The number of cancer cases in Singapore will rise by 2.5 times over the next 20 years due to an aging population, and around 50% of all cancer patients will require radiotherapy. Precise targeting by radiotherapy is thus crucial to maximise the therapeutic ratio of this integral treatment modality. The NCCS has therefore incorporated a Proton Beam Therapy (PBT) clinical programme in its new Centre, along with a comprehensive translational research framework to understand the physical and biological advantages of PBT in the lead up to its clinical implementation.
The clinical use of PBT is motivated primarily by its inverted, depth-dose profile as compared with the use of photons, and is uniquely characterised by the Bragg peak (Figure 1, right graph). PBT is thus able to offer a physical dosimetric advantage over the use of photons by avoiding unnecessary irradiation of the adjacent normal tissues. Compared with photons, PBT also causes enhanced cell killing due to the increased Linear Energy Transfer (LET) when proton particles approach the Bragg peak. High LET values are indicative of localised energy deposition, resulting in the induction of enhanced, irreparable biological damage. The increased effectiveness of protons compared to photons may be quantified by Relative Biological Effectiveness (RBE), which is scored as 1.1 in favour of PBT. However, despite the evidence from in vitro studies modelling the 1.1-fold increased efficacy of PBT over photon X-irradiation, the mechanisms underpinning the increased tissue responses are unclear.
On this note, we have thus assembled a multidisciplinary research team to conduct research from bench to bedside, encompassing fundamental research in cancer cells, translational research using animal models of cancers, and clinical research in PBT-treated cancer patients. Our programme is led by two clinician-scientists: Prof. Khee Chee Soo, NCCS Director (1997-2017) and a Principal Investigator at the Division of Medical Sciences (DMS), NCCS and Dr. Melvin Lee Kiang Chua at the Division of Radiation Oncology (DRO), NCCS. The programme encompasses eight research teams across institutes and universities that are specialised in physics, cancer molecular and stem cell biology, cancer genomics and epigenomics, pharmacology, radioresistance, in vivo tumour models for N = 1 novel radiosensitiser drug trials, and radiotherapy technological innovation. The members and scope of their work are as outlined (Figure 2).
Figure 1. Inverted dose distribution of the proton beam offers a reduced radiation dose to the tissue in the beam path in front of and behind the tumour (Bragg peak drop off; right) as compared with conventional X-ray photon beam (left).
Figure 2. Team leaders and their respective projects are depicted, highlighting our collaborative multidisciplinary approach to investigating physical, chemical, biological and clinical effects of proton beam therapy in comparison with traditional photon-based radiotherapy.
Theme 1 is led by Prof. Andrew Anthony Bettoil, at the Centre of Ion Beam Applications (CIBA), Physics Department, National University of Singapore (NUS), who works on experimental microbeam radiobiology as well as the construction of the proton beam line for cancer cell irradiation.
Theme 2 is led by Prof. Thomas Osipowicz at CIBA, Physics Department, NUS, who will explore computational simulations of proton beam track and its induced DNA damage.
Theme 3 is led by Prof. Bin Tean Teh at DMS, NCCS, who focuses on integrative profiling of genetic and epigenetic landscapes following cellular exposure to PBT.
Theme 4 is led by Prof. Kanaga Sabapathy at the Division of Cellular and Molecular Research (CMR), NCCS, who aims to investigate differential cancer cell signalling pathways that are induced by PBT and photon irradiation.
Theme 5 is led by Dr. Edward Kai-Hua Chow at the Cancer Science Institute, NUS, who will investigate the molecular mechanisms underpinning cancer stem cells radioresistance.
Theme 6 is led by Prof. Khee Chee Soo and Dr. Melvin Chua with the help from Prof. Giorgia Pastorin at the Pharmacy Department, NUS. Together, the group aims to develop novel nanoparticle compounds as radiosensitisers for PBT.
Theme 7 is led by Prof. The Hung Huynh at CMR, NCCS with the support from Dr. Ann-Marie Chacko at Cancer and Stem Cell Biology Program, Duke-NUS Medical School. This team will use photon and proton irradiation to treat patient-derived xenograft mouse models of hepatocellular carcinoma (HCC), and couple the in vivo experiments with real-time imaging of molecular processes in situ.
Theme 8 is led by Dr. Francis Kuok-Choon Chin and Dr. Jeffrey Kit-Loong Tuan at DRO, NCCS, who aim to develop a cancer registry to track patient demographics, treatment planning parameters, tumour responses, and survival outcomes, including quality of life and health-economic metrics. In recognition of this multidisciplinary approach, the Team was awarded a National-level Competitive Research Programme (CRP) Grant award by the Singapore National Research Foundation, with a funding quantum of SGD 9.13 million for 5 years from June 2017 to May 2022.
Some of the group’s notable achievements in the past year include: 1) Constructing a first-in-kind, single-cell and broad-beam proton irradiation facility in Singapore, located at CIBA, NUS. Our newly constructed facility can carry out live-cell proton targeting and imaging with cellular and sub-cellular resolution. 2) We have successfully developed radioresistant HCC tumour models, as well as immuno-competent syngeneic tumour models. 3) We have gained a preliminary understanding of DNA damage response in several cancer cell lines, including cancer stem cells.
In addition, as part of the CRP, we aim to foster close research collaborations with several academic institutes around the world, including the Chang Gung Memorial Hospital, Taipei; the Manchester Cancer Research Centre, UK; and The OncoRay Centre for Radiation Research in Oncology, Dresden, Germany. Each collaboration will be aligned with the respective Themes. We hope to leverage on the knowledge gained from this work to formulate a strong academic PBT programme that will coincide with the new NCCS building expected in 2021.
YOUNG INVESTIGATORDr. Melvin Chua is a Clinician-Scientist, and Principal Investigator of the Translational Radiation Oncology Research Group, Division of Radiation Oncology, with a track record of more than SGD 10,000,000 of competitive grant funding (as primary and joint applicant) since 2014. In addition, he has previous work experience in a large-scale cancer genomics programme, the Canadian Prostate Cancer Gene Network (CPC-GENE), which was the lead site for the International Cancer Genomics Consortium for prostate cancer. His research is focused on precision medicine using prognostic and predictive biomarkers, and experimental therapeutics in the management of prostate and nasopharynx cancers. In particular, his group is interested in using modern “omics” approaches to interrogate the molecular underpinnings of radioresistance of these tumours, and layering these datasetswith validated prognostic clinical tools developed by the group (www.PRANCIS.Medlever.com) to improve clinical risk stratification and precision treatment of patients. To date, his group has profiled >500 men in this and other molecular epidemiology studies.
Dr. Chua is also currently involved in an NRF-funded, 5-year clinical research programme (as the co-Principal Investigator) to investigate novel mechanisms of Proton Beam Therapy (PBT) targeting of tumours. The programme themes encompass characterising exclusive genomic and epigenomic alterations induced by PBT; deciphering differential immune responses between PBT and conventional photon irradiation; testing novel drug and nanoparticle conjugate combinations with PBT; and developing novel imaging tools to survey for treatment responses. Overall, the synergy among the projects contributes to the ultimate clinical goal: comprehensive patient profiling for precise risk stratification for modern PBT.
Dr. Chua’s laboratory is competent in most molecular biology techniques, including western blot, multi-gating flow cytometry, cell sorting, immunochemistry, cytogenetics, confocal microscopy, developing animal tumour models for novel drug testing, among others. His laboratory also collaborates with multiple academic and industrial partners on nextgeneration sequencing platforms (SYSUCC – Guangzhou, OICR– Toronto, etc.) and immune profiling (immunoSCAPE) using mass cytometry; developing and testing novel nanoparticle compounds for the sensitisation of cancer treatments (NUS, Singapore); and in building public cloud-based data resources comprising matched clinico-genomics datasets.
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