Dose Intensity in Real-World Patients With Metastatic Renal Cell Carcinoma Taking Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR) are oral therapies used to treat metastatic renal cell carcinoma (mRCC). VEGFR TKI treatment is often complicated by dose-limiting adverse events (AE). We sought to describe dose intensity and clinical outcomes in a real-world cohort of patients treated with VEGFR TKIs to better characterize dosing patterns and toxicity management compared with previously reported clinical trials. MATERIALS AND METHODS: We conducted a retrospective chart review of sequential patients with mRCC treated with VEGFR TKIs at 1 academic medical center from 2014 to 2021. RESULTS: 139 patients (75% male, 75% white, median age 63 years) were treated with 185 VEGFR TKIs in our real-world cohort. Per International Metastatic RCC Database Consortium criteria, 24% had good risk, 54% intermediate risk, and 22% poor risk mRCC. With their first VEGFR TKI, median relative dose intensity (RDI) was 79%. 52% of patients required a dose reduction, 11% discontinued treatment due to AEs, 15% visited the ED, and 13% were hospitalized for treatment-related adverse events. Cabozantinib had the highest rate of dose reductions (72%) but a low rate of discontinuation (7%). Real-world patients consistently had lower RDI than reported clinical trials with more frequent dose reductions, fewer drug discontinuations, shorter progression-free survival, and shorter overall survival. CONCLUSION: Real-world patients were less able to tolerate VEGFR TKIs compared to patients treated on clinical trials. Low real-world RDI, high dose reductions, and low overall discontinuation rates can inform patient counseling prior to treatment initiation and during therapy.

Borate Transporters and SLC4 Bicarbonate Transporters Share Key Functional Properties.

Borate transporters are membrane transport proteins that regulate intracellular borate levels. In plants, borate is a micronutrient essential for growth but is toxic in excess, while in yeast, borate is unnecessary for growth and borate export confers tolerance. Borate transporters share structural homology with human bicarbonate transporters in the SLC4 family despite low sequence identity and differences in transported solutes. Here, we characterize the S. cerevisiae borate transporter Bor1p and examine whether key biochemical features of SLC4 transporters extend to borate transporters. We show that borate transporters and SLC4 transporters share multiple properties, including lipid-promoted dimerization, sensitivity to stilbene disulfonate-derived inhibitors, and a requirement for an acidic residue at the solute binding site. We also identify several amino acids critical for Bor1p function and show that disease-causing mutations in human SLC4A1 will eliminate in vivo function when their homologous mutations are introduced in Bor1p. Our data help elucidate mechanistic features of Bor1p and reveal significant functional properties shared between borate transporters and SLC4 transporters.

Attempted use of PACE for riboswitch discovery generates three new translational theophylline riboswitch side products.

OBJECTIVE: The purpose of this project was to use an in vivo method to discover riboswitches that are activated by new ligands. We employed phage-assisted continuous evolution (PACE) to evolve new riboswitches in vivo. We started with one translational riboswitch and one transcriptional riboswitch, both of which were activated by theophylline. We used xanthine as the new target ligand during positive selection followed by negative selection using theophylline. The goal was to generate very large M13 phage populations that contained unknown mutations, some of which would result in new aptamer specificity. We discovered side products of three new theophylline translational riboswitches with different levels of protein production. RESULTS: We used next generation sequencing to identify M13 phage that carried riboswitch mutations. We cloned and characterized the most abundant riboswitch mutants and discovered three variants that produce different levels of translational output while retaining their theophylline specificity. Although we were unable to demonstrate evolution of new riboswitch ligand specificity using PACE, we recommend careful design of recombinant M13 phage to avoid evolution of "cheaters" that short circuit the intended selection pressure.