BIOLOGICAL EFFECTS OF ALPHA PARTICLE IRRADIATION AND COMBINATION THERAPIES ON PROSTATE CANCER CELLS

The overarching goal of this thesis is to establish a well-characterized platform to investigate the biological effectiveness of alpha-particle irradiations and to improve the efficacy of targeted alpha therapy on prostate cancer in combinatorial regimens. To that end, we have evaluated in vivo distribution of α particle radiotherapeutics, and in vitro effects using a novel α particle irradiation device. First, we have evaluated the effect of age in bone-targeting properties of the first approved α particle radiotherapeutic, Radium-223 dichloride. We also compared the biodistribution of therapeutic agent 223RaCl2 with the other two bone-seeking radionuclide imaging agents, 99mTc-MDP and Na18F. Na18F presented a high similarity with 223RaCl2 in skeletal uptake, which validates the potential of Na18F as an imaging surrogate to predict Radium-223 radiotherapeutic distribution in bone. To better understand the biological response of healthy and cancerous cells to irradiation, we have engineered and evaluated a high throughput α particle emitting irradiation platform. We have characterized the bench-top platform for accurate dosimetry, using semiconductor detection and Monte Carlo detection. Then, based on the well-characterized platform, we have observed the consistent potency of α particle radiation over the conventional X-ray radiation across a variety of prostate cancer cell lines. Aiming to improve the efficacy of radiotherapy in prostate cancer, we studied the biological effectiveness of radiotherapy in combination with androgen receptor (AR)-targeted therapies, including AR antagonist and supraphysiological androgen treatment. Our work revealed that enzalutamide, an AR antagonist, could delay DNA damage repair in irradiated cells, and the combination of radiation with enzalutamide could further inhibit AR-positive prostate cancer cell growth than radiation alone. Moreover, supraphysiological androgen treatment, as a monotherapy and in combination with radiation, can significantly inhibit AR-positive prostate cancer cell growth, even more effective than AR antagonist. Our research highlighted the role of AR in radiosensitizing cells and the diversity of cell resistance to therapy, which could provide more insights on treatment selection based on patient disease characteristics to generate better clinical outcome