The ultimate goal is to revolutionize cancer patient care by enhancing the effectiveness of radiopharmaceutical therapy, especially with alpha-particle emitters, promising minimal side effects.

Dr. Wesley Bolch and UF, along with collaborators at Johns Hopkins University, were awarded an NIH National Cancer Institute project grant of $12.9 million to conduct studies into the imaging, dosimetry, and radiobiology of cancer radiopharmaceuticals labeled with alpha-particle emitters. Bolch will work with UF faculty members Dr. John Aris from the Department of Anatomy and Cell Biology, Dr. Rowan Milner, and Dr Maria Von Chamier from the College of Veterinary Medicine.

Bolch, (PI) Distinguished Professor, will lead the efforts for the University of Florida. The UF Project 2 in the area of microscale tissue models for alpha-particle dosimetry is one of four efforts in this P01 grant. Other projects include those conducted at Johns Hopkins University in the areas of radiopharmaceutical imaging (Project 1), radioactivity apportionment factors (Project 2), and DNA damage and repair (Project 4), all focused on the unique challenges presented for radiopharmaceuticals labeled with alpha-particle emitting radionuclides. Alpha particles are doubly-charged helium nuclei, which can induce significant damage to the DNA structure of cancer cells in comparison to that from beta-particles.  As such, significantly lower amounts of administered activity need to be given to the cancer patient.

As with many forms of therapeutic radiopharmaceuticals, they are intravenously administered and thus are present in the general blood circulation prior to tumor uptake.  As such, there is unavoidable collateral irradiation of the bone marrow and kidneys.  Furthermore, some non-targeted uptake may be seen as is the case for the salivary and lacrimal glands for those radiopharmaceuticals targeting PSMA – prostate specific membrane antigen.  For each of these organs at risk, there exists a threshold radiation dose above which acute or chronic organ toxicity may be seen. The goal of optimized radiopharmaceutical therapy is thus to administered as high a level of activity as needed for efficient tumor cell kill, while also avoiding these dose thresholds for normal tissue damage. This approach requires state-of-the-art methods for assessing radiation dosimetry to normal organs. Traditional computational models of human organ anatomy are given at the macroscale of organ tissue structure. However, alpha particle ranges are only 50 to 100  microns, and thus a new generation of what are called microscale tissue computational models of normal organs is needed. In this study, Bolch and colleagues will construct new microscale models of bone marrow, kidneys, liver, lung, salivary glands, lacrimal glands, and small intestine.

With the involvement of Dr. John Aris and his laboratory, both human and murine microscale tissue models will be constructed using both existing and newly generated serially sectioned histology sections of these tissues from both human and mouse specimens.  Explicit consideration will be given to tissue expansion, tissue shrinkage, and blood/ECF loss so that the final polygon-mesh models will be of their in-vivo state. With the involvement of Dr. Rowan Milner, the project will provide intermediate-species microscale tissue models using the Micro-Yucatan swine pre-clinical model. The resulting mesh-type computational models will be incorporated into Monte Carlo simulation codes for radiation transport and dose assessment.

In advanced stages of cancer, where the patient might have tens to hundreds of tumors in their body, conventional radiation therapy by external beam delivery is not feasible, and systemic cancer therapies must be utilized. Chemotherapy and immunotherapy provide limited tumor targeting and the potential for cell signaling alternations and resulting therapy resistance, respectively.  Radiopharmaceutical therapy – especially with alpha-particle emitters – provides a way to directly deliver tumoricidal radiation doses that avoid these limitations. The work performed under this NCI P01 grant will provide the clinical community with the necessary imaging and dosimetry tools to advance cancer patient care with minimal side effects.