Imaging, Dosimetry and Radiobiology for α-particle Emitter Radiopharmaceutical Therapy

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Treatment for almost all patients with metastatic cancer has become a balance between managing often severe, treatment-induced toxicity and preventing cancer progression. Progression leads to increasingly toxic combination regimens until the patient succumbs either to treatment toxicity or to disease progression. Radiopharmaceutical therapy (RPT) is an emerging treatment modality that delivers radiation to targeted cells. Alpha-particle-emitter RPT (αRPT) is a new and fundamentally different therapeutic modality that can break this cycle. It is the only modality that can deliver highly potent, α-particles to disseminated cancer metastases. Fundamentally, it is a radiation delivery modality. The radiation type delivered is far less susceptible to the resistance mechanisms or unanticipated side-effects observed with biologic (or pathway inhibition) therapy and chemotherapy. Despite these key differences, αRPT is being administered in a prolonged multi-cycle scheme that severely compromises the potential efficacy of this treatment modality. In large part, this is because rigorous, validated dosimetry methods for α-emitters do not exist. Such methods would make it possible to project potential normal organ toxicity for individual patients so that treatment need not be prolonged for the sake of toxicity evaluation. Our primary objectives are: 1) to develop and test dosimetry methodologies that will enable precision medicine/treatment-planning-based αRPT for cancer therapy and 2) to gain the understanding needed to optimize combination therapies involving αRPT. The hypotheses underpinning this program project grant are as follows: 1. αRPT is a systemic cancer therapy modality that is particularly applicable to targeting metastatic cancer; it is far less susceptible to conventional resistance mechanisms. It is also amenable to dosimetry-driven treatment planning. 2. As currently implemented αRPT is not achieving its potential. Dosimetry-driven treatment planning for RPT has been demonstrated to substantially improve long-term survival. 3. No one cancer treatment modality is curative, and patients differ in their potential therapeutic response and toxicity. Promising agents are inevitably combined with other therapeutics. Although mechanistic studies are used to point towards rational combinations, clinical trials continue to be largely empirical in terms of the sequencing and amount of each administered drug. A dosimetry and radiobiology-driven approach will substantially reduce the scope of human experimentation. Considering these hypotheses, our overall objective is to develop methodologies and investigate how best to transition RPT implementation from that of a “radioactive chemotherapy paradigm” to one more closely aligned with treatment planning for radiation delivery. These foundational hypotheses motivate the work proposed in this program project. Put very simply: dosimetry has been proven to improve outcome for RPT agents but dosimetry for alpha-emitters is hard. Five years support of this program project will make αRPT dosimetry easy enough to implement widely and thereby improve survival for currently incurable cancers.