Strategies to restore p53 function to human cancers

Because of its central role in tumor suppression, p53 and its pathways have been recognized as a prime target for developing new cancer therapies [13, 24, 27, 35, 40, 46, 58, 64], and various strategies have been pursued. Wild-type p53 may be delivered through gene therapy approaches regardless of the p53 status of the cancer [3, 19, 71, 83, 92, 105]. Cancer cells lacking p53 function can be specifically targeted with mutant adenovirus [6, 63] or adeno-associated virus [80]. Inactive wild-type p53 and some p53 cancer mutants may be reactivated through targeting of the very carboxy-terminal putative autoregulatory domain of p53 with antibodies [1, 33, 41, 72] or peptides spanning part of this region [2, 42, 86]. If MDM2 overexpression is responsible for p53 inactivation, the inappropriate interaction between MDM2 and p53 may be disrupted by peptides and compounds [21, 40, 87]. The pursuit of this strategy has resulted in very potent small-molecule inhibitors of MDM2 [54, 94]. Yet, all these strategies have their limitations, such as lack of efficient local and/or systemic delivery, undesirable responses of the host immune system to the therapeutic agent, lack of specificity for the cancer cell and/or targeting of a small subset of human cancers.

Besides these strategies, one approach appears particularly appealing: small chemical compounds that endow p53 cancer mutants with function by restoring the integrity of the p53 core domain. Such compounds are highly desirable, because of the high frequency of p53 mutations and the large number of patients who could potentially benefit. It has been estimated that every year approximately 360,000 patients in the USA and 2.6 million patients worldwide are diagnosed with cancers that contain p53 mutations [34, 35]. This subset of human cancers (including lung, prostate, colorectal, breast, head and neck, pancreatic, and gastric cancers) is often resistant to conventional therapies and difficult to treat at advanced stages [5, 18, 24, 31, 35, 38, 58].

The strategy is, at least in theory, possible because of the unique pattern of p53 missense mutations in human cancers. Typically, p53 cancer mutants are full-length proteins with an intact transactivation domain and carboxy-terminal tetramerization domain. The problem is the altered core domain (amino acids 96-292) whose structural integrity needs to be restored in order to have functional p53. Compounds able to achieve this goal are predicted to be specific for the cancer cells, since the structurally intact wild-type p53 core domain of surrounding normal cells should not be affected. Furthermore, p53 cancer mutants are typically present at very high levels (thus providing a large drug target), since their lack of transcriptional activity abrogates negative feedback loops, such as with MDM2 [55]. The approach also has the advantage of combining systemic delivery with lack of a host immune response.

The attractive features of this strategy are easily rivaled by the enormous challenges it poses: such compounds may simply not exist, or, if they do, they may rescue only a very small fraction of the close to 1,000 different known p53 cancer mutants that have one amino acid change in the core domain. On a more optimistic note, looking at missense mutations of the p53 core domain (71% of the database entries; R9,, the 50 most frequent amino acid changes account for 55% of the total number, and of these 50, the 8 most common amino acid changes comprise the majority of them (30% of the total). Thus, chemical compounds that rescue a subset of these p53 mutants are likely to correspond to a large number of cancer patients.

Also, as a proof of principle, two classes of compounds have already been identified in large drug screens that appear to have the desired characteristics. The first screen utilized an antibody-based screening strategy that relied on partially unfolded wild-type p53 due to elevated temperatures. The isolated compounds appeared to partially restore function to a few p53 cancer mutants [25]. However, further characterization of the lead compound CP-31398 has thus far not established the exact mechanism of rescue. In addition, CP-31398 appears to have strong p53-independent activities [13, 16, 82, 93].

The second class of compound was isolated using a mammalian growth suppression assay [16]. Very impressively, this compound rescued the most common p53 cancer mutant R175H whose core domain is very likely entirely denatured [13-16, 106]. It still remains to be determined how many others of the most common p53 cancer mutants will be rescued by this compound and what the exact mechanism of rescue is.

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