A peptide that kills cancerous cells around the cancerous cell that are producing it (can be a peptide, however, any other approach will be appreciated)
mschiav3Apr 13, 2022
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Have you heard of buforin2b? or other cancer-depleting peptides? what if there is a peptide or something like a bacteriocin (the way bacteriocins work for bacteria) to cancerous cells? The best I can come up with is tricky engineered CRISPR ideas... which are, you know, tricky... I am looking for a way to turn the enemy into an ally, a cancerous cell modified to express a cancerous killing peptide. Be bold on the ideas, the crazy and the well-thought ones :)
Testing if it would work: Teaching tumor cells how to produce ACPs by the introduction of a transgene
jnikolaApr 29, 2022
A sort of dialysis, teaching, and reintroduction of cancer cells should be applied, to first see if the method would work. Then we should make sure these trained cells die, too.
Why?
ACPs are great cancer cell killers but are not naturally coded by the cells.
If applied systematically like chemotherapeutic they could harm all the cells, not only cancer.
Teaching only cancer cells to produce it locally would be great since it could destroy hard-to-reach solid tumors.
Required steps:
Isolation of solid tumor cells by biopsy of the mice.
Training cancer cells to produce the ACP by transfection of the transgene using plasmids.
Returning the trained cancer cells to the solid tumor mass.
Killing all the cancer cells.
How would it work?
Solid cancers would be grown in mice. Cancer cells would be extracted by biopsy and introduced to the "training". Training would consist of dialysis-like process where cells are extracted, transfected with a plasmid carrying a transgene for a ACP of choice, as well as a kill switch, and reintroduced to the solid tumor mass inside a mouse. After some time, kill switch is activated.
Problems:
How to make sure the introduced cancer cells producing peptide don't die too soon to not be able to spread the peptide?
How to make sure the introduced cancer cells producing peptide die soon enough to not support further tumor growth?
Additional information:
This idea was inspired by CAR-T cell immunotherapy. "Doctors collect a patient's T cells and place a protein on the outside of the cells. The engineered T cells are then injected back into the patient. The added protein has two roles: it guides the T cell directly to the tumor, and on arrival, it triggers the T cell's fighting power to attack the cancer cells. "This way you are attacking the cancer cell from the outside rather than from the inside, like with chemotherapy,"
Hi J. Nikola, that is one of the principles I am considering for creating a similar system. I have thought on the CAR-T approach, not in this specific way. I am currently working in a solution for treating cancerous cells, including that "turn the enemy into an ally" approach, and considering another concept to prevent resistance development. However, the Idea you propose is very interesting.
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Anticancer peptides were there all along!
Subash ChapagainApr 17, 2022
Anticancer peptides have existed all along in nature, and they’re being heavily pursued by biological scientists as an alternative to existing therapeutic interventions against cancer. In fact, I did a quick keyword search in PubMed, and this is what I got:
Anticancer peptides (ACPs) are a category of short peptides (30-60 amino acids long) that have anti-tumour activity. Not quite surprisingly, if you look into the database of clinical trials, there are already several clinical trial studies going on, and some ACPs have already been approved as well. ACPs are inherently cationic and amphipathic (hydrophobic and hydrophilic amino acids. Classically, ACPs were discovered to be antimicrobial in nature and only after 1985 they were found to have antitumour activities. Not just that, these peptides have antiviral, anti-biofilm, ant-parasitic and immune-modulatory activities as well.
Following are some ACPs with their modes of action shown in studies and clinical trials:
Destruction of cell membrane structure
ACPs can kill both the metabolically active as well as slow-growing tumours. HPRP-A1-TAT is a hybrid peptide that destroys the cell membrane causing leakage of cytoplasmic contents from the cancerous cells. This ACP has shown a significant effect in melanoma, gastric cancer, liver cancer and cervical cancer cells with an ICP50 value in the range of 10 uM, which is on par with the currently accepted therapeutic dosage. Temporin-La, another ACP derived from bullfrog skin enters cancer cells and destroys the tumour cell membrane. These ACPs are not toxic to the normal tissue and cells, and can selectively destroy the cancer cells.
Induction of Apoptosis
Some ACPs exert their antitumour activities by releasing cytochrome C to induce mitochondrial dysbiosis to cause programmed cell death of the cancer cells. Ra-V is one such ACP that triggers mitochondrial apoptosis by causing disruption of mitochondrial membrane potential, cytochrome C release and subsequent activation of the caspase apoptotic pathway in the human breast cancer cells. Dolastatin 10, an ACP isolated from marine mollusc Dolabella auricularia induces apoptosis in vitro in melanoma, sarcoma, colorectal cancer and ovarian cancer cells. Dolastanin 10 induces apoptosis in these cells by upregulating the pro-apoptotic gene Bax and downregulating the anti-apoptotic Bcl-2 gene . Another lipopeptide isolated from Bacillus subtilis caused ROS burst and mitochondria-dependent apoptosis in the myelogenous leukaemia cells .
Inhibition of tumour angiogenesis
Angiogenesis is the mechanism of the formation of new blood vessels. Cancer cells extensively use angiogenesis for nutrient transfer needed for their proliferation.
KV11 is a peptide that is native to human cells with just 11 amino acids, and it was found to reduce angiogenesis in the tumour model of human umbilical epithelial cells without any lethal effect in normal cells. KV-11 is found to actively suppress angiogenesis in breast cancer cells as well . PF1171A and PF1171C are two cyclic peptides from the soil living fungus Penicillium sp significantly reduced VEGF-induced migration, invasion, proliferation and neovascularization by downregulating the hypoxia-inducible factor-1 alpha, and phosphorylation of VEGF receptor . Temporin-1CEa is another ACP identified that inhibits the formation of new blood vessels in human melanoma. Since these ACPs indirectly kill the cancer cells, they have a strong promise for clinical application.
Immune regulation
Bovine lactoferrin (LfcinB) is lactoferrin derived cationic peptide that produces cytokines to boost host defence against the tumour of head and neck cells. This was brought about by activation of CD3+ cells.MENK is another endogenous neuropeptide that upregulates CD8+ T cells against tumour cells, acting as an immune booster.
These are only some selected examples of existing anticancer peptides. There are plenty other under investigation, and hopefully will be implied in clinical therapeutics.
Thank you for the detailed overview of the field. As I understood, anticancer peptides are useful molecules mostly isolated from other organisms or artificially synthesized. The only peptide you mention to be native to human cells is the KV-11, which is actually a part of the Apolipoprotein . In that context, native apolipoprotein is the only protein that is actually produced by the cells and potentially doesn't require genetic engineering techniques to be involved. Simple upregulation of its expression in cancer cells could be enough to potentiate beneficial effects, right?
However, I think mschiav3 was rather interested in how to "turn the enemy into an ally, a cancerous cell modified to express a cancerous killing peptide". You raised important candidates, but can you think of a method for how would you increase their expression around or inside cancer cells?
Thanks for taking the time to go through the contribution and more importantly pointing this question out. It helps to frame the solution around this specific problem.
To answer whether we can find ways to selectively express such ACPs in and around the tumour microenvironment, I think in principle it is doable.
How?
The first candidate that comes to my mind is the macrophage.
In this challenge from almost a year ago, I had briefed on how macrophages were engineered to carry a kind of ‘backpack’ that could be locked and loaded with a desired cargo and selectively driven to a tumour site to fight off cancer. What if we could use a similar approach to include these ACPs within the backpack, and let the macrophages do what they do best: eat up/destroy cancerous cells?
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jnikola2 years ago
Subash Chapagain Definitely seems doable!
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General comments
Michaela D2 years ago
The closest I can think about is indeed CRISPR. In a recent study, researchers used CRISPR as a way to create holes (double-strand breaks) in the DNA of cancer cells. CRISPR targeted indels (mutations) that were specific for those cancer cells . I am not aware of a peptide that would only kill cancer cells. Unless it is a generally toxic protein/peptide that is packaged and only delivered to cancer cells. That could be done by using an agent, like an antibody, that recognizes surface markers of cancer cells.
[1]Kwon, Taejoon, Jae Sun, Soyoung Lee, In-joon Baek, Keon Woo, and Eun A. Lee. 2022. “Precision Targeting Tumor Cells Using Cancer-Speci Fi c InDel Mutations with CRISPR-Cas9.” doi: 10.1073/pnas.2103532119/-/DCSupplemental.Published.
mschiav3 Apr 13, 2022
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