Comment by hn_throwaway_99
2 years ago
Very interesting article!
I'm curious if anyone in the field can comment how this compares to other targeted cancer therapies.
That is, the way these drugs are created is essentially one "end" of the drug binds to a protein that is specific to cancer cells. That end is attached to some radiogenic nuclide that is then taken up by the cancer cell which damages DNA and then causes cell death.
It's seems to me, as a layman, that the hard part would be designing the "targeting" end of the drug, but I would think that there would be a whole host of agents/poisons that you could attach to that targeting end that would damage the cancer cell. The article talks at length about the practical manufacturing complexities of getting the radioactive substance attached to the targeting molecule an delivering it in a timely fashion. So my question is, why is using a radioactive agent here better than using some cytotoxic chemical agent? Seems to me like using some chemical poison would be easier to manufacture and deliver than radiation.
I have no experience in this field so just curious.
Disclaimer: Haven’t read the article.
Radiation has benefits that your chemical cytotoxics do not. An individual tumor often comprises of many subclonal cancer cell populations, all of which could have unique resistance mechanisms to allow that subclone to survive and proliferate in the presence of a single cytotoxic payload (say from an antibody-drug conjugate).
Targeting cancer cells with a radioactive payload can bypass many resistance mechanisms common to cytotoxic payloads.
Pluvicto (lutetium-177) is one of the hotter radioligand therapies as of late (approved for metastatic prostate cancer). Take a look at Fig 1a here - the responses can be quite striking for patients with extensive metastatic disease: https://www.frontiersin.org/articles/10.3389/fnume.2023.1291...
What I find most interesting are the supply chain challenges and logistics for radioligand therapies. Given the half-life of the payload, this is not something one can just manufacture and set on a shelf for the next patient. And of course the regulations involved with anything radioactive provide additional challenges.
> Radiation has benefits that your chemical cytotoxics do not. An individual tumor often comprises of many subclonal cancer cell populations, all of which could have unique resistance mechanisms to allow that subclone to survive and proliferate in the presence of a single cytotoxic payload (say from an antibody-drug conjugate).
Interestingly cancers can develop resistance to radiation induced cell damage as well.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914062/
It's been known for a while since distal metastases would develop when primary tumors were treated with radiation.
What might be interesting is dual treatment - use a cytotoxin-link and radionuclide-linked antibodies together. No idea if it's been tested, but it's an obvious approach since combination therapy is being attempted with damn near every cancer therapy.
I get that radiation is generally biocidal, but so are a lot of things.
Following the reasoning of the parent comment,
> It's seems to me, as a layman, that the hard part would be designing the "targeting" end of the drug
It fits nicely with this statement:
> An individual tumor often comprises of many subclonal cancer cell populations, all of which could have unique resistance mechanisms
If the unique features of a tumor cell are the lock, then your search space has a relatively small number of keys, compared to a larger toolkit of known biocides. The key needs to fit a specific cancer cell, while the biocide merely needs to avoid the cancer cell’s needle-in-a-haystack resistance mechanisms, which are tailored for surviving in the human body rather than against laboratory chemicals. The harder problem seems to be finding the one or more keys needed to target a diverse population of cancer cells.
> why is using a radioactive agent here better than using some cytotoxic chemical agent? Seems to me like using some chemical poison would be easier to manufacture and deliver than radiation.
It's a question of dose, you need very small amount of radioactive molecules for it to be effective, cytotoxic drugs need much higher doses and harm healthy tissues even when you try to highly target it to some over-expressed receptors on he cancer cells
Non-radioactive poisons are also used in targeted therapies.
Perhaps one advantage of these agents is that they degrade fast enough that they cause relatively limited harm after destroying their host cell, maybe unlike other poisons?
> Non-radioactive poisons are also used in targeted therapies.
you also risk selecting for some population of cancer cells to become resistant, thereby changing their biochemical profile and finding other drugs that work can become tricky
Because the body is robust to chemical interference but not the energy scale of radioactive decay.
1 atom undergoing fission has energy to kill a cell made of 1 trillion atoms.
I feel the same way reading this. Nuclear tech sometimes comes across as a solution searching for a problem — here, a treatment searching for a disease.