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Mutant p53 as a Potential Target Across Many Cancer Types


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Posted 30 June 2016 - 10:51 PM


In the scientific commentary I'll point out today, the authors advocate for the expansion of efforts to target mutations of the cancer suppressor gene TP53, encoding the protein p53, as a path to cancer therapies that might be broadly applicable to many cancer types. As I've noted in the past, the biggest problem with the majority of today's cancer research isn't that it is challenging and expensive, but rather that the therapies resulting from these efforts are only applicable to one or a few of the hundreds of subtypes of cancer. This is no way to defeat cancer; there are too few scientists and too little funding to do things this way, one cancer at a time. What is needed is a shift in high level strategy to focus much more aggressively on paths that will produce technology platforms that can, out of the box, target a wide variety of cancers, or where the cost of adapting the technology to different cancer types is very low.

This strategic focus is the reason for the SENS-advocated approach of blocking telomere lengthening, for example. All cancers must lengthen telomeres in order for continual cellular replication to take place, and there are a limited number of mechanisms by which that can happen. Without telomere lengthening, a cancer will wither away in short order. This is the most cost-effective way to deal with cancer: a small set of targets that can lead to a truly universal cancer therapy, a technology platform that can be easily adapted to each new type of cancer. That research is still in its early stages, and still very much in search of widespread support, however. Closer to the mainstream you'll find things like the use of chimeric antigen receptors in immunotherapy, which is an incremental improvement over most therapies from the past few decades in that it should have a reduced cost to adapt the technology to attack a wide variety of cancer types.

This leads to the research review for today, in which scientists note that TP53 is mutated in half of all cancers, and therefore an attractive target. This is somewhat conditional on the ability to produce an effective therapy from this basis, of course, but it seems a plausible goal at this point in time. The worst outcome would be to find that targeting p53 caused a large fraction of cancers to evolve around that attack, and turn into varieties that did not depend on p53 mutations to survive and grow. This is unfortunately a fairly likely outcome - it has been observed in the field in connection with other cellular mechanisms. It is also what makes a blockade of telomere lengthening, as mentioned above, very attractive: telomere-related mechanisms are so very fundamental to cellular replication that cancer cells should be incapable of evolving new ways around that attack. Regardless, it is always good to see more discussion in the cancer research community that acknowledges the problems in the field, and proposes technical solutions to those problems:

Targeting mutant p53 for cancer therapy

The p53 tumor suppressor protein serves as a major barrier against cancer; consequently, mutations in the TP53 gene, encoding p53, are the most frequent single genetic alteration in human cancer, occurring in about half of all individual cancer cases. Besides abrogating the tumor suppressive effects of the wild type (WT) p53 protein, many of the TP53 mutations endow the mutant p53 protein with new oncogenic gain-of-function activities, which actively promote a variety of features characteristic of aggressive tumors, such as increased migratory and invasive capacities and increased resistance to many types of anti-cancer therapy agents. This realization has led to extensive attempts to restore full p53 functionality in cancer cells, as a novel cancer therapy strategy. However, these attempts have been seriously hampered by the fact that p53 has no known enzymatic activities, and rather operates primarily as a sequence-specific transcription factor. Furthermore, restoring the activity of a defective tumor suppressor protein is vastly more difficult than abrogating the activity of a hyperactive oncoprotein.

Nevertheless, significant advances have been achieved in recent years, and hopes for the introduction of p53-based novel cancer therapies into the clinic are becoming increasingly supported by evidence. In principle, attempts to develop such therapies have taken 3 main approaches: [1] Introduction of WTp53, mainly via viral transduction ("gene therapy"), into tumors that have sustained TP53 mutations; [2] enhancement of the functionality of the endogenous WTp53 in tumors that have retained a non-mutated TP53 gene, mainly be disrupting the interaction of the WTp53 protein with its major negative regulator MDM2; and [3] "correction" of the mutant p53 protein in tumors that have sustained TP53 missense mutations, thereby restoring its ability to perform the tumor suppressive activities of WTp53.

The latter approach, namely the "re-education" of mutant p53, is particularly appealing. First of all, it can simultaneously reinstate WTp53 tumor suppressive activity together with abrogating the gain-of-function oncogenic effects of the mutant p53 protein. Additionally, since cancer cells bearing TP53 missense mutations often accumulate massive amounts of the mutant p53, its conversion into a WT-like state will potentially flood the cancer cell with excessive amounts of tumor suppressive p53, far beyond what one finds in normal cells. This may provide a large therapeutic window and may potentially circumvent the severe limiting toxicity observed with compounds that augment the activity of non-mutated p53 in cancer cells.

Indeed, attempts to "re-educate" mutant p53 in cancer cells have seen substantial progress in the last several years. The most advanced effort has identified a small molecule named PRIMA-1, which can reactivate mutant p53. We have opted for a different approach, based on identification of small peptides that specifically stabilize mutant p53 proteins in a functional state. These peptides can stabilize the WT conformation of mutant p53, and restore its ability to activate canonical WTp53 target genes. Moreover, they promote selective apoptotic death of cancer cells harboring mutant p53, and very effectively reduce, and even completely block, the growth of human cell line-derived mouse xenograft tumors representing several types of highly aggressive cancer. Importantly, all common p53 mutants tested in our study were found to be amenable to functional stabilization by these peptides. Bringing small peptides into the clinic remains challenging, mainly owing to the need to deliver the peptides efficiently into the tumor cells. Nevertheless, their greater specificity, relative to small molecules of the types described above, bears the hope for minimal non-specific toxicity, rendering such approach potentially highly promising in the long run.


View the full article at FightAging




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