# Peptides That Block RAS-p21 Protein-Induced Cell Transformation
## 5 Assessment of Peptide Therapy for Ras-Induced Tumors
In this regard, a major problem in cancer treatment is pancreatic cancer for which the five-year survival remains low (about 5 percent). As it happens, 90 percent of pancreatic cancers contain mutated ras-gene-encoded p21 proteins with substitutions for Gly 12, of which half harbor G12D-KRAS-p21 [39]. Thus, there is a major need for agents like KD2 (provided it can be made to enter cells) and MRTX1133. On the other hand, a significant number of solid tissue tumors that harbor ras mutations express G12V-K-RAS-p21. As a percentage of all ras-induced tumors, G12V-K-RAS-p21 occurs in about 22 percent of lung adenocarcinomas, 30 percent of colon cancers and 40 percent of pancreatic cancers [39]. Thus, there is a clear need to block this mutant form of RAS-p21, which cannot be treated with agents targeting G12C- and G12D-K-RAS-p21. As discussed above, other peptide agents and approaches to design additional peptide agents, although less fully developed, show promise in being able to block ras-induced tumor growth irrespective of the mutations at position 12 and other positions in the RAS-p21 sequence. Among these peptides, PNC-1, 2 and 7 peptides linked to the cell-membrane-penetrating leader sequence block oncogenic RAS-p21-induced tumors selectively by interfering with signal transduction pathways that are unique to mutant RAS-p21. It is vital to investigate these pathways further as there appears to be \"escape\" pathways that allow for the wild-type RAS-p21 protein to function normally in normal cells. These agents induced either the phenotypic reversion of cancer cells heterozygous for mutant RAS-p21 or tumor cell necrosis for cancer cells that are homozygous for mutant RAS-p21. None of these peptides have a demonstrable effect on the viability or growth of untransformed cells. These peptides remain to be tested in vivo. The immunological approach involving the attachment of the anti-ras Y13 259 scFv heavy and light chain segments to the tumor cell membrane recognition peptide, BR2, seems to be another productive approach in the design of specific anti-RAS-p21 agents. Using this agent, specificity for cancer cells is provided by the BR2 peptide that allows for the anti-RAS-p21 antibody to enter ras-transformed cancer cells. Again, in vivo studies with this construct remain to be performed. Finally, much of the successful development of anti-ras peptides and small molecules has resulted from library searches for these molecules. These were involved in the development of AMG510 and MRX849 and KD2, the latter resulting from a combination of library searches, use of expression vectors to produce peptides and use of cyclization methods to produce the cyclic peptides. The screening procedures for all of these peptidesand small molecules are based upon the ability of these agents to bind to specific forms of oncogenic RAS-p21. In view of the need for more general anti-ras agents, the use of informatic approaches such as the ones described in Section 3.3 above will provide an essential computer-based analysis of peptide constructs, leading to therapeutic advances in targeting ras-induced tumors. Conceptualization, M.R.P. and W.B.B. ; methodology, M.R.P. ; software, N.Z., M.R.P., W.B.B. and B.L. ; validation, M.R.P., W.B.B., B.L., E.G., N.Z. and P.P. ; formal analysis, M.R.P., W.B.B., B.L., E.G., N.Z. and P.P. ; investigation, M.R.P., W.B.B., B.L., E.G., N.Z. and P.P. ; resources, M.R.P., W.B.B., B.L., E.G., N.Z. and P.P. ; data curation, M.R.P., W.B.B., B.L., E.G., N.Z. and P.P. ; writing--M.R.P., W.B.B., B.L., E.G., N.Z. and P.P. ; original draft preparation, M.R.P. ; writing--review and editing, M.R.P., W.B.B., B.L., E.G., N.Z. and P.P. ; visualization, M.R.P., B.L. and N.Z. ; supervision, M.R.P. and W.B.B.B. ; project administration, M.R.P. All authors have read and agreed to the published version of the manuscript. This research received no external funding. Not applicable. None of the authors of this paper have any real or perceived conflicts of interest concerning any aspects of the work presented in this paper.