} Losses of chromosomal regions harboring TGFB receptors TGFBR1 and TGFBR2 (located on chromosomes 9 and 3, respectively) have also been reported.⁸
• Gene Copy Number Variation: Deletion of the TGFB1 locus (and relocation to chromosome 5q21) has been detected in 5/21 chordomas tested.⁹

Gene Expression

• TGF-β1 gene expression was found to be significantly higher in INI1-loss chordoma compared to INI1-positive chordoma.¹⁰
• TGF-β1 gene expression was measured in 57 frozen primary chordoma samples and TGF-β1 was higher in hard type skull base chordomas compared to soft type and higher in females compared to males. Multivariate Cox analysis showed that high TGF-β1 expression, conventional subtype, and hard tumor texture were all independent prognostic factors for tumor progression.¹¹
• Upregulation of miR-671-5p and miR-193a-5p have been observed in SMARCB1/INI1-immunonegative cases and are thought to downregulate TGF-β signaling in pediatric chordoma.¹⁰
• Downregulation of miR-16-5p has been observed in chordoma compared to nucleus pulposus samples. miR-16-5p is believed to have a tumor suppressive role and target Smad3, a critical component of the TGF-β signaling pathway. High Smad3 expression in chordoma was correlated with surrounding invasion.¹²

Protein Expression

TGFβ was detected in 2/3 chordoma samples tested.¹³ miRNAs known to target TGFB1 were found to be downregulated in 13 chordoma samples analyzed.¹⁴ In a more recent study, TGFβ was detected in 22/23 samples tested, and expression level was suggested to correlate with degree of bone invasion.¹⁵

Preclinical Evidence

In-vitro Efficacy

• Overexpression of miR-16-5p or Knockdown of Smad3: Independent overexpression of miR-16-5p or knockdown of Smad3 had similar effects in U-CH1 and U-CH2 cell lines. Each significantly suppressed cell migration and invasion and significantly upregulated the expression of E-cadherin and downregulated the expression of N-cadherin and vimentin. Overexpression of miR-16-5p was also shown to suppress cell proliferation in vitro.¹²

In-vivo Efficacy

• Overexpression of miR-16-5p: Overexpression of miR-16-5p in a U-CH1 xenograft model resulted in significantly decreased tumor volume compared to control suggesting that that miR-16-5p may act as a suppressor of chordoma proliferation.¹²
  

Clinical Evidence

 Phase I Trial

• M7824 (MSB0011359C): M7824 is a bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to a TGF-β “trap”. Treatment of a chordoma patient with 20mg/kg M7824 resulted in early progression and drug discontinuation on day 85 followed by late-onset tumor shrinkage observed on day 280 despite no further therapeutic interventions after discontinuing M7824.¹⁶