CDK4/6 are key cell-cycle regulators. CDK4/6 inhibitors encounter obstacles from therapeutic resistance and haematological toxicity, primarily due to potent CDK6 inhibition. Developing selective inhibitors against specific CDK members could address these limitations, but faces challenges from the high homology of ATP-binding sites. SCP-7 is a sesquiterpene lactone derivative with potent anti-non-small cell lung cancer (NSCLC) activity. Carbamate modification yields the optimised analogue SCP-7e. Biotinylated probe-based target fishing, MCODE analysis, DARTS, CETSA, SPR, circular dichroism and tryptophan fluorescence quenching analysis identified CDK4 as the target. The binding site on CDK4 was determined by LC-MS/MS, site-directed mutagenesis and covalent molecular docking. Co-immunoprecipitation was employed to elucidate the molecular mechanisms. SCP-7 and SCP-7e selectively bind to CDK4, excluding CDK6 and promote the ubiquitin-proteasome degradation of CDK4. SCP-7e exhibits enhanced metabolic stability, superior in vivo anti-NSCLC activity, higher CDK4 binding affinity and greater degradation efficiency than SCP-7. Mechanistically, SCP-7e covalently binds to Cys78, a residue located outside the ATP-binding pocket of CDK4, thereby sterically blocking CDK4-cyclin D1 interaction and inducing SKP2-mediated degradation of CDK4. This study identified Cys78 as a novel druggable site on CDK4 and provided a selective CDK4 degrader, advancing next-generation selective CDK inhibitors.
Text message reminders (TMRs) and patient navigation (PN) increase bowel cancer screening uptake. To date, no studies have directly compared these interventions with one another. We conducted a three-arm randomised controlled trial with individuals, in London, who had not completed bowel cancer screening within 18 weeks of invitation. Participants were randomised to receive no reminder (usual care), TMRs at 19, 21, 23 and 25 weeks, or a TMR at 19 weeks, with telephone PN at 21, 23 and 25 weeks. The primary outcome was participation within 26 weeks of invitation. Differences were assessed using logistic regression. On an intention-to-treat basis (n = 3129), uptake was higher in the TMR and PN groups, compared with usual care (6.5% vs. 2.0%, p < 0.001; 7.5% vs. 2.0%, p < 0.001). There was no significant difference between TMR and PN groups. In the per-protocol analysis (n = 2294), uptake was significantly higher in the PN group than the TMR group (8.6 vs. 12.6%, p < 0.025). Subgroup analyses revealed telephone PN was significantly more effective than TMRs for men, specifically (14.5% vs. 6.7%, p < 0.001). While TMRs are no more effective than PN in general, implementing PN could help reduce disparities in uptake between men and women. ISRCTN17245519.
Fatigue is a common symptom in cancer patients associated with impaired quality of life (QoL). Little is known about long-term fatigue trajectories in prostate cancer (PCa) patients. Using the European Organisation for Research and Treatment of Cancer Quality of Life Group Core Questionnaire (EORTC QLQ-C30), 1758 men treated with radiotherapy (2014–2016) for non-metastatic PCa prospectively reported fatigue up to five years later. Associations between pre-radiotherapy characteristics and clinically important fatigue (Score: ≥39/100) two years post-radiotherapy were investigated using logistic regression. Fatigue trajectories were explored using latent class growth analysis and multinomial regression. About 35% (608/1758) of patients experienced clinically important fatigue at least once from the start of radiotherapy up to five years later. Two years post-radiotherapy, 14% of patients reported fatigue, which was associated with pre-radiotherapy fatigue level (OR: 8.67), self-reported diabetes (OR: 1.94), BMI (OR: 1.07), and age (OR: 1.03). Long-term fatigue was strongly linked to pain, insomnia, pelvic symptoms, functional impairments, and reduced QoL. Four fatigue trajectories were identified, characterised by low (45%), moderate (42%), elevated and decreasing (8%), and (6%) increasing mean fatigue levels. Diabetes was associated with a 6 percentage point increase in the probability of experiencing an increasing fatigue trajectory. The findings emphasise the need for early identification of PCa patients susceptible to long-term fatigue. PCa patients with elevated pre-radiotherapy fatigue levels and diabetes may require closer monitoring in risk-stratified aftercare programmes.
The WHO recommends a “screen, triage, treat” approach for cervical cancer screening for Women Living with HIV (WLWH) in resource-limited settings, with HPV testing preferred for screening. We sought to compare Visual Assessment with Acetic Acid (VIA) assisted with the Pocket Colposcope to naked eye VIA for triage of HPV + WLWH. In a randomized clinical trial across six clinics in Kisumu, Kenya (November 2022 to June 2023), HPV + WLWH were randomized to VIA or Pocket colposcopy. Exam positivity was determined by presence of aceto-white epithelium (AWE); biopsies were taken from AWE or randomly if negative. Diagnostic accuracy was confirmed with pathology. Providers and participants completed post-exam surveys. Positive exam rates were 17.3% (VIA) and 14.3% (Pocket). Overall, CIN2/3 prevalence was 15.4% (12.2% VIA, 18.8% Pocket). Sensitivity, specificity, and negative predictive value were similar between arms. However, the Pocket showed a non-significant higher positive predictive value (37.5% vs 20.6%). Both providers and patients found the Pocket acceptable for triage. The Pocket colposcope detected more treatable disease and reduced overtreatment. This study shows the Pocket colposcope is a feasible, lower-cost device that could facilitate biopsy confirmation, increase provider training, improve patient education, and enable remote diagnosis.
