Auger Electron Radiotherapy of Late-Stage, Castration-Resistant Prostate Cancer using a Brominated Dihydrotestosterone Analogue

使用溴化二氢睾酮类似物对晚期去势抵抗性前列腺癌进行俄歇电子放射治疗

• 批准号: 9023992
• 负责人: BRADLEY J BEATTIE
• 金额: $ 19.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023992
• 关键词: Affinity; Androgen Receptor; Androgens; Animal Model; Antiandrogen Therapy; Beneficence; Binding; Blood; Castration; Cell Death; Cell Nucleus; Cells; Chemicals; Clinical Research; Complex; DNA; DNA Binding; Data; Diagnostic Neoplasm Staging; Disease; Electrons; Enzymes; Exhibits; Gene Amplification; Gene Targeting; Goals; Growth; Guns; Hormone Receptor; Hormone use; Hormones; Image; Implant; In Vitro; Isotopes; Malignant neoplasm of prostate; Mediating; Metabolism; Methods; Modeling; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Patient Selection; Patients; Plasma; Positron; Positron-Emission Tomography; Prostatic Neoplasms; Radiation; Radiation therapy; Radioactive Elements; Rattus; Receptor Inhibition; Resistance; Resistance development; Signal Transduction; Site; Specificity; Staging; Stanolone; System; Testosterone; Therapeutic; Toxic effect; Travel; Tumor stage; Work; analog; base; cancer cell; cancer imaging; castration resistant prostate cancer; cell growth; cell killing; density; deprivation; design; follow-up; hormone response element; imaging agent; ionization; killings; liver metabolism; men; nanometer; next generation; oncology; overexpression; prostate cancer cell; public health relevance; receptor; receptor binding; receptor expression; resistance mechanism; response; standard of care; stem; targeted agent; theranostics; therapy design; therapy resistant; tumor; uptake

 DESCRIPTION (provided by applicant): Prostate cancer's growth and progression is largely driven by hormones (for example, testosterone) that are naturally present in the blood. Aiming to reduce the hormone levels in the blood, surgical and chemical castration methods have been a standard of care for prostate cancer for over 70 years. Although castration is initially very effective, dramatically reducing tumor size, castration resistant prostate cancer inevitably develops. At this stage, the tumor continues to grow and spread despite reduced hormone levels. Often the mechanism by which prostate cancer becomes castration resistant is to over produce the receptor targets to which the hormones bind, thereby continuing to generate a growth signal. Once prostate cancer becomes castration resistant, the second tier of treatment is to try to delay growth by inhibiting these receptors. Such an approach potentially affords lengthened survival, but is not curative. In this proposal, we plan to develop a new type of therapy for castration resistant prostate cancer that turns this mechanism of resistance into a therapeutic advantage. The more a prostate cancer cell over produces its hormone receptors, the more sensitive it should be to the killing effects of our proposed therapy. Specifically, we do this by producing a molecule that emits a very special type of radiation. This molecule is similar to one of the hormones used by the tumor in that it binds to the over produced receptor and then travels to the cell nucleus where it binds to the DNA. The radioactive element that we incorporate into the molecule is special in that, unlike other forms of radiation, this radiation hs an extremely limited range of lethality. It is somewhat like a shot-gun, very lethal when it is cloe to critical molecules like DNA, but virtually harmless when it is elsewhere in the cell or in the blood. Radiation of this type is routinely injected into patients without harmful effect because these molecules do not bind to DNA. The main objective of this proposal is to develop this therapeutic molecule to bind selectively and lethally only to the DNA within prostate cancer cells. As a secondary objective in this proposal, we plan to produce a molecule that acts identically to the therapeutic molecule but uses a non-therapeutic isotope that can be used to make three-dimensional images of the tumor. These images can be used to select the patients that are most likely to be successfully treated by this therapy.