Selected Articles from This Issue

Although combination therapies have improved outcomes in rhabdomyosarcoma (RMS) patients, prognosis remains poor for those who relapse, emphasizing a need for new targeted therapies. The multi-tyrosine kinase inhibitor (TKI) regorafenib targets several kinases associated with RMS, including VEGFR, FGFR, and PDGFR, and has demonstrated promising preclinical antitumor activity in Ewing sarcoma (EWS), neuroblastoma, and RMS models. In this phase I trial, Casanova and colleagues establish a maximum tolerated dose for regorafenib and evaluate the efficacy of regorafenib combined with vincristine and irinotecan in pediatric patients with recurrent/refractory RMS, EWS, neuroblastoma, and Wilms tumor. Treatment was well tolerated, with less than 20% of patients experiencing grade 3/4 adverse events. The authors report an overall response rate of 48% and a disease control rate of 86%, with 2 of 21 of patients achieving complete response, 8 patients demonstrating partial response, and 7 patients maintaining stable disease. Median progression-free survival was 7.0 months, and median overall survival was 8.7 months. The authors find that regorafenib in combination with vincristine and irinotecan demonstrated a manageable safety profile and promising antitumoral activity in patients with relapsed/refractory RMS, EWS, neuroblastoma, and Wilms tumor, warranting further study in a larger population.

Patients with high-risk or relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), including those with MECOM gene rearrangements, have shown limited response to hypomethylating agents (HMA) and venetoclax, highlighting a need for new treatments. Bromodomain and extra-terminal domain inhibitors (BETi) exert antitumoral effects by targeting BET proteins and attenuating BET-mediated oncogene transcription, and have shown synergistic antitumoral effects when combined with proapoptotic therapies in preclinical AML and MDS studies. In this phase I study, Senapati and colleagues assess the safety and efficacy of the BETi PLX51107 combined with the HMA azacytidine in patients with R/R AML or high-risk MDS, with or without MECOM rearrangements. The authors report no dose-limiting toxicities and an overall response rate of 22%. To evaluate resistance mechanisms, the authors performed RNA sequencing in mononuclear cells collected before and during treatment and identified multiple differentially expressed genes between treatment-responsive and nonresponsive patients, representing gene expression correlates of PLX51107-induced clinical responses. The authors’ report of well-tolerated PLX51107/azacytidine combination therapy with modest clinical benefit emphasizes a need for further clinical trials evaluating BET inhibitors in expanded AML/MDS populations.

Exercise has been shown to reduce the risk of colon cancer in the general population and is a promising nonpharmacologic approach to reduce colon cancer risk in patients with hereditary Lynch syndrome (LS). The mechanism by which exercise reduces colon cancer risk remains unclear, yet several studies have linked colon cancer risk to an exercise-induced reduction in prostaglandin E2 (PGE2) synthesis and PGE2-mediated inflammation. In this clinical trial, Deng and colleagues assess changes in gene expression and the immune system in response to a 12-month exercise program in LS carriers. Enrolled participants completed three 45-minute cycling classes per week, with control patients receiving a one-time exercise counseling session. The authors report a significant reduction in colonic PGE2 levels in the exercise group compared to the control group, as well as a significant increase in oxygen consumption, measured by VO_2peak. Through mRNA sequencing and spatial transcriptomics, the authors found that differentially expressed genes related to immune pathways were enriched in the exercise group compared to controls, as well as an increase in natural killer and CD8⁺ T-cell levels in the colonic mucosa. Given these results, the authors highlight the ability of exercise to regulate levels of inflammatory molecules and immune cell populations in a high-risk genetic cancer population, stressing the need for additional clinical trials to confirm the efficacy of exercise in cancer prevention.

Standard treatments for 1p/19q-codeleted oligodendrogliomas, including maximal safe resection and radiotherapy with adjuvant alkylating chemotherapy, have successfully advanced long-term outcomes, leading to therapeutic de-escalation efforts by substitution of current chemotherapy regimens with temozolomide (TMZ). Unfortunately, the high molecular heterogeneity of grade 2 and 3 gliomas has thus far impeded identification of biomarkers to predict response to alkylating chemotherapy and guide substitute treatment selection. Previous studies have shown that MGMT promoter methylation (mMGMT) and subsequent MGMT silencing can predict TMZ response and progression-free survival (PFS) in glioblastoma, yet its role in grade 2 and 3 glioma remains unclear. Here, Kinslow and colleagues assessed the effect of mMGMT on overall survival (OS) in patients with newly diagnosed 1p/19q-codeleted gliomas. The authors found that 77.8% of patients had methylated MGMT promoters and that mMGMT patients were associated with better OS than patents with unmethylated MGMT (uMGMT) promoters. Additionally, the authors report that uMGMT was associated with worse survival in patients who received chemotherapy but not in patients who did not receive chemotherapy. Together, these data expand upon previous work to correlate mMGMT status in 1p/19q-codeleted glioma patients with OS, highlighting the utility of MGMT methylation status for treatment selection in future clinical trials.