Precision medicine phosphoproteomics: Untamed avenues in sarcomas

Avani Dave, Jai Hind College

Sarcomas are a category of uncommon malignant tumours that develop in mesenchymal tissues such as bone, muscle, fat, blood vessels, lymphatic vessels, nerves, ligaments, and tendons. Sarcomas affect people of all ages, although they are more frequent in the pediatric, adolescent, and young adult (AYA) age groups. Between 2001 and 2010, an extensive review of 153 global cancer registries representing 62 countries revealed the significant disease burden that sarcomas represent, with soft tissue sarcomas (STS) accounting for approximately 20% of cancer diagnoses and bone tumours accounting for 14% of cancer diagnoses in patients aged 0 to 14 years.

Rapid advancements in genomic technology have allowed in-depth analysis of cancer genomes, finding novel and unexpected treatment targets in a variety of cancers. Finding actionable dependencies in the varied and heterogeneous group of sarcomas, especially those that affect children, adolescents, and young adults, is extremely difficult. There are few patients with actionable genetic abnormalities, no targeted medicines have been authorized, and results have remained dismal for decades. This emphasizes the need to improve our target identification approaches.

Phosphoproteomics studies in sarcoma have shown the ability of such analysis to identify novel actionable drivers that are not associated with mutations or gene amplification. In juvenile and AYA sarcoma patients, integrating phosphoproteomic molecular profiling with (functional) genomics technologies can dramatically extend therapeutic target discovery and pinpoint medication mechanisms of action. A study conducted by Fordham, A. M., et al. looks at how phosphoproteomics may be used in customized medicine and what the future holds.

Discussion: 

Phosphoproteomics technologies are particularly important for the study of pediatric sarcoma biology, not least because they have led to the discovery of novel driving and/or co-driving signatures in pediatric/AYA sarcomas, the majority of which are not linked to recognizable activating genomic events. They’ve also revealed important details about the mechanisms of action. 

This knowledge may be used to develop reasonable, molecularly directed medication combinations. Diverse activation patterns within and among pediatric/AYA sarcoma subtypes, especially for highly actionable tyrosine kinases, highlight the necessity of precision medicine platforms to record unique activation events rather than recurrent activation events.

The study further delineated the following:

• Patients with pediatric/AYA sarcoma face abysmal outcomes, and there are no specific therapies available.
• Patients with pediatric and AYA sarcomas seldom have identifiable genetic abnormalities.
• Phosphoproteomics identified unique responsive drivers that genomics screens had overlooked.
• Phosphoproteomics clarified important directed drug action/resistance mechanisms.
• The preclinical effectiveness of phosphoproteomics-guided treatments was impressive.
• Phosphoproteomics may improve outcomes in customized medicine systems.

The future prospects of the study:

According to the researchers, these findings imply that the goal is to use phosphoproteomics techniques more often in clinical trials as part of high throughput, “multi-omics” research strategy to gain a better knowledge of different cancers. The subsequent results add to the growing body of evidence that it’s critical to have a sufficient number of well-processed samples on hand. However, a small number of focused phosphoproteomics profiling studies on clinical sarcoma samples give some strong evidence of the value of applying phosphoproteomics to patient tumour specimens, opening the way for more widespread clinical use of phosphoproteomics methods. 

The researchers noted in their findings that such information might give extra useful context for evaluating patients’ health and may allow early screening for ASD and other neurodevelopmental disorders in individuals born preterm. However, exploratory research in this area is required to have a comprehensive understanding of the underlying mechanisms.

Also read: 28,000 years old preserved lion cub found in the Siberian cave

Reference: Fordham, A. M., Ekert, P. G., & Fleuren, E. D. G. (2021). Precision medicine and phosphoproteomics for the identification of novel targeted therapeutic avenues in sarcomas. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer, 188613. https://doi.org/10.1016/j.bbcan.2021.188613

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Author’s Info: Avani Dave is currently in the final year of her bachelor’s degree, majoring in Life Sciences. Holding a good academic and extra-curricular record, she is on a constant journey of acquiring exposure in her field of interest while simultaneously not limiting herself to just that. Avani likes studying Diseases and Syndromes and everything under this umbrella! That being said, she is adept at working across departments and promises to deliver.