Three-Pronged Therapy: A New Treatment for Incurable Brain Tumours

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Image1467878096?1467878096  You Can Innovate Award

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1. Summary of your project

In Australia, brain cancer kills more children than any other disease and kills more people under 40 than any other cancer. The Australian survival rates for brain cancer have hardly changed over the past 30 years (2% increase) compared to prostate (35% increase) and breast (18% increase) cancer. The treatment of malignant brain tumour (i.e high-grade gliomas) poses a major challenge as they are resistant to radiotherapy and chemotherapy often fails because of inadequate drug delivery inside the tumour. A new effective method to treat high-grade gliomas is desperately needed.

 

This project develops a novel three-pronged therapy that selectively targets high-grade glioma brain tumour cells. Our innovative approach uses the synergy created by combining two pharmacological drugs with optimised x-ray energies. The two drugs are a radiosensitiser, which makes the tumour more sensitive to radiation, and a chemotherapy drug, which impairs the growth of tumour cells and DNA damage repair after irradiation. When these drugs are used In combination with X-rays tuned to an optimum energy, a synergy was revealed.

 

There have been no breakthroughs in treating severe brain cancer in the last thirty years. My innovative approach promises to increase the dosage delivered to the tumour, whilst decreasing the dosage applied to the patient: more ‘radiative bang’ for less ‘radiative buck’.


2. Describe your approach and any preliminary findings.

My approach is to improve the treatment of radioresistant brain tumours by taking advantage of the synergy between pharmacological drugs and optimised radiation. This technique allows a reduction in the required dose of both radiation and chemotherapy drugs without compromising the treatment outcome. The greater uptake of radiation by the cancer cells increases the localised lethal damage to the tumour target with less toxicity delivered to the surrounding normal tissue.

 

In my PhD, I obtained very promising in vitro results using a treatment method that combined the use of two pharmacological drugs with optimised x-ray radiation. The novelty of this research was to increase the dose absorbed by a target locally in the region of target cancer cells by using a chemical compound with a high atomic number (i.e. bromine Z=35) to `attract’ the radiation in conjunction with an anticancer drug. The drugs used were a chemotherapy drug (MTX – methotrexate) and a radiosensitiser (BrUdR – bromodeoxyuridine). The chemotherapy drug blocks tumour growth. The radiosensitiser is incorporated into the DNA of the cancer cells. This ensures that radiation is preferentially absorbed by cancer cells rather than surrounding healthy tissues.

 

Our preliminary findings show that the surviving fraction of glioma tumour cells is significantly reduced when bromodeoxyuridine (BrUdR) and methotrexate (MTX) drugs are combined together with photon irradiation, compared to the cases of irradiation alone or either drug and irradiation (Oktaria et al. 2015). This method can maximise the killing of tumour cells whilst minimising the effect on healthy tissue. An innovative aspect of this work is the investigation into optimising X-ray beam energies using conventional external beam radiotherapy X-rays machines or medical Linear Accelerators (LINAC). No previous studies investigated the dependence upon X-ray energy.

 

Glioma cells irradiated in a 125 kVp X-ray field showed the greatest sensitisation enhancement ratio (SER) value, 2.3, compared to all other energies investigated (Oktaria et al. 2015). In other words, the combination therapy needed 2.3 times less dose that radiation alone to kill 90% of the tumour cells.These results support the feasibility of chemotherapy drug-enhanced radiotherapy through the improved biological effectiveness of X-ray irradiation. Furthermore, my results validate the use of chemo-radiotherapy in conventional external X-ray beam radiotherapy modality fields.

 

In the proposed project, I aim to further improve the treatment efficiency by replacing the radiosensitive BrUdR by iododeoxyuridine (IUdR). I expect the dose enhancement of radiotherapy IUdR to be greater than BrUdR due to the higher atomic number of iodine (Z = 53). I established in vitro the combination of drugs with optimised X-ray energies more than doubles the number of glioma tumour cells killed compared to a radiation-only control (Oktaria et al. 2015). This proposed project extends this method, culminating in the study of small animal models: the first step to taking it to pre-clinical trial.

 

Reference:

Oktaria S et al. 2015. Phys Med Biol 60:7847-59.

3. What is the impact of your research to help cancer patients?

In Australia, brain cancer kills more children than any other disease and kills more people under 40 than any other cancer. The Australian survival rates for brain cancer have hardly changed over the past 30 years (2% increase) compared to prostate (35% increase) and breast (18% increase) cancer. Despite this, relatively small amounts of funding are spent on brain cancer research (less than 5% of federal government cancer research funding). This study will develop a new multi-modal treatment for brain cancer patients who currently have poor outcomes. This innovative therapy treats the tumour with optimised x-rays energy precisely targeted to boost the killing of cancer cells resulting in a significant improvement in the treatment of gliomas, patient quality of life and survival times. To improve the control of local tumours and to reduce tumour recurrence improvements two factors are required. There needs to be an improved delivery of the radiation dose to the tumour and there needs to be more efficient killing of the cancer cells.

 

A promising feature of this research is that the external x-ray beam irradiation source used, LINAC, is commonly available already in hospitals across Australia. By way of contrast treatment methods employed elsewhere, such as synchrotrons in Japan or stereotactic radiosurgery (i.e. gamma knife), use irradiation sources that are not commonly available in Australian hospitals. Thus their adaptation would impose restrictions to their use based upon geographical considerations. Thus the use of a medical LINAC will enable a treatment avenue for many patient groups.

 

At the conclusion of this project we will have validated the effectiveness of this multi-modal treatment. The potential end benefits of this project are multifaceted: patients can be exposed to a lower dose of radiation because the tumour has been ‘primed’ using drugs; there is a decrease in treatment side-effects (toxicity); increased tumour reduction; improved quality of life. All of these directly translate to longer remission and increased cure rates for brain cancer sufferers.


4. What ideas would you like to explore, or currently are exploring, to take this research further?

The treatment of high-grade gliomas poses a major challenge as they are resistant to radiotherapy and chemotherapy often fails because of inadequate drug delivery inside the tumour. Thus, the optimum mode of drugs administration in combination with radiotherapy is another challenging step.

 

I would like to explore the potential of creating a new form of implants made of biodegradable polymer that contains both of drugs. The implants made of biodegradable polymer can be placed into the site of the brain tumour, which slowly release the drugs directly into the localised target and dissolve over a period of time.


5. Please demonstrate your track-record. Share a selection of publications, citations, awards etc.


Top 5 publications in the last 5 years

1.    A. Briggs, S. Corde, S. Oktaria, R. Brown, A. Rosenfeld, M. Lerch, K. Konstantinov, M. Tehei. 2013. Cerium oxide nanoparticles: influence of the high-Z component revealed on radioresistant 9L cell survival under X-ray irradiation. Nanomedicine: Nanotechnology, Biology, and Medicine 9:1098–1105.

2.    R. Brown, M. Tehei, S. Oktaria, A. Briggs, C. Stewart, K. Konstantinov, A. Rosenfeld, S. Corde, M. Lerch. 2014. High-Z nanostructured ceramics in radiotherapy: first evidence of Ta2O5-induced dose enhancement on radioresistant cancer cells in an MV photon field. Particle and Particle Systems Characterisation 31(4): 500–505.

3.    C. Stewart, K. Konstantinov, M. McDonald, D. Cardillo, K. Bogusz, S. Oktaria, D. Shi, M. Lerch, T. Devers, S. Corde, A. Rosenfeld, M. Tehei. 2014. Engineering of bismuth oxide nanoparticles to induce differential biochemical activity in malignant and non-malignant cells. Particle and Particle Systems Characterisation 31(9): 960–964.

4.    S. Oktaria, S. Corde, M. Lerch, K. Konstantinov, A. Rosenfeld, M.Tehei. 2015 Indirect radio-chemo-beta therapy: A targeted approach to increase biological efficiency of x-rays based on energy. Physics in Medicine and Biology 60: 7847–7859.

5.    R. Brown, S. Corde, S. Oktaria, K. Konstantinov, A. Rosenfeld, M. Lerch, M. Tehei. 2017. Nanostructures, concentrations and energies: An ideal equation to extend therapeutic efficiency on radioresistant 9L tumour cells using Ta2O5 ceramic nanostructured particles. Biomedical Physics and Engineering Express 3(1):015018.


 

The most significant paper from the perspective of this project is the pioneering paper on indirect radio-chemo-beta therapy (Oktaria et al. 2015), which was published in ‘Physics in Medicine and Biology’. The Institute of Physics published a review news item publicising this research (Three-pronged glioma therapy shows promise on MedicalPhysicsWeb, November 2, 2015). This research was also picked up by University of Wollongong (UOW) Media appearing on the front page of the UOW website and TV news. A non-technical article appeared in the Summer 2015 Illawarra Health Medical Research Institute (IHMRI) newsletter and 2015-2016 annual report. As summarised below (media):

·      Three-pronged glioma therapy shows promise – Medical Physics Web

http://medicalphysicsweb.org/cws/article/research/63064

·      Precise targeting to boost cancer drug activity – Research Matters: Summer IHMRI Newsletter 2015

http://ihmri.uow.edu.au/content/groups/public/@web/@ihmri/documents/doc/uow205473.pdf

·      New brain cancer treatment twice as effective – UOW Media Release 30 November 2015

http://media.uow.edu.au/news/UOW206297.html

(Medical Xpress-http://medicalxpress.com/news/2015-12-brain-cancer-treatment-effective.html)

·      Three-pronged glioma therapy shows promise – Medical Physics Web Review 2016(page 14)

·      A new treatment for ‘incurable’ brain tumours – IHMRI Annual Report 2015-2016

https://ihmri.uow.edu.au/content/groups/public/@web/@ihmri/documents/doc/uow224076.pdf




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