Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity.

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. SIGNIFICANCE: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.

Controlling the Mesostructure Formation within the Shell of Novel Cubic/Hexagonal Phase Cetyltrimethylammonium Bromide-Poly(acrylamide-acrylic acid) Capsules for pH Stimulated Release.

The self-assembly of ordered structures in mixtures of oppositely charged surfactant and polymer systems has been exploited in various cleaning and pharmaceutical applications and continue to attract much interest since their discovery in the late twentieth century. The ability to control the electrostatic and hydrophobic interactions that dictate the formation of liquid crystalline phases in these systems is advantageous in manipulation of structure and rendering them responsive to external stimuli. Nanostructured capsules comprised of the cationic surfactant, cetyltrimethylammonium bromide (CTAB), and the diblock copolymer poly(acrylamide-acrylic acid) (PAAm-AA) were prepared to assess their potential as pH responsive nanomaterials. Crossed-polarizing light microscopy (CPLM) and small-angle X-ray scattering (SAXS) identified coexisting Pm3n cubic and hexagonal phases at the surfactant-polymer interface. The hydrophobic and electrostatic interactions between the oppositely charged components were studied by varying temperature and solution pH, respectively, and were found to influence the liquid crystalline nanostructure formed. The lattice parameter of the mesophases and the fraction of cubic phase in the system decreased upon heating. Acidic conditions resulted in the loss of the highly ordered structures due to protonation of the carboxylic acid group, and subsequent reduction of attractive forces previously present between the oppositely charged molecules. The rate of release of the model hydrophilic drug, Rhodamine B (RhB), from nanostructured macro-sized capsules significantly increased when the pH of the solution was adjusted from pH 7 to pH 2. This allowed for immediate release of the compound of interest "on demand", opening new options for structured materials with increased functionality over typical layer-by-layer capsules.