there's a new field of "pan-cancer" where you make (mostly molbio) comparisons across cancers, including vulnerability screens where you use CRISPR or RNAi to knock down each gene and see which ones kill the cancer cells when absent.
https://link.springer.com/content/pdf/10.1186/s13059-023-03020-w.pdf CRISPR and RNAi both have their strengths and weaknesses but if you look at the overlap there are still a bunch of "pan-essential" genes that all cancers need to survive. (do healthy cells also need those, or are they good therapeutic targets? we just don't know.)
https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30656-5 when you target pan-essential genes you are in the chemo zone, where by default the therapeutic index is low (kills cancer AND healthy cells) and you need to put more work in to handling toxicity.
tumors -- most tumors -- get coated with IgG, much more than other tissues. is this a systemic defense against cancer or a tumor-secreted IgG? hard to say.
a call to work harder dammit and treat it like a true war on cancer, not a sedate and bureaucratic academic field
a call for more pan-cancer RNAi vulnerability screens
a call to focus on transcription factors as targets, particularly things like Myc and BRD4 that are particularly involved in the transition to metastasis -- we don't yet have any good drug therapies that work well on metastatic cancers
transcription factors are obviously causally upstream of what makes cancer cancer -- its invasiveness, its metastatic potential, its evasion of immune surveillance, etc
they are hard to drug though, because they're in the nucleus, not on the cell surface. but we can start to do hard things now!
cell surface growth factors (think EGFR) are the easiest to target but the associated drugs have unimpressive clinical effects in most patients because targeting growth factors only slows growth, it doesn't kill cancer cells. usually just slightly delays the inevitable.
a statement of his redox hobbyhorse -- ROS is good, ROS is how the body fights cancer, etc.
not sure how to operationalize this as a strategy. it might, as it turns out, be redundant with immunotherapy.
a couple specific targets/mechanisms he thinks deserve more attention -- apparently the circadian regulator PER2 is a tumor suppressor. i'm always down for more attention to circadian stuff.
the Halifax Project researched the hypothesis that low-dose combinations of environmental carcinogens might synergistically increase cancer risk:
https://en.wikipedia.org/wiki/CpG_oligodeoxynucleotide this is the inflammatory molecule on bacteria that's the reason bacterial infections sometimes cause complete regressions of very difficult tumors (like sarcoma -- we have no drugs for sarcoma! it's either surgery or death!). fortunately the immunooncology people are On It and researching this as an immunostimulant.
if you've heard of "Coley Toxins", they're kind of an alt-med thing with a tantalizing grain of truth -- but we don't need to inject bacteria into tumors any more, we know how they work, we can replicate the effect with well-defined compounds now.
basically this is using the same principle as old-fashioned chemo -- hit it in the DNA replication -- but with a new target, and with modern structural-biology-based rational drug design to hit the cancer version of the target rather than the healthy-cell type.
would I have guessed there was room for optimism here a priori? no way.
but apparently we have not explored this space sufficiently. now try it with AlphaFold.
https://www.nature.com/articles/s41419-021-04468-z inducible caspase 9 allows conditional apoptosis. it's incredibly powerful. unfortunately it doesn't always work and this raises drug resistance concerns.
I haven't yet seen many examples of "put the iCasp9 in the cell if-and-only-if the cell has some molecular marker" but that's the obvious place to go.
you can kinda reduce the drug resistance thing by putting a promotor to increase iCasp9 expression. buddy if this is where we are in 2022 i'm going to predict there is a LOT of potential value in continuing to work out the kinks in this system. get in on the ground floor!
https://www.sciencedirect.com/science/article/abs/pii/S0006291X0302504X if you actually measure what % of ATP comes from glycolysis, cancers cover a wide range, and the distribution overlaps substantially with the distribution of healthy cells. glycolysis dominance is not a distinguishing characteristic of all or even most cancers.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8274378/ mechanical stress is also a natural feature of cancer -- tumors get more rigid and experience pressure. in fact this stress can be a trigger for increased proliferation or metastasis, so watch out!
are cancer cells selectively vulnerable to electrical stress? also kinda yeah
https://www.mdpi.com/2072-6694/13/9/2283 "tumor treating fields", just an oscillating electric field, are actually an approved therapy in glioblastoma that extends life a few months. (not saying much though...glioblastoma is so deadly that it's easy mode from an FDA standpoint)
https://aacrjournals.org/cancerres/article/64/9/3288/517864/Disruption-of-cancer-Cell-Replication-by ah this actually IS a differential effect in tumor vs. non cancer cell lines. plus in vivo, in mice.
i don't even know man. somebody who knows physics explain this. little nanoelectrodes with some chemical functionalization kill cancer cells? "quantum biological tunneling?" https://www.nature.com/articles/s41565-023-01496-y
cancer cells have depolarized membranes -- you can literally distinguish them from healthy cells by voltage alone.
this is a Michael Levin thing. https://pmc.ncbi.nlm.nih.gov/articles/PMC3528107/ you can give a frog a tumor -- or make the tumor go away -- through manipulating voltage alone! it does not matter what ion channel you use, it's about the voltage.
literally, you can try this at home! stick a voltmeter across your boob!
https://aacrjournals.org/cancerres/article/40/6/1830/484668/Cellular-Potentials-of-Normal-and-cancerous cancerous cells have lower membrane potential than their healthy counterparts
something in (some of?) the neutrophils in (some) humans and a cancer-resistant strain of mice can kill cancer, including when transferred. a Zheng Cui research program.
my take is, he's not an immunologist and modern methods could elucidate the specific clonal population a LOT better than this, but I like the thought process.
https://www.cell.com/heliyon/fulltext/S2405-8440(17)31693-6 they did some infusions from young blood donors into 3 patients with advanced metastatic cancer got a bunch of tumor necrosis and a cytokine release syndrome. all died within 3 months though.
eg https://www.cell.com/cell-reports/pdfExtended/S2211-1247(22)00984-6 we can determine the "good guy" neutrophil subpopulation that infiltrates tumors and promotes an anti-tumor immune response: it's HLA-DR+CD80+CD86+ICAM1+PD-L1-. in metastasis these guys become PD-L1+ and immunosuppressive.
so like...the secret to replicating Zheng Cui's miracle mice...might be nivolumab?? don't get me wrong it's a good drug but this is anticlimactic.
https://www.science.org/doi/abs/10.1126/scitranslmed.3007646 alkylphosphocholine is a type of lipid especially present in cancer cells, across cancer types, via lipid rafts. a synthetic analog has preferential uptake in basically all rodent & human tumors. usable for imaging and radiotherapy.
they found a fusion transcript and a corresponding fusion protein -- the root cause
they did the reasonable thing: screen a compound library against tumor samples.
one hit is napabucasin, usually known as a STAT3 inhibitor (but that's not the mechanism here) but somebody owns it
another was irinotecan. and navitoclax...but navitoclax has platelet toxicity
irinotecan + a BcrX PROTAC is being investigated though
or you can just. shRNA the fusion transcript. that's a thing you can do now.
apparently Elana wanted to do that in 2013 but her dad said "pshaw RNA breaks down in the body." now Spinraza is a thing (antisense oligonucleotide.) not to mention the mRNA world. truly these are the days of miracle and wonder.