Singapore study supports use of a personalised medicine in treatment of soft tissue sarcomas

Researchers from the Agency for Science, Technology and Research (A*STAR), National Cancer Centre Singapore (NCCS) and National University of Singapore (NUS), in collaboration with biotech company, KYAN Technologies, have shown a precision medicine approach improves the selection of treatments for patients with soft tissue sarcomas (STS) in the clinic.

STS are rare, heterogeneous tumours making up fewer than 1% of all cancers annually around the world but disproportionately represent a significant portion – 20% -- of malignancies in paediatric and young adult patients.

Treating STS with conventional chemotherapy often results in unpredictable and poor outcomes. These tumours have a wide range of biological diversity and are rare which makes it difficult to conduct large-scale clinical trials. Researchers have theorised that the best way to approach STS would be with precision medicine, by analysing the characteristics of each patient's tumour in an effort to improve response rates and reduce toxicities.

The team used a Quadratic Phenotypic Optimisation Platform (QPOP) in its application of precision medicine approaches to treat STS. QPOP is a data-driven, phenotypic screening system which identifies optimal cancer treatment combinations from a panel of approved drugs and investigational treatments, in a turnaround time of seven days.

The team analysed whether QPOP was clinically accurate in predicting drug sensitivity by screening the tumour samples of 45 primary STS patients. Results of more than 70% of patient responses to standard of care treatments matched with results from ex vivo testing in QPOP, validated the platform’s accuracy and reliability.

The researchers further identified unconventional personalised drug combinations through QPOP for a subset of STS patients unresponsive to standard treatments. These targeted approaches were used to select treatments for two patients who had compelling clinical responses. This application underscores the potential of functional precision medicine to identify alternative treatment strategies for complex and treatment-resistant STS.

And finally the team also explored the use of QPOP to identify new treatment combinations for STS, thereby discovering that the combination of AZD5153 (a BRD4 inhibitor) and pazopanib (a multi-kinase blocker) is more effective than standard treatment across multiple STS subtypes. This was further validated in the lab in patient-derived cell lines and in vivo models. The combination therapy effectively repressed MYC, a well-known oncogene that is difficult to target, and other related pathways that play critical roles in STS and various other cancers.

The study was led by Assistant Professor Valerie Yang, Visiting Consultant in the Division of Medical Oncology at the National Cancer Centre Singapore (NCCS) and Joint Research Clinician and Group Leader at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB), with co-corresponding authors from NUS, Dr Tan Boon Toh and Dr Edward Kai-Hua Chow, with bioinformatics expertise contributed by Dr Xing Yi Woo of A*STAR Bioinformatics Institute.

“This work is game-changing for several reasons. We show that ex vivo drug testing of patient-derived cells in these rare cancers can not only accurately predict patient responses to drugs but can also provide important information to derive good disease control in selected cases in patients who have exhausted all treatment options.

“What is also exciting is the novel drug combination that was identified may supersede existing treatment for soft tissue sarcomas,” said Asst Prof Yang.

“This study marks a pivotal step toward transforming how we treat rare and aggressive cancers like soft tissue sarcomas.

“By leveraging QPOP to match patients with optimised drug combinations based on their tumour biology, we move closer to realising the promise of functional precision medicine — offering real hope for better outcomes where conventional therapies have fallen short,” said Dr Toh, Head of the Translational Core Laboratory at the N.1 Institute for Health at NUS and Senior Research Fellow at the Institute for Digital Medicine (WisDM) at the NUS Yong Loo Lin School of Medicine.

Further clinical trials are needed to confirm these results and to explore the broader applicability of QPOP in other cancer types. The team are currently planning to run a prospective clinical trial in Singapore.