AB1, a novel protein targeting TP53 mutated GI tumors

96 Background: The tumor suppressor gene TP53 is one of the most frequently deleted or mutated genes in gastrointestinal cancers. Normal p53 regulates several important proteins that control cell cycle, cell death, DNA damage/repair, stemness, differentiation and other key cellular functions. If the TP53 gene is damaged, tumor suppression is severely compromised. On the other hand, and downstream of p53, p21 a potent cyclin-dependent kinase inhibitor (CKI) protein binds and inhibitsthe activity of cyclin - CDK2, - CDK1, and - CDK4/6, thus functioning as a regulator ofcell cycle progression at G 1 and S phase. It can act as de facto p53 repair/ replacement mechanism. We have thus hypothesised that, if we were able to deliver wild type p21 into all p53 mutated cancer cells, it would have a possible therapeutic effect. Methods: We have constructed recombinantly a new fusion protein, named AB1, composed of a cell penetrating protein (antennapedia) ANTP and wild type p21 and tested it in in vitro and in vivo preclinical models prior to clinical studies. AB1 could also be constructed semi-synthetically by conjugating recombinant ANTP chemically to p21 protein. Results: AB1 penetrated and killed p53 mutated cancer cells but did not kill cells that did not have p53 mutations AB1 penetrated but did not kill p53- or p21- wild-type cells. AB1 was not immunogenic in normal New Zealand White rabbits. AB1 was more cytotoxic when administered with conventionally-used chemotherapeutic agents. Conclusions: We have generated a selectively cytotoxic fusion protein against p53 mutated GI cancers which is effective when used as a single agent but more so when used in combination with chemotherapy. The phaseI/II clinical trial will include eligible patients who have p53 mutated GI cancers