Research

Microbeam Radiation Therapy

The Djonov group focuses on investigating novel anti-cancer treatment strategies in the field of radiation oncology, specifically microbeam radiation therapy.

Microbeam radiation therapy (MRT) is a novel form of preclinical radiotherapy delivering spatially fractionated X-rays at dose rates orders of magnitude greater than those offered by conventional clinical regimens. The highly collimated X-ray beam allows for the heterogeneous delivery of therapeutic doses in a pattern of discrete, micrometre-wide beams that deposit high (peak) doses separated by regions of low-dose deposition (valleys). Currently, MRT is administered by third generation synchrotron sources allowing for dose delivery in fractions of a second. The unique relationship between dose rate and geometry has proven to effectively treat a variety of solid tumours that are often refractory to conventional treatment while, at the same time, promoting exceptional normal tissue sparing. The mechanisms governing the effects of MRT remain to be adequately defined, thus limiting the development of specific treatment strategies and ultimately its clinical translation.

Our research focuses on elucidating these mechanisms, which define the therapeutic potential of MRT. By employing a variety of tumour and normal tissue models our investigations focus on the following effects and applications of MRT:

1. MRT selectively destroys tumour-like vasculature:
   
   Susceptibility of a tissue to MRT is, in part, dependent on the degree of organization of its vasculature.  Normal, healthy tissue is vascularized by an organized network of mature vessels and microvasculature in contrast to tumour tissue, which is often characterized by disorganized, immature vasculature. Using the chick chorioallantoic membrane, zebrafish and murine vascular models we study the effects of MRT on these differential states of vascular maturity. These investigations have shown the selective destruction of immature, tumour-like vessels, by MRT and the preservation of the mature vasculature of healthy tissue¹,^2.
2. MRT induces transient vascular permeability:
   
   The partial disintegration of immature tumour vessels following lower doses of MRT promotes a window of transient vascular permeability that can be exploited for enhanced drug delivery to the tumour and increase the therapeutic potential of existing chemotherapeutic drugs and nanoparticles²
3. Treatment of radioresistant tumour types with MRT:
   
   Our group described for the first time that MRT is an efficient treatment strategy for radioresistant melanoma leading to increased survival of tumour bearing mice3. Furthermore, by application of a temporal fractionation regime, we can achieve complete remission in 50% of the treated melanomas⁴
4. Using MRT to treat tumours in radiosensitive tissues:
   
   One of the major challenges in radiotherapeutic treatment of lung carcinoma is the development of radiation-pulmonary fibrosis. We have seen in preliminary data that MRT does not induce significant fibrosis in the irradiated rodent lung making it a valuable treatment strategy that we are actively pursuing in a mouse model of lung carcinoma.
5. MRT enhances recruitment of circulating immune cells to tumour:
   
   We have shown that MRT selectively increases infiltration of immune cell populations with phenotypes associated with anti-tumour effects into the tumour tissue3. This increased immune cell migration to an MRT-irradiated tumour is an important immunoprophylactic treatment strategy and is the focus of our current and future investigations in a variety of tumour types.
6. Clinical translation of MRT:
   
   Given the limited accessibility to synchrotron sources for clinical treatment, we are investigating approaches to modifying MRT treatment strategies to make them more accessible for clinical translation5. These include the assessment of different fractionation schemes as well as the efficacy of alternative microbeam sources.