IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers.
Hesham M AminAjaykumar C MoraniNajat C DawSalah-Eddine Lamhamedi-CherradiVivek SubbiahBrian A MenegazDeeksha VishwamitraGhazaleh EskandariBhawana GeorgeRobert S BenjaminShreyaskumar PatelJuhee SongAlexander J LazarWei-Lien WangRazelle KurzrockAlberto PappoPeter Meade AndersonGary K SchwartzDejka AraujoBranko CuglievanRavin RatanDavid C McCallSana MohiuddinJonathan A LivingstonEric R MolinaAung NaingJoseph A LudwigPublished in: Cancers (2020)
Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. Methods: We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/- mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. Conclusion: Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients.
Keyphrases
- pi k akt
- binding protein
- growth hormone
- pet ct
- systematic review
- cell proliferation
- signaling pathway
- end stage renal disease
- randomized controlled trial
- cancer therapy
- bone marrow
- chronic kidney disease
- stem cells
- free survival
- positron emission tomography
- mesenchymal stem cells
- drug delivery
- peritoneal dialysis
- photodynamic therapy
- cross sectional
- data analysis
- prognostic factors
- current status
- replacement therapy
- squamous cell