Targeting Prostate Cancer Stem Cells with Alpha-Particle Therapy

Abstract

Modern molecular and radiopharmaceutical development has brought the promise of tumor-selective delivery of antibody-drug conjugates to tumor cells for the diagnosis and treatment of primary and disseminated tumor disease. The classical mode of discourse regarding targeted therapy has been that the antigen targeted must be highly and homogenously expressed in the tumor cell population, and at the same time exhibit low expression in healthy tissue. However, there is increasing evidence that the reason cancer patients are not cured by current protocols is that there exist subpopulations of cancer cells that are resistant to conventional therapy including radioresistance and that these cells express other target antigens than the bulk of the tumor cells. These types of cells are often referred to as cancer stem cells (CSCs). The CSCs are tumorigenic and have the ability to give rise to all types of cells found in a cancerous disease through the processes of self-renewal and differentiation. If the CSCs are not eradicated, the cancer is likely to recur after therapy. Due to some of the characteristics of alpha particles, such as short path length and high density of energy depositions per distance traveled in tissue, they are especially well suited for use in targeted therapies against microscopic cancerous disease. The characteristics of alpha particles further make it possible to minimize the irradiation of non-targeted surrounding healthy tissue, but most importantly, make it possible to deliver high-absorbed doses locally and therefore eradicating small tumor cell clusters on the submillimeter level, or even single tumor cells. When alpha particles pass through a cell, they cause severe damage to the cell membrane, cytoplasm, and nucleus, including double-strand breaks of DNA that are very difficult to repair for the cell. This means that very few hits to a cell by alpha particles are needed in order to cause cell death, enabling killing of cells, such as CSCs, exhibiting cellular resistance mechanisms to conventional therapy. This paper presents and evaluates the possibility of using alpha-particle emitting radionuclides in the treatment of prostate cancer (PCa) and discusses the parameters that have to be considered as well as pros and cons of targeted alpha-particle therapy in the treatment of PCa. By targeting and eradicating the CSCs responsible of tumor recurrence in patients who no longer respond to conventional therapies, including androgen deprivation and castration, it may be possible to cure the disease, or prolong survival significantly.

Keywords: alpha particles; cancer stem cells; prostate cancer; radioimmunotherapy; targeted therapy.

Figure 1

Generalized image showing an antibody–drug complex (1), and a schematic way in which it is targeted to a cancer stem cell (CSC). The antibody should be specific for CSC-associated antigens so that its payload, in the shape of a therapeutic agent, is not delivered to normal cells causing unwanted side effects. The linker should firmly attach the therapeutic agent to the antibody, enabling delivery of the drug to its target (2), and not being released during circulation. The therapeutic agent should be able to kill the targeted CSC when the antibody–drug complex is either bound to the cell surface or internalized in sufficient numbers (3). Receptor-mediated endocytosis (4) of the payload (e.g., an alpha-particle emitting radionuclide or a cytotoxic agent) may cause disruption of cellular processes (including microtubule networks), mitotic arrest, or cell death due to double-strand breaks of the DNA (5). If the targeted antigen on all of the CSCs is sufficiently expressed, the therapeutic agent may eradicate the relapse-causing cells and eventually stop the disease. If for example beta-particles emitted from ⁹⁰Y or ¹⁷⁷Lu (maximum energy, maximum range, and average linear energy transfer (LET) equal to 2.3 and 0.5 MeV, 11.3 and 1.8 mm, and 0.18 and 0.20 keV/µm, respectively) are used as therapeutic agents, the number of hits to the CSC required to kill it would be at least in the order of 2,000. However, if alpha particles emitted from for example ²¹¹At or ²¹³Bi (maximum energy, maximum range, and average LET equal to 7.4 and 8.4 MeV, 66 and 80 µm, and 125 and 120 keV/µm, respectively) are used instead, the number of hits required would instead be in the order of 20. This means that the likelihood of eradicating the CSCs using alpha-particles greatly exceeds that of using beta particles, especially if the targeted antigen is expressed in low numbers on the CSCs. It should also be noted that, although the range of the alpha particles is in the order of typically only two to three cell diameters, some crossfire will still occur of neighboring eventually untargeted cells.