Guatelli, Susanna Dr.

<p><strong><strong>Clinical landscape in Glioblastoma: </strong></strong>Of all cancers, 2% are classified as glioblastoma multiforme (GBM) corresponding to an incidence of two to three per 100,000 adults per year. Of all primary brain tumours, GBM accounts for 52 percent, and when including both primary and metastatic tumours, GBM accounts for 17 percent of all tumours of the brain. Because GBM often strikes young people, it is responsible for the fourth highest loss of potential years of life. Patients that die of GBM loose an average of 12 years of potential life, which is the highest average loss of life from any type of cancer (Source: cancer council Australia and AANS.org).</p><p>The current standard of care for glioblastoma consists of surgical resection or biopsy, followed by radiotherapy with concomitant chemotherapy, followed by maintenance of chemotherapy for 6 to 12 months. Two year survivals have improved with the addition of Temozolomide but the 5-year survival rates for patients aged 20 to 44 years are still less than 20% and the median survival for this age group is 21.5 months, while it is less than one year when taking all patients into account. The subsequent disease progression, is attributed to the presence of more resistant stem-like cancer cells, able to metabolically escape the effects of Temozolomide. It is therefore logical to seek to address these residual cells by a second-line of attack approach, in the form of reactive oxygen species generated in-situ. Various forms of treatment escalation have shown initial promise but failed due to treatment related necrosis. Such failure highlights an unmet clinical challenge related to the lowering of the required radiotherapy dose while retaining the desired treatment effect (satisfactory tumour control).<strong><br /><br /></strong></p><p><strong><strong>Methotrexate (F</strong><strong>olic acid drug analogue)</strong> </strong>is a approved cancer drug. It has a high affinity for folate receptors (FR) overexpressed in a variety of tumour types, including in human brain tumours. Conversely, in non-cancer cells, the expression of FR is low or highly limited, as it is confined to the apical membrane surface (except in the placenta), facing away from the blood. In healthy cells, this FR is thus inaccessible to folic acid administrated via the blood. Intrathecal (regional) and systemic (via the blood) administrations of nanoparticles conjugated with methotrexate are therefore suitable for the treatment and control of progression in brain tumours. Such methotrexate targeted nanoparticles are applied in this project.</p><p><strong><strong>Cytotoxicity of reactive oxygen species (ROS): </strong></strong>Cytotoxic ROS are produced in cells in the course of normal processes such as cellular metabolism where their levels are normally controlled by the cellular ROS defence mechanisms to ensure homeostatic balance. Disturbing this balance can lead to DNA damage, lipid peroxidation and protein oxidation, and the induction of apoptosis which some anti-cancer strategies aim to use to treat cancer. Ionising radiation is an established way of generating cytotoxic ROS in cells, and this forms the physical foundations of cancer radiotherapy. Maximising the levels of ROS at minimal radiation doses is one of significant aspects of our approach.</p><p><strong><strong>Reducing radiotherapy dose by the approach of “dose enhancement” </strong></strong>Most of the recent technological advances in radiation oncology are linked with state-of-the-art techniques for better geometrical targeting of lesions. Such targeting increases the local energy deposition in the tumour, leading to an effective sparing of surrounding noncancerous tissues and critical organs. Among such approaches, the dose enhancement radiotherapy is a technique that involves the introduction of high-Z (high atomic number) atoms into close proximity to the tumour. Following exposure by the local radiation field, the presence of these high-Z atoms increases selective damage to the tumour cell. This increase in radiosensitivity in the vicinity of high-Z atoms is facilitated by their production of charged particles and ROS. The megavoltage X-ray beams widely used clinically for cancer radiotherapy treatment of tumours located deep within the body do not offer the optimal energy range for a maximal dose enhancement using high-Z nanoparticles. The optimal X-ray energy for such enhancement is lower (40-100 keV), as this yields the clinically desired intense secondary electron and ROS generation. The demonstrated dose enhancement by the high –Z atoms in the kilovoltage energy range is due to photo-electric interactions, whose interaction cross sections are highly Z dependant (Z³). The resulting Auger electrons have a very short range, leading to a decrease in the radio-necrosis effects on healthy tissues, and they can deposit energy with greater radiobiological effectiveness due to high linear energy transfer in these conditions. In order to facilitate the treatment of deep seated tumours using such low photon energies, the beam attenuation must be addressed. The high photon flux from a synchrotron generated X-ray source can potentially solve this challenge and is therefore justifiably be investigated.<strong><br /><br /></strong></p><p><strong>The overall aim</strong> is to improve the treatment of radioresistant brain tumours by producing an equivalent biological effect at lower radiotherapy doses. The radiation is administered together with specially engineered methotrexate targeted nanoparticles. They will selectively deliver to tumour the clinically approved agents with complementary modes of cytotoxicity: chemotherapy drug methotrexate  and increased ROS triggered by the interaction of radiation with high-Z nanoparticles.</p>

<p><strong><strong>Clinical landscape in Glioblastoma: </strong></strong>Of all cancers, 2% are classified as glioblastoma multiforme (GBM) corresponding to an incidence of two to three per 100,000 adults per year. Of all primary brain tumours, GBM accounts for 52 percent, and when including both primary and metastatic tumours, GBM accounts for 17 percent of all tumours of the brain. Because GBM often strikes young people, it is responsible for the fourth highest loss of potential years of life. Patients that die of GBM loose an average of 12 years of potential life, which is the highest average loss of life from any type of cancer (Source: cancer council Australia and AANS.org).</p><p>The current standard of care for glioblastoma consists of surgical resection or biopsy, followed by radiotherapy with concomitant chemotherapy, followed by maintenance of chemotherapy for 6 to 12 months. Two year survivals have improved with the addition of Temozolomide but the 5-year survival rates for patients aged 20 to 44 years are still less than 20% and the median survival for this age group is 21.5 months, while it is less than one year when taking all patients into account. The subsequent disease progression, is attributed to the presence of more resistant stem-like cancer cells, able to metabolically escape the effects of Temozolomide. It is therefore logical to seek to address these residual cells by a second-line of attack approach, in the form of reactive oxygen species generated in-situ. Various forms of treatment escalation have shown initial promise but failed due to treatment related necrosis. Such failure highlights an unmet clinical challenge related to the lowering of the required radiotherapy dose while retaining the desired treatment effect (satisfactory tumour control).<strong><br /><br /></strong></p><p><strong><strong>Methotrexate (F</strong><strong>olic acid drug analogue)</strong> </strong>is a approved cancer drug. It has a high affinity for folate receptors (FR) overexpressed in a variety of tumour types, including in human brain tumours. Conversely, in non-cancer cells, the expression of FR is low or highly limited, as it is confined to the apical membrane surface (except in the placenta), facing away from the blood. In healthy cells, this FR is thus inaccessible to folic acid administrated via the blood. Intrathecal (regional) and systemic (via the blood) administrations of nanoparticles conjugated with methotrexate are therefore suitable for the treatment and control of progression in brain tumours. Such methotrexate targeted nanoparticles are applied in this project.</p><p><strong><strong>Cytotoxicity of reactive oxygen species (ROS): </strong></strong>Cytotoxic ROS are produced in cells in the course of normal processes such as cellular metabolism where their levels are normally controlled by the cellular ROS defence mechanisms to ensure homeostatic balance. Disturbing this balance can lead to DNA damage, lipid peroxidation and protein oxidation, and the induction of apoptosis which some anti-cancer strategies aim to use to treat cancer. Ionising radiation is an established way of generating cytotoxic ROS in cells, and this forms the physical foundations of cancer radiotherapy. Maximising the levels of ROS at minimal radiation doses is one of significant aspects of our approach.</p><p><strong><strong>Reducing radiotherapy dose by the approach of “dose enhancement” </strong></strong>Most of the recent technological advances in radiation oncology are linked with state-of-the-art techniques for better geometrical targeting of lesions. Such targeting increases the local energy deposition in the tumour, leading to an effective sparing of surrounding noncancerous tissues and critical organs. Among such approaches, the dose enhancement radiotherapy is a technique that involves the introduction of high-Z (high atomic number) atoms into close proximity to the tumour. Following exposure by the local radiation field, the presence of these high-Z atoms increases selective damage to the tumour cell. This increase in radiosensitivity in the vicinity of high-Z atoms is facilitated by their production of charged particles and ROS. The megavoltage X-ray beams widely used clinically for cancer radiotherapy treatment of tumours located deep within the body do not offer the optimal energy range for a maximal dose enhancement using high-Z nanoparticles. The optimal X-ray energy for such enhancement is lower (40-100 keV), as this yields the clinically desired intense secondary electron and ROS generation. The demonstrated dose enhancement by the high –Z atoms in the kilovoltage energy range is due to photo-electric interactions, whose interaction cross sections are highly Z dependant (Z³). The resulting Auger electrons have a very short range, leading to a decrease in the radio-necrosis effects on healthy tissues, and they can deposit energy with greater radiobiological effectiveness due to high linear energy transfer in these conditions. In order to facilitate the treatment of deep seated tumours using such low photon energies, the beam attenuation must be addressed. The high photon flux from a synchrotron generated X-ray source can potentially solve this challenge and is therefore justifiably be investigated.<strong><br /><br /></strong></p><p><strong>The overall aim</strong> is to improve the treatment of radioresistant brain tumours by producing an equivalent biological effect at lower radiotherapy doses. The radiation is administered together with specially engineered methotrexate targeted nanoparticles. They will selectively deliver to tumour the clinically approved agents with complementary modes of cytotoxicity: chemotherapy drug methotrexate  and increased ROS triggered by the interaction of radiation with high-Z nanoparticles.</p>