Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. SAH-SOS1 peptides bound in a sequence-specific manner to KRAS and its mutants, and dose-responsively blocked nucleotide association. Importantly, this functional binding activity correlated with SAH-SOS1 cytotoxicity in cancer cells expressing wild-type or mutant forms of KRAS. The mechanism of action of SAH-SOS1 peptides was demonstrated by sequence-specific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D^V12 activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.

Therapeutic manipulation of the BCL-2 family using BH3 mimetics is an emerging paradigm in cancer treatment and immune modulation. For example, peptides mimicking the BIM BH3 helix can directly target the full complement of anti- and pro-apoptotic BCL-2 proteins to trigger apoptosis. This study has incorporated the potent BH3 α-helical death domain of BIM into peptide amphiphile (PA) nanostructures designed to facilitate cellular uptake and induce cell death. This study shows that these PA nanostructures are quickly incorporated into cells, are able to specifically bind BCL-2 proteins, are stable at physiologic temperatures and pH, and induce dose-dependent apoptosis in cells. The incorporation of a cathepsin B cleavable linker between the BIM BH3 peptide and the hydrophobic tail resulted in increased intracellular accumulation and mitochondrial co-localization of the BIM BH3 peptide while also improving BCL-2 family member binding and apoptotic reactivation. This PA platform represents a promising new strategy for intracellular therapeutic peptide delivery for the disruption of intracellular protein:protein interactions.

Objective: To highlight a case from 1960 connecting endolymphatic sac tumour and von Hippel–Lindau disease.Case report: In 1960, a 24-year-old woman presented with unilateral hearing loss, pulsatile tinnitus and a mass visible on otoscopy. The patient underwent surgical biopsy, which was complicated by haemorrhage, and ultimately resulted in death. At autopsy, a destructive temporal bone neoplasm with cystic and papillary architecture was observed that had eroded into the otic capsule. Intra-abdominal lesions consistent with von Hippel–Lindau disease were also observed, and the surgeon postulated a connection between endolymphatic sac tumour and von Hippel–Lindau disease.Method: A review of the literature was carried out using PubMed.Conclusion: Endolymphatic sac tumours are rare neoplasms of the temporal bone that can occur sporadically or as part of von Hippel–Lindau disease. The connection between endolymphatic sac tumour and von Hippel–Lindau disease was first proposed in 1988 and formalised in 1997. We believe that this case represents the first documented connection between endolymphatic sac tumour and von Hippel–Lindau disease.