Emily
Editor, Senior Moderator
The concept of living with an incurable cancer for as long as well as possible -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968758/
Bordonaro M. Hypothesis: Cancer Is a Disease of Evolved Trade-Offs Between Neoplastic Virulence and Transmission. J Cancer. 2018;9(10):1707-1724. Published 2018 Apr 19. doi:10.7150/jca.24679
...
Of importance with respect to evolutionary optimization of therapeutics is the concept of “competitive release” [SUP]58[/SUP][SUP]-[/SUP][SUP]60[/SUP]. Neoplastic cells that are highly resistant to therapy often exhibit sub-optimal fitness compared to normal and low-resistant cells, due to costs incurred by the more resistant cells to maintain their phenotype. More highly resistant cells are held in check by the presence of those less resistant (these less resistant cells are more fit in the absence of the therapeutic selective pressure), in a form of niche and resource competition. However, elimination of normal and low-resistant competitors (e.g., by therapy) releases the more resistant cancer cells from this competition, allowing for the outgrowth of a resistant and virulent tumor.
An example using anti-microbial chemotherapy is illustrative [SUP]60[/SUP]. High dose therapy has trade-offs. On the one hand, it attempts to select against mutational development of resistance; on the other hand; it more effectively eliminates less resistant pathogens, facilitating competitive release and expansion of highly resistant strains [SUP]60[/SUP]. Low dose therapy would have the opposite effect; it would preserve less resistant competitors (good) but provide greater opportunity for the development of resistance (bad). Intermediate dosing, which is the most common clinical choice (as the “middle ground” between potential toxicity of higher doses and decreased effectiveness of lower doses), is the worst choice, as it both facilitates mutational resistance and facilitates competitive release by eliminating more benign microbial competitors [SUP]60[/SUP]. Thus, optimal dosing typically lies at the extremes of the continuum (high or low), with the choice dependent on context [SUP]60[/SUP]. This principle applies to cancer, and has been demonstrated experimentally [SUP]58[/SUP][SUP],[/SUP][SUP]59[/SUP].
The underlying evolutionary rationale is that highly chemoresistant cancer cells incur costs (resources, energy, etc.) to maintain resistance and as such are less fit than less resistant cells in the absence of the chemotherapeutic selection. Similarly, by analogy, researchers who perform plasmid preps understand that the bacteria must be grown under antibiotic selection to retain the plasmid; otherwise, bacteria that have lost the plasmid will overgrow the others, since they no longer incur the (unnecessary in the absence of antibiotic selection) cost of reproducing the plasmid along with their own genome. For cancer therapy, it is therefore optimal to maintain a population of therapy-sensitive cells to restrain resistant outgrowth via intratumor competition [SUP]58[/SUP]. Thus, maximal dose therapy, which would eliminate the less-resistant and non-resistant populations, is to be avoided, and replaced by flexible, minimal regimens that restrain tumor growth without facilitating competitive release of more resistant strains from the intratumor competition. This approach was experimentally verified in a orthotopic mouse model of breast cancer [SUP]59[/SUP]...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968758/
Bordonaro M. Hypothesis: Cancer Is a Disease of Evolved Trade-Offs Between Neoplastic Virulence and Transmission. J Cancer. 2018;9(10):1707-1724. Published 2018 Apr 19. doi:10.7150/jca.24679
...
Of importance with respect to evolutionary optimization of therapeutics is the concept of “competitive release” [SUP]58[/SUP][SUP]-[/SUP][SUP]60[/SUP]. Neoplastic cells that are highly resistant to therapy often exhibit sub-optimal fitness compared to normal and low-resistant cells, due to costs incurred by the more resistant cells to maintain their phenotype. More highly resistant cells are held in check by the presence of those less resistant (these less resistant cells are more fit in the absence of the therapeutic selective pressure), in a form of niche and resource competition. However, elimination of normal and low-resistant competitors (e.g., by therapy) releases the more resistant cancer cells from this competition, allowing for the outgrowth of a resistant and virulent tumor.
An example using anti-microbial chemotherapy is illustrative [SUP]60[/SUP]. High dose therapy has trade-offs. On the one hand, it attempts to select against mutational development of resistance; on the other hand; it more effectively eliminates less resistant pathogens, facilitating competitive release and expansion of highly resistant strains [SUP]60[/SUP]. Low dose therapy would have the opposite effect; it would preserve less resistant competitors (good) but provide greater opportunity for the development of resistance (bad). Intermediate dosing, which is the most common clinical choice (as the “middle ground” between potential toxicity of higher doses and decreased effectiveness of lower doses), is the worst choice, as it both facilitates mutational resistance and facilitates competitive release by eliminating more benign microbial competitors [SUP]60[/SUP]. Thus, optimal dosing typically lies at the extremes of the continuum (high or low), with the choice dependent on context [SUP]60[/SUP]. This principle applies to cancer, and has been demonstrated experimentally [SUP]58[/SUP][SUP],[/SUP][SUP]59[/SUP].
The underlying evolutionary rationale is that highly chemoresistant cancer cells incur costs (resources, energy, etc.) to maintain resistance and as such are less fit than less resistant cells in the absence of the chemotherapeutic selection. Similarly, by analogy, researchers who perform plasmid preps understand that the bacteria must be grown under antibiotic selection to retain the plasmid; otherwise, bacteria that have lost the plasmid will overgrow the others, since they no longer incur the (unnecessary in the absence of antibiotic selection) cost of reproducing the plasmid along with their own genome. For cancer therapy, it is therefore optimal to maintain a population of therapy-sensitive cells to restrain resistant outgrowth via intratumor competition [SUP]58[/SUP]. Thus, maximal dose therapy, which would eliminate the less-resistant and non-resistant populations, is to be avoided, and replaced by flexible, minimal regimens that restrain tumor growth without facilitating competitive release of more resistant strains from the intratumor competition. This approach was experimentally verified in a orthotopic mouse model of breast cancer [SUP]59[/SUP]...
