👤 Tugba Barlas

Aberrant expression of glucose-dependent insulinotropic peptide receptors (GIPR) might regulate increased steroidogenesis in patients with ACTH-independent cortisol hypersecretion. This study investigated the presence of aberrant GIPR expression in patients with ACTH-independent cortisol hypersecretion and bilateral adrenal adenomas.Patients with bilateral adrenal adenomas, ACTH-independent CS and aberrant GIPR screened via mixed meal test were included. Patients' demographic features and laboratory and imaging findings were obtained retrospectively.Twenty-one patients were included. Overt CS findings were present in 14.3% of the patients. One patient (4.7%) had a complete positive response (537% increase) and one patient (4.7%) had a partial response (41% increase) to the mixed meal test. In the remaining 19 patients, a mean change of -10.1% (range: -56.5% to+24.7%) in cortisol levels was observed at 120 min compared to baseline. The patient with a complete positive response was confirmed using 100 µg of IV octreotide. The patient underwent unilateral adrenalectomy after an inadequate long-term response to octreotide LAR therapy. The histopathology revealed bilateral macronodular adrenal cortical disease. We identified a germline heterozygous frameshift variant in the KDM1A gene in the patient's blood sample and a recurrent deletion of the p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample.These results may provide useful insights into the screening of aberrant GIPR expression in patients with ACTH-independent hypercortisolism. It is essential to further investigate which patients require screening. Moreover, a significant cortisol peak observed during the mixed meal test in the presence of these receptors has drawn attention. Show less

We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649. Show less