Project 2: Specifically Targeting Oncoproteins with PCC Agent-Loaded Nanoparticles: KRASG12D and AktE17K

点击翻译按钮获取中文摘要

PROJECT 2: Specifically Targeting Oncoproteins with PCC Agent-Loaded Nanoparticles: KRASG12D and AktE17K. ABSTRACT: Activating point mutations in oncogenes are often cancer driver mutations. Common examples include the RAS family when mutated at codons 12, 13, or 61[1]. The E17K mutation of Akt [2], plus mutations in the epidermal growth factor receptor (EGFR)[3], or Phosphatidylinositol 3-kinases (PI3k)[4] are other examples. Reagents selective for such oncoproteins can serve as in vitro (tissue staining) tools, or potentially as drugs that target only the disease-associated mutant, thus avoiding the toxic side-effects that stem from inhibition of the wild-type (wt) variants [5] that reside in healthy tissues. For example, the EGFR inhibitor CO-1686 (currently in trials[6]) is specific for the T790M mutation associated with some non-small cell lung carcinomas, and is designed to minimize toxicities (such as skin rash) that can appear when wt EGFR is targeted[7]. However, activating mutations are often not associated with a binding pocket, which is a requirement for small molecule inhibitor development. Monoclonal antibodies (mAbs) can be raised against mutant oncoproteins,[8- 10] but mAbs do not enter the living cells that often harbor the oncoproteins[11, 12]. We propose to build upon three Caltech technologies: epitope targeted Protein Catalyzed Capture (PCC) Agents (Heath)[13, 14], polycyclodextrin nanoparticle (NP) delivery systems (Davis)[15], and proteolysis-targeting chimeric molecules (protacs)[16] (Deshaies), to develop an approach for selectively detecting and drugging mutant oncoproteins. Rationale with NSBCC theme A unique value brought by oncoprotein specific drugs as combination therapy components[17, 18] is that they should significantly open up the therapeutic window for drug combinations.