Linear Energy Transfer Alpha Research Articles

Abstract 3056: Alpha particle radiobiology and the treatment of prostate adenocarcinoma

Abstract Background: Castration-resistant prostate cancer (CRPC) is treated with the androgen receptor (AR) antagonist Enzalutamide (ENZA). However, early positive outcomes are later reversed by acquired resistance, ultimately leading to lethal AR-independent disease progression. High linear energy transfer (LET) alpha particle emitting drugs targeting Prostate Specific Membrane Antigen (e.g., [Actinium-225]-PSMA617) are potent and specific, yielding radiological and biomarker disease regression, but are not curative. DNA damage responses (DDR) in irradiated cells repair double strand breaks (DSB) allowing CRPC to escape. We are exploring the pharmacological effect of AR signaling on alpha particle therapy. AR signaling has a significant role in DDR and a better understanding of the alpha radiobiology is necessary to better deploy these potent drugs in combination. Methods: Alpha particle-induced DDR was investigated using readouts of clonogenic survival, cell cycle, apoptosis, and gene expression in AR-positive LNCaP-AR and AR-negative DU145 cells that were also treated with ENZA and an ATM inhibitor (ATMi, KU59403). Briefly, cells were seeded on mylar, treated with ENZA and ATMi and subsequently irradiated with alpha particles. Clonogenic survival was quantified at 10 days post alpha-irradiation. DNA damage was confirmed by imaging gamma-H2AX foci. Flow cytometry was used to analyze cell cycle arrest and apoptosis. Relative gene expression was quantified from RNA extracted immediately after and 10 days post-irradiation via RT-qPCR. Results: We observed the formation of increased DNA DSB (gamma-H2AX foci) versus controls after irradiation. ENZA radiosensitized LNCaP-AR versus untreated cells as evidenced by the D0 values obtained from clonogenic assays. However, combination of ENZA and alpha particles also upregulated expression of DDR genes. LNCaP-AR were in G2 arrest with increased apoptosis following irradiation. An ATMi was added to the regimen to address the upregulated DDR and increased apoptosis was observed. Altogether, these results indicate that cells are radiosensitized by ENZA but concomitant activation of DDR requires ATMi to improve therapy. Conclusion: DNA damage caused by alpha particles alone does not eradicate CRPC because some cells can repair DSB. Cell control from ENZA treatment alone is transient, leading to development of acquired resistance and disease relapse. Combining alpha particles and ENZA radiosensitizes AR-dependent prostate cancer cells, but DDR rescues a fraction of cells. Inhibiting the ATM pathway in AR-antagonized cells, in combination with high LET alpha irradiation, is a better approach to overcome prostate cancer cell resistance mechanisms. Combination ENZA/ATMi/alpha particles is a strategy designed to address the radioresistant subpopulation and could avoid CRPC progression to the more lethal, non-treatable stage of this disease. Citation Format: Barbara P. Mello, Ekaterina Revskaya, David A. Scheinberg, Michael R. McDevitt. Alpha particle radiobiology and the treatment of prostate adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3056.

A high-throughput alpha particle irradiation system for monitoring DNA damage repair, genome instability and screening in human cell and yeast model systems.

Ionizing radiation (IR) is environmentally prevalent and, depending on dose and linear energy transfer (LET), can elicit serious health effects by damaging DNA. Relative to low LET photon radiation (X-rays, gamma rays), higher LET particle radiation produces more disease causing, complex DNA damage that is substantially more challenging to resolve quickly or accurately. Despite the majority of human lifetime IR exposure involving long-term, repetitive, low doses of high LET alpha particles (e.g. radon gas inhalation), technological limitations to deliver alpha particles in the laboratory conveniently, repeatedly, over a prolonged period, in low doses and in an affordable, high-throughput manner have constrained DNA damage and repair research on this topic. To resolve this, we developed an inexpensive, high capacity, 96-well plate-compatible alpha particle irradiator capable of delivering adjustable, low mGy/s particle radiation doses in multiple model systems and on the benchtop of a standard laboratory. The system enables monitoring alpha particle effects on DNA damage repair and signalling, genome stability pathways, oxidative stress, cell cycle phase distribution, cell viability and clonogenic survival using numerous microscopy-based and physical techniques. Most importantly, this method is foundational for high-throughput genetic screening and small molecule testing in mammalian and yeast cells.

An evaluation of the various aspects of the progress in clinical applications of laser driven ionizing radiation

There has been a vast development of laser-driven particle acceleration (LDPA) using high power lasers. This has initiated by the radiation oncology community to use the dose distribution and biological advantages of proton/heavy ion therapy in cancer treatment with a much greater accessibility than currently possible with cyclotron/synchrotron acceleration. Up to now, preclinical experiments have only been performed at a few LDPA facilities; technical solutions for clinical LDPA have been theoretically developed but there is still a long way to go for the clinical introduction of LDPA. Therefore, to explore the further potential bio-medical advantages of LDPA has pronounced importance. The main characteristics of LDPA are the ultra-high beam intensity, the flexibility in beam size reduction and the potential particle and energy selection whilst conventional accelerators generate single particle, quasi mono-energetic beams. There is a growing number of studies on the potential advantages and applications of Energy Modulated X-ray Radiotherapy, Modulated Electron Radiotherapy and Very High Energy Electron (VHEE) delivery system. Furthermore, the ultra-high space and/or time resolution of super-intense beams are under intensive investigation at synchrotrons (microbeam radiation and very high dose rate (> 40 Gy/s) electron accelerator flash irradiation) with growing evidence of significant improvement of the therapeutic index. Boron Neutron Capture Therapy (BNCT) is an advanced cell targeted binary treatment modality. Because of the high linear energy transfer (LET) of the two particles (7Li and 4He) released by 10BNC reaction, all of the energy is deposited inside the tumour cells, killing them with high probability, while the neighbouring cells are not damaged. The limited availability of appropriate neutron sources, prevent the more extensive exploration of clinical benefit of BNCT. Another boron-based novel binary approach is the 11B-Proton Fusion, which result in the release of three high LET alpha particles. These promising, innovative approaches for cancer therapy present huge challenges for dose calculation, dosimetry and for investigation of the biological effects. The planned LDPA (photons, VHEE, protons, carbon ions) at ELI facilities has the unique property of ultra-high dose rate (> Gy/s−10), short pulses, and at ELI-ALPS high repetition rate, have the potential to develop and establish encouraging novel methods working towards compact hospital-based clinical applications.