Advanced

Targeting prostate cancer stem cells with alpha-particle therapy

Elgqvist, Jörgen and Ceder, Jens LU (2017) In Frontiers in Oncology 6.
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... (More)
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. © 2017 Ceder and Elgqvist. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Frontiers in Oncology
volume
6
pages
11 pages
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85012123667
  • wos:000391399500001
ISSN
2234-943X
DOI
10.3389/fonc.2016.00273
language
English
LU publication?
yes
id
8579fa50-879e-4a69-b7a5-b1458df9036c
date added to LUP
2017-01-05 21:53:37
date last changed
2018-01-16 13:22:34
@article{8579fa50-879e-4a69-b7a5-b1458df9036c,
  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. © 2017 Ceder and Elgqvist.},
  articleno    = {273},
  author       = {Elgqvist, Jörgen and Ceder, Jens},
  issn         = {2234-943X},
  language     = {eng},
  month        = {01},
  pages        = {11},
  publisher    = {Frontiers Media S. A.},
  series       = {Frontiers in Oncology},
  title        = {Targeting prostate cancer stem cells with alpha-particle therapy},
  url          = {http://dx.doi.org/10.3389/fonc.2016.00273},
  volume       = {6},
  year         = {2017},
}