Biomarkers of Treatment Response in Sarcoma

In the evolving landscape of modern medicine, biomarkers are at the forefront of clinical research. Biomarkers can serve as objective measures of treatment response, guiding patients towards the most suitable therapies and reducing the risk of unnecessary and potentially harmful treatments.

However, there are numerous challenges associated with biomarker development, including rigorous validation, extensive testing, time, resources, and investment. Additionally, disease heterogeneity is problematic, particularly for rare diseases where low prevalence limits comprehensive clinical studies.

The development of biomarkers is a complex process requiring different levels of analytical and clinical validation. Causaly can streamline this process by accelerating the identification and prioritization of biomarkers. In this context, we focus on biomarkers of doxorubicin treatment response in soft tissue sarcomas.

Soft tissue sarcomas are rare cancers of the connective tissue which can develop anywhere in the body. Around 13,000 cases of soft tissue sarcomas are diagnosed in the United States each year.¹

As with many cancers, incidence increases with age. Approximately 40% of soft tissue sarcomas are diagnosed in patients aged 65 and over.² Genetic mutations present further risk factors. For example, patients with Li-Fraumeni syndrome, are more likely to suffer from sarcomas.³

The diverse and rare nature of sarcoma subtypes complicates clinical trials and the development of targeted therapies. This highlights the need for identifying biomarkers of treatment response in sarcoma research. Such biomarkers can enhance the precision and efficacy of therapies, paving the way for personalized treatment strategies. Here, we use Causaly to identify biomarkers of treatment response in soft tissue sarcomas.

Around 80 biomarkers for treatment response in soft tissue sarcoma have been reported, according to Causaly. By refining biomarkers by the amount of evidence, it was revealed that tumor suppressor protein (p53) and programmed death-ligand 1 (PD-L1) had the most supporting evidence.

P53 is a tumor suppressor protein that regulates DNA repair and cell division. Genetic abnormalities in p53 play a significant role in the progression of various types of sarcomas, including leiomyosarcoma, liposarcoma, and angiosarcoma.⁴ Researchers continue to uncover other gene mutations associated with sarcomas, such as a novel PHF20-NTRK1 fusion seen in recurrent pulmonary sarcomatoid carcinoma.⁵

PD-L1 is a cell surface receptor protein, encoded by the CD274 gene, which suppresses the action of immune system T cells, thereby enabling tumor progression. PD-L1 is overexpressed in multiple cancers and has been associated with poor clinical outcomes.⁶ PD-L1 expression in sarcomas is highly variable and depends on the type of sarcoma.⁷ Recent studies have nevertheless shown that patients with advanced soft tissue sarcomas whose tumors express PD-L1 are less likely to respond to pazopanib,⁷ which works by blocking tumor blood vessel growth.

Very few biomarkers for doxorubicin treatment response in the context of soft tissue have been reported, according to Causaly. The overexpression of ubiquitin ligase MDM2 (Murine Double Minute 2) – which regulates p53 – has long been associated with chemotherapeutic resistance to doxorubicin.⁸ In soft tissue sarcomas, in vivo studies in dedifferentiated liposarcomas cell lines treated with doxorubicin followed by an MDM2 inhibitor have shown to improve sensitivity to chemotherapy.⁹

Additionally, recent findings have linked MDM2 dysregulation in a pulmonary sarcomatoid carcinoma patient to poor therapeutic response.¹⁰ However, this study was based on a single case treated with a combination of doxorubicin, ifosfamide and pemetrexed. Therefore, larger scale research to evaluate the potential of MDM2 as a predictive biomarker for treatment response in sarcoma is required.

Identifying robust biomarkers is essential for effective care in sarcomas, which are often resistant to traditional therapies. Effective biomarkers play a vital role in identifying potential treatments used in other conditions that could benefit some sarcoma patients. They also guide treatment strategies and streamline drug development by enabling the selection of the most suitable drug candidates for clinical trials. This approach allows researchers to enroll patients who are more likely to respond positively to the treatment, leading to improved patient outcomes and reduced study size, duration, and associated costs.

To find out more about the identification of treatment response biomarkers in soft tissue and bone sarcoma, download our Biomarker Discovery Spotlight report.