UCLA

One promising treatment option for metastatic castration-resistant prostate cancer is systemic radionuclide therapy targeting prostate-specific membrane antigen (PSMA). PSMA is a highly overexpressed protein on prostate cancer cells, but has low expression in normal organ tissues. Small molecule inhibitors of PSMA specifically bind to PSMA and can therefore be labeled with imaging or therapeutic isotopes to deliver the radiation directly to the site of cancer cells. When labeled with a therapeutic isotope, such as a beta- or alpha-emitter, PSMA ligands acts as a delivery vector for a lethal payload of radiation to cancer cells. This therapy is known as radionuclide therapy (RNT).

The most commonly used therapeutic isotope in PSMA-targeted RNT is lutetium-177 (177Lu). Treatment response rates to 177Lu-PSMA RNT vary widely across treatment studies and patient cohorts from 30 to 70%. However, actinium-225 (225Ac), an alpha particle emitter, has emerged as a promising alternative isotope with favorable therapeutic decay properties. Alpha particles are of interest in RNT due to higher energy deposition over a shorter tissue penetration range, ostensibly causing more dense ionizations and inducing more DNA damage as compared with beta particles. While fewer clinical studies have been conducted with 225Ac-PSMA RNT, the studies so far report impressive response rates, particularly in chemotherapy-na�ve patients. Despite improved biochemical response in 225Ac-treated patients, this comes at the cost of higher-grade toxicities. Overall, PSMA RNT using either therapeutic isotope is not curative and even in those patients who do respond, the disease almost inevitably relapses. One possible explanation for treatment failure and disease relapse is that the tumor targets are not receiving a sufficiently high radiation dose necessary to kill the cancer cells.

The current treatment paradigm is to treat with fixed activities for the same number of cycles at fixed intervals. However, treatment with a fixed activity neglects the fact that the mechanism of action of RNT is by radiation, and as such warrants radiation dose evaluation. To move away from a “one size fits all” approach to more individualized treatment, dosimetry can be used to devise safe therapeutic activities to deliver maximal tumor doses while delivering as low as achievable doses to non-target volumes.

This dissertation addresses two overarching goals: i) to identify clinically relevant differences between 177Lu and 225Ac by incorporating dosimetry in translational RNT research, and ii) to evaluate the clinical dosimetry of imaging and therapy theranostic agents. The first specific aim uses various in vivo murine models of prostate cancer for the optimization of preclinical PSMA RNT exploring the effect of different therapeutic isotopes and targeting ligands relative to intervention time and lesion size. The second specific aim evaluates the clinical radiation dosimetry profile of two new imaging theranostic tracers. Finally, the third specific aim seeks to quantify the patient-specific absorbed doses in tumors and normal organs for therapeutic 177Lu and 225Ac PSMA RNT agents.