CRISPR to cure "cancer"

[scarbrtj]

In the NEJM... CRISPR treatment of a man's HIV and his "cancer," an ALL. Cancer has been and always will be an aberration in host DNA. XRT (and traditional chemo to some extent) doubles down on this to make (part of) the host's DNA so aberrant the cells go from relative immortality to zero chance of multi-generational replicative ability. Or, at least in the case of long-term cure this is thought to happen. I always say, "Radiation was the first genetic therapy," but I never really see that exact turn-of-phrase anywhere else. I haven't had to study for a radiation oncology "cancer biology" exam in my life so I don't really know if CRIPSR could theoretically cure real cancer. Maybe someone else could weigh in with his/her two cents. This is supposedly "quite an historical moment."

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[Krukenberg]

In the NEJM... CRISPR treatment of a man's HIV and his "cancer," an ALL. Cancer has been and always will be an aberration in host DNA. XRT (and traditional chemo to some extent) doubles down on this to make (part of) the host's DNA so aberrant the cells go from relative immortality to zero chance of multi-generational replicative ability. Or, at least in the case of long-term cure this is thought to happen. I always say, "Radiation was the first genetic therapy," but I never really see that exact turn-of-phrase anywhere else. I haven't had to study for a radiation oncology "cancer biology" exam in my life so I don't really know if CRIPSR could theoretically cure real cancer. Maybe someone else could weigh in with his/her two cents. This is supposedly "quite an historical moment."

I don’t believe CRISPR was used to treat his cancer. The ALL was treated with the BMT and CRISPR was used to try to treat his HIV.

That being said I think CRISPR can be used to create cell-based therapies but to this point they haven’t worked well for solid tumors.

 

[ramsesthenice]

In the NEJM... CRISPR treatment of a man's HIV and his "cancer," an ALL. Cancer has been and always will be an aberration in host DNA. XRT (and traditional chemo to some extent) doubles down on this to make (part of) the host's DNA so aberrant the cells go from relative immortality to zero chance of multi-generational replicative ability. Or, at least in the case of long-term cure this is thought to happen. I always say, "Radiation was the first genetic therapy," but I never really see that exact turn-of-phrase anywhere else. I haven't had to study for a radiation oncology "cancer biology" exam in my life so I don't really know if CRIPSR could theoretically cure real cancer. Maybe someone else could weigh in with his/her two cents. This is supposedly "quite an historical moment."

Uncertain at best. In my view, no gene therapies will cure cancer for the same reason targeted therapies don’t work. Mostly because there are almost no true driver mutations, redundant signaling, and tumor heterogeneity. On top of it all, there are no perfect delivery systems. You will never modulate every, or even close to every tumor cell with any gene therapy, though theoretically you could engineer a vector to target CSCs or other proliferative sub populations. IMHO, the most realistic potential for all gene therapies in cancer is to manipulate the phenotype to one that is more responsive to RT, chemo, or immunotherapies. In this setting, partial and/or transient modulation may be sufficient to promote meaningful clinical gains. But in the near future, no gene therapies (CRISPR included) are going to be magic bullet cures on their own.

 

[nkmiami]

CRISPR may not address malignant cells per se (would be impossible to affect every malignant cell), but certainly can be used to change the immune system, which could do the job. Just wanted to post a talk from the other day by David Sinclair at Harvard about gene therapy, cancer, and reversing aging. It also clearly outlines a mechanism for radiation hormesis, (dna breaks activate sirtuins/stress pathways associated with longevity)

" are almost no true driver mutations"- that is true for genes, but certainly there are a lot of mutations/changes in the dna between genes-dna that encodes micro rnas, long and short non coding rnas, retrotransposons (all the stuff we used to think of as junk dna). genes only make up 2-3% of dna, although 98% is transcribed and presumably important. Next generation sequencing may not reveal a mutation in a gene, but its expression can be drastically changed by a mutation in regulatory dna between the genes. a drug recently was approved for the treatment of a type of amyloidosis that targets a micro-rna.

#70 - David Sinclair, Ph.D.: How cellular reprogramming could slow our aging clock (and the latest research on NAD) - Peter Attia

In this episode, David Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School and co-Director of...

peterattiamd.com

 

[Lamount]

As I understand it, CRISPR can remove specific segments of DNA as well as insert genes, but does so fairly inefficiently (I.e will only work on a small percentage of cells in vivo). Thus, CRISPR is most effective when the edited cells have a survival advantage over dysfunctional native cells (E.g DNA is edited to reintroduce the gene for a deficient/mutated enzyme or the edit allows the cell to survive a viral infection). With cancer, the native cells are “dysfunctional” BECAUSE of their survival survival advantage. Cancer cells will always outlive benign cells. Perhaps CRISPR can be used to prime the immune system to better recognize tumor antigens (as mentioned above), but one would need to know how to code an optimal TCR or antibody... and if you can do that, why not just make a biological agent? With regards to cancer, CRISPR is most likely to help with research (I.e creation of tumor models)

 

[Krukenberg]

CRISPR will be revolutionary for diseases caused by a single gene mutation, esp heme like SCID or sickle
Cell since you can do an auto transplant with engineered cells. Somatic mutations in non-heme like CF would have to be corrected as an embryo which is much more problematic ethically.

 

[ramsesthenice]

CRISPR may not address malignant cells per se (would be impossible to affect every malignant cell), but certainly can be used to change the immune system, which could do the job. Just wanted to post a talk from the other day by David Sinclair at Harvard about gene therapy, cancer, and reversing aging. It also clearly outlines a mechanism for radiation hormesis, (dna breaks activate sirtuins/stress pathways associated with longevity)

" are almost no true driver mutations"- that is true for genes, but certainly there are a lot of mutations/changes in the dna between genes-dna that encodes micro rnas, long and short non coding rnas, retrotransposons (all the stuff we used to think of as junk dna). genes only make up 2-3% of dna, although 98% is transcribed and presumably important. Next generation sequencing may not reveal a mutation in a gene, but its expression can be drastically changed by a mutation in regulatory dna between the genes. a drug recently was approved for the treatment of a type of amyloidosis that targets a micro-rna.

#70 - David Sinclair, Ph.D.: How cellular reprogramming could slow our aging clock (and the latest research on NAD) - Peter Attia

In this episode, David Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School and co-Director of...

peterattiamd.com

The term driver mutation refers to a singular event that promotes and supports the oncologic process. The 9:22 fusion in CML is one of the very few driver mutations in cancer. Gleevec can provide complete and long-term disease control. All other targeted therapies fail because virtually all cancers are the result of a compilation of defects. Doesn't matter if you referring to genes, non-coding DNA, miRNAs, proteins. Editing a single DNA element of any kind will ultimately fail for the same reasons.

 

[nkmiami]

driver mutations concept as developed by Vogelstein are mutations that improve fitness of cancer cells. As opposed to bystander mutations which accumulate randomly from extra cell
Divisions and genetic instability in cancer. voglesteins models predicted that in general most solid malignancies would have 4-6 driver mutations, but after genome was sequenced they found much less than that and feel much of those mutations are in dna outside of genes.

 

[scarbrtj]

CRISPR back in news, again, re: cancer, the world's most debilitating genetic disease. Radiation, the original genetic therapy, always getting challenged I guess...
CRISPR Approach To Fighting Cancer Called 'Promising' In 1st Safety Test

It's already "curing" sickle cell, aka "sick as hell anemia," which is pretty great.

Here's a not too bad animation about CRISPR.

 

[Palex80]

Hematologic malignancies and hematologic disorders are unique in being strictly clonal. Usually all the cells look the same and therefore share the same weakness/target. It's why CML is "curable" nowadays with TKIs while the same cannot be said for EGFR-mutated NSCLC.

 

[scarbrtj]

Hematologic malignancies and hematologic disorders are unique in being strictly clonal. Usually all the cells look the same and therefore share the same weakness/target. It's why CML is "curable" nowadays with TKIs while the same cannot be said for EGFR-mutated NSCLC.

Polyclonality likely to be a big challenge esp in NSCLC.