Head and neck cancers (HNC) are traditionally associated with risk factors such as smoking, alcohol or HPV infection, but more than 50% of cases that occur locally have none of these risk factors. Genomics analyses suggest that the underlying mutations in these cancers without the classical risk factors differ from traditional tobacco-related cancers. Despite a multidisciplinary approach involving surgery, radiation and chemotherapy, more than 50% of patients fail treatment. In addition, there has been little progress in the rational use of conventional treatment modalities and in the use of targeted therapeutics. Indeed, therapeutic targeting requires appropriate patient stratification into disease and prognostic risk groups, as well as the maintenance of annotated databases and tissue samples and the use of state-of-the art technologies.
Other important areas of focus include the development of novel technologies to improve diagnostics and tumour imaging, and new approaches to cancer screening, prevention, and the assessment of post-surgical reconstruction outcomes. Collaborations with allied health professionals are essential to obtain good quality data on various aspects of post-treatment functional outcomes and quality of life assessments. The recent data purporting the benefits of immunotherapy in a selective patient cohort cannot be ignored and we thus require a major paradigm shift in our approach to biomarker discovery. To this end, profiling now extends to examining the tumour microenvironment as well as exploring the role of cell-based therapy in these lethal malignancies.
The overall aims of this programme are to:
HEAD AND NECK CANCER GENOMICS, RADIOMICS, AND IMMUNOMICS PROGRAMME (HNCGRI)
Precision radiotherapy has significantly improved cure rates for patients with nasopharyngeal cancers (NPC). However, despite radiotherapy treatment, 20% to 30% of cancers still recur locally. There is a need to identify patients with a high risk of recurrence and develop new therapies to improve cure rates. NPC, commonly known as “nose cancer”, occurs when cancer cells develop from the tissues in the nasopharynx—the area behind the nasal cavity and above the back of the throat. In Singapore, NPC is most frequently seen among Chinese patients.
The HNCGRI Programme aims to study pre- and post-radiotherapy recurrent NPC to identify the mutations that drive cancer development and cause cells to become resistant to radiation therapy. These mutations could serve as targets for testing new therapeutic agents. In this area of study, the NCCS programme has a strong collaboration with Sun Yat-Sen University Cancer Center in Guangzhou, China. Additionally, the group aims to explore the integration of large “–omics” datasets, including genomics, epigenomics, transcriptomics, and radiomics, to build robust models and personalise risk stratification and therapies in patients.
Some of these information will be added to a prognostic index (PRANCIS – http://PRANCIS.Medlever.com) that wasconstructed internally to help personalise risk stratification for salvage radiotherapy for radioresistant NPC patients. The tool was made publicly available in collaboration with MedLever (Mountain View, CA). The Programme also includes a platform for research on understanding the tumour and host immune response to conventional therapies (chemotherapy, radiotherapy and surgery) and novel biological therapies (monoclonal antibodies and immunotherapies). To this end, the NCCS is collaborating with a local start-up biotechnology company (ImmunoSCAPE) to explore high-dimensional mass cytometry profiling coupled with high-resolution single-cell sequencing to understand the complex interplay between tumour and its microenvironment with the systemic T-cell response (Figure 1).
NPC THERANOSTICS PROGRAMME
In our NPC Theranostics Programme, we aim to use imaging to assist clinicians in prognosticating and selecting patients for the most appropriate therapy and in the planning of radiotherapy. We are currently investigating a few novel radionuclide tracers in NPC, including 68Gallium-Dotatate, 177Lutetium-Dotatate, and 18F-Misonidazole. We have seen for the first time the presence of somatostatin receptor 2 on 68Gallium-dotatate imaging in patients with treatment-refractory metastatic NPC, who have seen multiple lines of treatment (Figure 2). This opens up a new treatment modality for these patients using 68Gallium-dotatate for radiotherapy planning, and to select patients for 177Lutetium-Dotatate therapy or its related analogues for therapy in patientswith NPC.
To date, the team’s achievements are as follows:
Figure 1. (Upper) The PRANCIS oneline tool. (Lower) Schema of the radiomics workflow (Left) and high-dimensional mass cytometry for deep immune profiling using 41 T cell- and myeloid-specific expression markers.
Figure 2. (Upper) Model of NPC Theranostics. (Lower) 68Gallium-Dotatate positron emission tomography (PET) in apatient with metastatic nasopharyngeal carcinoma (NPC). Gross Tumour Volume (GTV) target delineation using 68Gallium-Dotatate positron emission tomography (PET) vs 18F-Fludeoxyglucose PET.
Prof. Khee Chee Soo is actively involved in clinical and translation research across a range of different projects. He currently leads a multi-centre Phase III clinical trial in Asia, involving 11 countries and 22 centres, which examines the role of EGFR blockade using nimotuzumab in high-risk patients with head and neck squamous cell carcinoma. This trial aims to recruit over 700 patients across all sites. More importantly, this trial aims to establish a new Asia-centric oncology research platform for future phase III trials in head and neck oncology. Prof Soo is also the Lead PI of a National Research Foundationfunded competitive research programme (S$9.1million in funding, 2017–2022) – Radiobiology Investigations into Cancer Therapy using High Energy Protons. This multi-disciplinary programme encompasses eight research teams across NCCS, NUS, and Duke-NUS.
Assoc. Prof. N. Gopalakrishna Iyer leads the head and neck clinical research programme in the Division of Surgical Oncology and is the PI of the Cancer Therapeutics Research Laboratory. His clinical research includes the establishment and maintenance of a live, tumour board-based head and neck cancer database for all patients with HNSCC, which is actively mined for outcome analyses, prognostic factors, relationships with socio-economic factors, quality of life analyses, and various other allied health projects. The latter involves speech therapists and nurse clinicians who are focused on improving surgical and functional outcomes, patient’s rates of return to normal activity and work, and social support services. The clinical team is also involved in the development and advancement of state-of-the-art surgical techniques, including robotic surgery for thyroid, oropharyngeal and nasopharyngeal cancers.
Dr. Ngian Chye Tan and Dr. Hiang Khoon Tan are head and neck surgeons whose principal areas of research include the development of novel approaches in head and neck reconstruction, the management of complex wound care, and quality-of-life analyses in patients after major head and neck surgery. They also lead several technology-driven projects which are at various stages of development. They have successfully progressed prototypes into licensed products including novel lighting solutions for the oral cavity and low cost nasoendoscopy devices for developing countries.
Dr. Joseph Wee is a radiation oncologist and co-leads the clinical research programme for Nasopharyngeal Carcinoma (NPC). He was the PI of the seminal SQNP01 trial that defined chemoradiotherapyas the standard of care in NPC. He was also the Co-PI for a recently completed Phase III randomised controlled trial exploring the efficacy of induction chemotherapy when added to chemo-radiotherapy for advanced NPC. Dr. Wee is also deeply interested in the epidemiology of NPC and East and South Asian anthropology.
Dr. Melvin Lee Kiang Chua is a radiation oncologist and Clinician-Scientist, and leads the DISCLOSE (DIScovery ofbiomarkers for CLinical respOnSE to radiotherapy) Programme. Specifically, Dr. Chua leads several international collaborations within the HNCGRI programme on NPC. He also has a deep interest in understanding the molecular drivers and biomarkers of radiation and therapeutic resistance. Dr. Chua also co-leads the National Research Foundation-funded proton clinical research programme.
Dr. Wen Long Nei is a radiation oncologist with an interest in exploiting novel theranostics in NPC. He collaborates closely with the Department of Nuclear Medicine and Imaging, SGH.
Dr. Yoke Lim Soong and Dr. Kiattisa A/P Sommat are radiation oncologists and clinical investigators in the programme; Dr. Soong leads the clinical HN programme within the Division of Radiation Oncology, and is the site-PI for the ongoing NRG-sponsored HN001 trial for NPC. Dr. Sommat leads several clinical and imaging studies relating to the role of hypoxia imaging for adaptive radiotherapy planning in NPC and quality of life outcomes after radiotherapy in NPC.
Dr. Mei Kim Ang and Assoc. Prof. Eng Huat Tan are medical oncologists and clinical investigators who lead several HNC trials at the NCCS. Of note, Dr. Ang was the site investigator for the LUX-Head and Neck 1 trial on maintenance afatinib in HPV- and smoking-related HNCs. Assoc. Prof. Tan was the Co-PI for several of our randomised Phase III trials in NPC, and is currently the Co-PI for our local INH-01 randomised controlled trial on the role of concurrent nimotuzumab and chemo-radiotherapy as adjuvant treatment for high-risk HNCpost-surgery.
Assoc. Prof. Darren Wan-Teck Lim leads various important immunotherapy trials in NPC, particularly focused on potential biomarkers of response. He also has a research focus on the capture and analysis of circulating tumour cells to better understand tumour biology of metastatic states and treatment selection for patients.
Dr. Daniel Shao-Weng Tan (Individualised Molecular Profiling for Allocation to Clinical Therapeutics (IMPACT) is working with several pharmaceutical and biomarker analytic companies to bring individualised medicine and clinical therapeutics to patients. He also leads a number of critical window-ofopportunity studies in HNSCC, where obtaining longitudinal tissues pre- and post-immunotherapy could be analysed to identify early biomarkers of response to drugs. Dr. Tan co-leads the Cancer Therapeutics Research Laboratory.
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