Core 1: Animal Models, Pathology and Tissue

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Project Summary Alpha-particle -emitter radiopharmaceutical therapy (αRPT) is a new and rapidly evolving therapeutic modality that can deliver highly potent, alpha-particles to disseminated cancer metastases, with 100 micron precise radiation trajectory, and less toxicity in patients. Since almost all of the radionuclides used in αRPT emit photons that can be imaged non-invasively, valuable pharmacokinetic and anatomical data is provided. Precisely targeting the cancer without side effects to normal tissues would be a breakthrough for patient care. All patients are different though and each patient may need αRPT dose adjustments but current implemented αRPT protocols don’t achieve this goal. To address this unmet need, in experiments outlined in the application, facilitated by Core B, dosimetry-driven treatment planning, in combination with a radiobiologic understanding of how absorbed dose translates to biologic effect, will reduce the scope of human experimentation (costs and timeline) needed to clinically optimize αRPT. To achieve these goals and test project hypotheses, Projects 1-4 address multiple steps to improve αRPT and rely on the Animal Models, Pathology and Tissue Core to facilitate all projects using animal models or human tissue-based analyses. Core B molecular tissue techniques will address the role of DNA damage by αRPT and DNA repair pathway inhibitors in project 4. The overall hypothesis of this PPG is that αRPT is a systemic cancer therapy modality that is particularly applicable to targeting metastatic cancer; and far less susceptible to conventional resistance mechanisms; yet it is amenable to dosimetry-driven treatment planning. In the experiments proposed, S values measurements can be perfected down to a microscale to focus the alpha-particle delivered dose on cancer and eliminate peripheral collateral organ damage. The Animal models, Pathology and Tissue Core are led by an experienced veterinary pathologist/toxicologist and a MD pathologist at Johns Hopkins University who have long contributed to cancer therapeutic research at this institution. The emphasis of the Core is to assist PIs of the four projects in three different areas, (1) animal models (2) necropsy, tissue sampling, processing, and histopathology with αRPT image correlation and (3) in situ assays on human and animal tissues to assess DNA damage and repair. Standard operating procedures of the Core for biospecimens incorporate the guidelines as outlined by the 2011 Revised NCI Best Practices for Biospecimen Resources. Rigor and reproducibility, as well as sex as a biological variable and appropriate animal numbers will be addressed in experimental design. The PIs of this Core have the necessary expertise and methodologies to provide pathology consultation for use of the human specimens and animal tissues for the proposed studies with a combined 30 years of collaboration with members of this program project and JHU research community. This valued knowledge and experience is applied to improving patient cancer αRPT therapeutics, reducing toxicity resulting in a high impact on public health and patient care.