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Friday, May 29, 2015 8:51:09 PM
It's interesting that in some ways, they kind of talk against their own drug, which reactivates some mutant forms of p53.
"the structural heterogeneity of mutant p53 proteins raises concerns as to the feasibility of designing or identifying therapeutic agents that can rescue more than one specific mutant form of p53 or a subset of mutants."
I think I may have mentioned this before, that perhaps their mutant p53 reactivation drug may only work on a few selected mutants.
Further, they argue it may be better to eliminate the mutant p53 rather than reactivate it. That's kind of the whole point of the article - focusing on p53 as an oncogene. p53 is typically considered a tumor suppressor gene, so loss of it causes cancer. This isn't necessarily the most important thing about p53 mutations, however, as mice without p53 don't develop aggressive cancer. Rather it's mice with certain mutant p53 that develop aggressive carcinomas like seen in humans. Thus, it isn't the loss of normal p53 that's as important as the gain of some new harmful function in mutant p53 that is critical (and these different functions may vary considerably).
Reactivating the transcriptional activity of mutant p53 may not be that important, as mice without 3 important genes transcriptionally activated by p53 (p21, PUMA, and NOXA) do not get cancer! So, p21 activation via reactivated mutant p53 may not be that important. It may still serve as an important biomarker for us, however.
What is it, then, that causes cancer with mutant p53? If it's not the loss of normal function (esp. the transcriptional function), then perhaps it's the gain of some new oncogenic "gain of function" (GOF).
"the realization that mutant p53 can have GOF activity may open possibilities for therapeutic strategies designed to inhibit these functions, which may be easier to achieve than full restoration of wild-type function."
and the ideas is repeated again:
"In light of the growing evidence in favor of GOF activities of mutant p53, a more modest but still attractive aim for therapeutic targeting of mutant p53 is inhibition of the oncogenic properties of mutant p53 (Figure 4). This may be easier to achieve than full restoration of wild-type function."
They talk briefly about removing mutant p53 via the HSP90 (and HDAC6) method as shown in Figure 4.
They then describe one strategy for nonsense mutations, where the protein code reading is abnormally stopped: to have drugs that help "read through" the abnormal stop signal and produce the full protein instead of a non-functional truncated one.
Their conclusion fits with what I was thinking the last few days, how different mutants might be treated with different drugs, depending on what the mutants do:
"defining p53 mutants as oncogenes with heterogeneous GOFs that affect multiple pathways must be considered. Designing drugs to target specific p53 mutants seems an attractive strategy, as several of these mutants are among the most frequent protein variants found in several cancer types and associated with the death of 4 120,000 patients worldwide."
Looking forward to seeing new details of the Kevetrin trial from the poster tomorrow - especially later to see if Kevetrin works best with normal p53 or certain p53 mutants.
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