The case for a therapeutic cancer vaccine
RAS proteins are important for normal development. Active RAS drives the growth, proliferation, and migration of cells. In normal cells RAS receives signals and obeys those signals to rapidly switch between the active (GTP) form and the inactive (GDP form) states. Mutated RAS* is stuck in the active state, ignores signals to the contrary, and drives cells to become cancerous.
https://www.cancer.gov/research/key-initiatives/ras/about
Despite repeated attempts, researchers failed to develop a drug that could inhibit the activity of RAS proteins in cancers. They had hoped to find a small molecule that could preferentially bind the unique features of the RAS protein, but they couldn’t find a surface on the protein that would bind a drug.https://www.cancer.gov/research/key-initiatives/ras/about
It is being increasingly recognized that cell signaling is being carried out via phase separation of liquid compartments consisting of the signaling components.
https://pubmed.ncbi.nlm.nih.gov/31792379/
https://pubmed.ncbi.nlm.nih.gov/32203417/
I hypothesize that since, the mutant ras protein is stuck in an active signaling state, there should be a greater number of phase separated droplets in a cell carrying the mutant ras protein versus the wild-type ras protein. An effective drug should be able to inhibit the formation of these phase separated droplets.
In the 2010s, the Shokat Lab at the University of California San Francisco and the Fesik Lab at Vanderbilt University developed innovative drug screening and medicinal chemistry techniques that identified molecules that could bind mutated KRAS proteins. https://www.cancer.gov/research/key-initiatives/ras/about
Rationally designed drugs, may be used to target, matrix metallo-proteinases and collagenases, which are "ENZYMES" that function, to degrade the extracellular substrate in the tumor micro-environment,so as to inhibit cancer cells, escaping from the primary tumor into circulation, to establish secondary metastases. However, such drugs are works in progress.
The case..
Since many challenges exist toward developing effective anti-cancer drugs, another approach would be to develop a therapeutic anti-metastatic cancer vaccine, directed specifically toward the antigen profile of circulating tumor cells, that express altered levels and types of cell-surface biomarkers. The goal would be a multi-epitope anti-metastatic therapeutic cancer vaccine.
Such a vaccine would prevent secondary metastases, since data support the idea that the majority of deaths from solid tumors are caused by metastases. https://pubmed.ncbi.nlm.nih.gov/31397113/
When the drug fails to contain the primary tumor (anti-cancer drug resistance), the anti- metastatic cancer vaccine could prevent the spread of the primary tumor to secondary sites, by targeting tumor cells in circulation.
No comments:
Post a Comment