MICA: Radiobiology for effective alpha particle and Auger electron molecular radionuclide therapy in neuroendocrine cancer

在英国，每两分钟就有一个人被诊断出患有癌症。这里的重点是神经内分泌癌，它始于激素释放的神经内分泌细胞，可以发生在身体的任何地方，包括肺、阑尾、小肠、直肠和胰腺。虽然罕见，但它们很难治疗；因此，需要有新的选择来治疗原始肿瘤和扩散到全身的癌细胞。我们将通过创造新的可注射的放射性药物来解决这个问题，这些药物特别是体内任何地方的癌细胞的家园。这里研究的放射性化合物使用附着在DOTATE上的镓-67和铊-201，DOTATE将放射性传递到神经内分泌癌细胞。镓-67和铊-201都释放出短距离、高能俄歇电子。它们只照射它们附着的细胞，而且很容易获得。该项目还将使用铅-212，因为它也会在短距离内发出高能辐射(阿尔法粒子)。这是杀死单一癌细胞所必需的。但铅-212也同时释放出在治疗肿瘤球体时有用的贝塔粒子。与其他阿尔法粒子发射器不同，铅-212可以在临床上获得可行、可持续治疗所需的数量，这一点至关重要。我们正在与一家公司合作，该公司生产了用于神经内分泌肿瘤成像和治疗的放射性铅标记多肽(203Pb-和212Pb-VMT-α-net)。然后，我们将在实验室培养的神经内分泌癌细胞中进行研究，以更好地模拟肿瘤，以及神经内分泌癌症的动物模型。这些研究将使我们了解辐射剂量与对肿瘤细胞和健康肾脏细胞的损害之间的关系。这与计算机模拟一起，将为未来的临床试验提供所需和处方的放射性化合物注射量，以在不损害肾脏等健康组织的水平上有效地杀死肿瘤。最后，将进行研究，以确定放射性化合物在杀死经过化疗预处理的癌细胞方面的效果。通过这项工作，我们将不仅推进对高能量和短距离放射性形式的放射生物学的理解，如67Ga和201Tl-DOTATE和212Pb-VMT-α-Net，而且还将促进对癌症模型中俄歇电子和α粒子发射体的放射生物学的理解。我们的研究还将指导其他形式的具有治疗潜力的放射性的进一步工作。

Every two minutes, someone in the UK is diagnosed with cancer. The focus here is on neuroendocrine cancer, which begins in hormone-releasing neuroendocrine cells and can occur anywhere in the body including the lungs, appendix, small intestine, rectum and pancreas. Although rare, they are very hard to treat; there is therefore a need for novel options to treat both the original tumour and cancer cells that have spread throughout the body. This will be addressed by us creating new injectable, radioactive drugs that specifically home to cancer cells anywhere in the body. The radioactive compounds investigated here use gallium-67 and thallium-201 attached to DOTATATE, which delivers the radioactivity to neuroendocrine cancer cells. Gallium-67 and thallium-201 both release short-distance, high energy Auger electrons. These only irradiate cells to which they are attached and are available with ease. The project will also use lead-212, as it too emits radiation at a high energy across a short distance (alpha particles). This is needed to kill singular cancer cells. But lead-212 also simultaneously releases beta particles that are useful when treating tumour spheres. Unlike other alpha particle-emitters, lead-212 can crucially be obtained at quantities needed for a feasible, sustainable therapy in the clinic. We are working with a company that has produced radioactive lead-labeled peptides (203Pb- and 212Pb-VMT-alpha-NET) for imaging and therapy of neuroendocrine tumours. We will then carry out studies in neuroendocrine cancer cells grown in the lab in layers and as spheres, to better mimic a tumour, as well as in animal models of neuroendocrine cancer. These studies will allow us to understand the relationship between radiation dose delivered and damage to tumour cells as well as healthy kidney cells. This, alongside computer modelling, will inform future clinical trials in terms of required and prescribed injected amounts of radioactive compounds for effective tumour killing at levels that do not damage healthy tissues such as the kidneys.Finally, studies will be carried out to ascertain how effective the radioactive compounds are in killing cancer cells that have been pretreated with chemotherapies. Hopefully, we will show that combining chemotherapies with the radioactive compounds increases the overall tumour killing ability and work out how this is achieved.Through this work, we will have advanced the radiobiological understanding not only of forms of radioactivity that are high in energy and short in distance, such as 67Ga- and 201Tl-DOTATATE and 212Pb-VMT-alpha-NET but of Auger electron and alpha particle-emitters in cancer models in general. Our research will also guide further work with other forms of radioactivity that have therapeutic potential.