SUMMARY The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the “WIN site” of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.

No abstract

as well as RT within 30 days of each other. Demographics, and treatment factors such as timing of ICB, histology, site, and type of RT, were recorded and overall survival (OS) was analyzed from start of either therapy. Multivariate Cox proportional hazard and log-rank Kaplan Meier survival analyses was performed on these factors. Results: Seven hundred fifty-eight patients were identified who received 1798 courses of radiation with median follow-up of 17 months (range 1-71). Sites of RT were primarily to the brain (n Z 693), thorax (n Z 238), spine (n Z 321), abdomen/pelvis (n Z 236), extremities (n Z 125) and head and neck (n Z 63). Median OS was 9 months in the entire cohort. In patients where ICB and RT was not concurrent, median OS was 6 months and 7 months in those who received ICB first (n Z 178) and RT first (n Z 174), respectively. In patients who received ICB and RT simultaneously, median OS was 20 months for patients who started receiving ICB for at least 1 month before RT and continued throughout RT (n Z 128) compared with 11 months for those that started ICB less than 30 days prior to starting RT and continued ICB throughout RT (n Z 172, P Z 0.01). In the cohort of patients who received concurrent therapy, hypofractionated radiotherapy (dose >400 cGy per fraction, HR Z 0.66, CI Z 0.50-0.88, P Z 0.006) and ICB greater than 30 days before RT (HR Z 0.72, CI Z 0.55-0.96, P Z 0.03) was associated with improved overall survival in multivariate analysis corrected for age, ICB agent class, anatomic site and histology. Conclusion: This retrospective review suggests an improvement in OS with concurrent ICB and RT and hypofractionated RT, particularly when ICI is started at least 1 month before RT. These results imply a benefit to "induction" ICB prior to RT and may inform trial design. Future work will evaluate response in unirradiated lesions before and after radiation and its association with treatment factors.

Purpose/Objective(s): Thoracic radiotherapy combined with PD-1 inhibitor can promote the activation of T cell and improve the treatment outcomes of patients with chest cancer. However, it also increases the risk of myocardial injury. A mouse model was used to observe the effects of PD-1 inhibitors on myocardial immune microenvironment and radiation induced injury, and to explore the potential mechanism of PD-1 inhibitors aggravating myocardial injury using. Materials/Methods: Totally 20 C57BL/6 mice were randomly divided into 4 groups, including group A as normal control, group B receiving intraperitoneally injected with anti-PD-1 antibody, group C receiving full thoracic x-ray irradiation with 15 Gy in one fraction, D group receiving anti−PD1 as the same as B group and full thoracic x-ray irradiation as C group. At 1 months after irradiation, mice were killed under anesthesia. Hematoxylin-eosin staining and Mason staining were used to observe myocardial injury and fibrosis. The levels of CD3+, CD3+CD4+, CD3 +CD8+ lymphocyte and cytokines (IL-4, IL-6, IL-17A, TNF-a, TGF-b1, INF-g) in myocardium were detected by flow cytometry. The apoptosis rate of myocardial cells was detected by TUNEL assay. Results: Mason staining showed that no obvious myocardial fibrosis in group B, and collagen fibers were distributed in the myocardial interstitium in groups C and D. The results of semi-quantitative analysis showed that the myocardial collagen volume fraction (CVF) of each group A, B, C and D were (1.97 § 0.36)%, (2.83 § 1.03)%, (5.39 § 0.77)% and (7.72 § 1.43)%, respectively. The CVF of group A was similar to that of group B (P = 0.314). There were statistically significant differences in CVF among other groups (P < 0.05). Compared with group A, the absolute value and percentage of CD3+T lymphocytes in groups B, C and D were increased (P < 0.01), and those in group D were higher than those in group B and C (P < 0.01). The absolute value and percentage of CD3+CD4+T lymphocytes in groups A, C, B and D were similar (P > 0.05). The absolute value and percentage of CD3+CD8+T lymphocytes in group D were higher than those in groups A, B and C (P < 0.001). The levels of IL-6, IL-17A and TGF-b1 in group D were higher than those in groups A, B and C (P < 0.001). The apoptotic index of groups A, B, C and D increased gradually, and the difference of apoptotic index among all groups was statistically significant (P < 0.001). Conclusion: PD-1 inhibitors can aggravate radiation-induced myocardial injury by promoting myocardial immunoinflammatory response.