Recommended
More Related Content
Similar to 02-pre-CDR-Radiobiology-Motivation-March-2020.pptx
Similar to 02-pre-CDR-Radiobiology-Motivation-March-2020.pptx (20)
More from Nishant835443
More from Nishant835443 (10)
Recently uploaded
Recently uploaded (20)
02-pre-CDR-Radiobiology-Motivation-March-2020.pptx
- 1. Radiobiological motivation for LhARA Dr Jason Parsons Cancer Research Centre Department of Molecular and Clinical Cancer Medicine
- 2. Radiotherapy in cancer treatment • ~50 % of all cancer patients will receive radiotherapy. • Conventional (photon) radiotherapy is the still the most effective treatment for solid tumours (e.g. head and neck). • Dose rates of ~1-5 Gy/min utilised. • Significant irradiation of normal tissues and organs at risk in proximity to the tumour being treated. • Biological factors including oxygen (hypoxia) and inherent radioresistance of tumours (e.g. glioblastoma) are a barrier to effective treatment.
- 3. Particle beam therapy (PBT) • In contrast to conventional (x-ray) radiation, PBT can deliver energy within a finite region (termed the Bragg peak) which can directly target cancer cells. • This limits radiation dose to proximal normal, healthy tissues and organs at risk. Depth in tissue Relative dose Distal fall-off Tumour Particle energy LET Bragg peak • Currently, ~90 PBT centres worldwide and 40 in construction demonstrating the importance of this precision radiotherapy. Vitti and Parsons (2019) Cancers
- 4. Eye Proton Therapy Centre and Radiobiology Research Facilities at Clatterbridge • Successfully treating patients (currently ~300/year) with cancers of the eye for >25 years with 60 MeV proton beam. • Limited time and proton beam access due to patient treatments. • Limited in vitro capabilities and unable to perform in vivo research.
- 5. Biological uncertainties with particle radiotherapy Bragg peak Depth in tissue Relative dose Distal fall-off Tumour Proton energy LET A constant relative biological effectiveness (RBE) value of 1.1 is used in clinical practice for protons. However, there is a large uncertainty with using this approach as RBE is variable and dependent on many factors, including:- • Proton energy (therefore linear energy transfer, LET) and dose/dose rate. • Radiosensitivity/radiobiology of the specific tumour tissue (e.g. based on DNA repair capacity, hypoxia and tumour microenvironment). • Biological end-point examined (e.g. clonogenic survival, tumour growth delay). Taken from Paganetti and van Luijk (2013) Sem Rad Oncol Vitti and Parsons (2019) Cancers Further research exploiting the biological impact of particle ions is vital for investigating RBE, and thus improving clinical use of PBT.
- 6. DNA damage and relationship to LET • Low-LET radiation produces repairable DNA damage (e.g. single and double strand breaks). • High-LET radiation generates increased amounts of complex DNA damage (containing multiple DNA lesions) that are more difficult to repair, utilises multiple DNA repair pathways, and which can enhance cell death. 0 5 10 15 20 25 30 35 40 45 Control 0 1 2 4 % Tail DNA Hours post-IR Proton-IR (58 MeV) Proton-IR (58 MeV; modified) Proton-IR (11 MeV) Proton-IR (11 MeV; modified) **** * *** ** CDD Carter et al, and Parsons (2018) IJROBP Carter et al, and Parsons (2019) IJROBP 0.1 1 0 1 2 3 4 Surviving fraction Dose (Gy) 58 MeV 11 MeV Low-LET High-LET Low-LET Low-LET (modified assay) High-LET High-LET (modified assay) RBE=~1.7
- 7. Modulation of proton-induced cellular sensitivity following siRNA knockdown screening Low-LET protons 0 1 2 3 4 5 6 Mock MPND UCHL1 BRCC3 USP4 JOSDI FBX08 DUB3 FBX07 DUB1A CYLD USP27X BAP1 USP3 OTUD1 AMSH USP9X MYSM1 OTUD4 OTUB2 USP6 USP44 USP52 OTUD6B CEZANNE SENP2 A20 USP47 OTUD7 USP41 UBL3 USP45 USP48 USP50 USP28 USP51 USP54 UBL4 USP15 USP5 USP9Y USP40 USP49 USP21 UBR1 USP53 USP16 OTUD5 UBTD1 USP14 USP18 ATNX3 USP46 USP37 DC-UBP USP26 USP25 OTUB1 USP2 USP1 UCHL5 USP10 USP13 USP24 USP22 USP17 USP8 USP35 PARP11 USP20 USP12 JOSD2 USP31 USP29 USP11 UCHL3 USP42 STAMBP1 USPL1 USP19 USP32 USP30 YODI USP38 USP34 USP7 UEVLD VCPIP1 ZRANB1 UFD1L USP33 USP36 USP43 USP39 Normalised surviving fraction 0 1 2 3 4 5 6 Mock UEVLD USP16 USP13 USP17 USP45 USP54 USP46 USP49 USP51 USP1 USP34 USP11 USP19 OTUB1 UBR1 USP48 UBL3 USP50 UBTD1 UCHL1 USP5 USP14 CEZAN… DC-UBP UCHL3 UBL4 USP10 UMPK OTUB2 USP2 USP12 JOSD2 USP18 UCHL5 A20 ATNX3 PARP11 AMSH USP3 USP52 USP27X USP40 USP22 BRCC3 BAP1 USP25 USP33 MYSM1 USP15 OTUD6B OTUD1 USP42 USP26 USP24 USP32 USP28 USP44 USP20 JOSD1 USP30 USP41 USP35 USP47 USP29 USP37 VCPIP1 USP4 USP21 USP38 USP53 OTUD4 OTUD5 USP8 DUB3 FBX07 ZRANB1 UFD1L DUB1A MPND SENP2 USP9Y YODI USP43 STAMB… USP39 USP36 FBX08 USP6 USP9X USP31 UBL5 USP7 CYLD Normalised surviving fraction High-LET protons HeLa Carter et al, and Parsons (2019) IJROBP • Significant variability in the response of cells to low and high-LET protons dependent on cellular proteome. • Will identify specific cellular targets (e.g. for combinatorial drugs/inhibitors) to exacerbate the effects of PBT.
- 8. • Using ultra high-dose rates (>100 Gy/s). FLASH radiotherapy • However, the mechanism of the FLASH effect is unclear (role of oxygen?). • Impact of FLASH on specific tumour models not well defined. • Effect of FLASH photon vs protons (and impact of LET), not been demonstrated. Further research exploiting the biological impact of FLASH on appropriate in vitro and in vivo models is important for translation to the clinic.
- 9. Challenges and opportunities for PBT radiobiology research Challenges • The radiobiology of PBT at the molecular and cellular level is still not entirely understood (e.g. impact of LET, dose rate delivery). • Other factors that impact on RBE of PBT not well defined (e.g. hypoxia, tumour microenvironment, drug-IR combinations, fractionated doses, FLASH). • More research required using specific and validated cancer models, plus relevant normal tissue models, in vitro (e.g. 3D spheroids/organoids) and in vivo. • Significant lack of access to PBT facilities for radiobiology research. • Current facilities not fully equipped for in vitro, but more so in vivo experiments. Opportunities with LhARA • Highly accessible facility for both in vitro and in vivo particle ion radiobiology research, capable of analysing a multitude of biological end-points. • Enhance our understanding of the radiobiological effects of particle ions (protons and carbon ions), including examining dose delivery (FLASH) and combinatorial treatments through high-throughput screening. • Significant opportunity to develop research that will have a major Worldwide impact through the optimisation and personalisation of cancer treatments using PBT in the clinic.
- 10. Feedback from Yolanda Prezado • LhARA is a very promising facility which would offer unique beam features and infrastructure for radiobiology research. • LhARA has the potential to drive a change in current clinical practice by increasing the wealth of radiobiological knowledge. The main characteristics to be highlighted are:- Flexibility Flexible temporal and spatial beam structure allowing exhaustive investigations of beam parameters (pulse length, repetition rate, instantaneous dose, FLASH) on biological response utilising a stable beam. Different beam species One of the few places in the World to offer the evaluation of different particle ions (protons to heavier ions) within the same facility. Accessibility Greater accessibility of LhARA in comparison to clinical facilities, with greater flexibility (e.g. in vitro and in vivo experiments; dose fractionation; more complex biological end-points; immunotherapy/chemotherapy combinations).