Lu Chen

Development and Acceptability of a Rebuilding Osteo Strength With Exercise (ROSE) Program for Women With Breast Cancer

Background: Women with breast cancer are more prone to bone loss, joint pain, and other musculoskeletal symptoms, especially those receiving aromatase inhibitors and/or undergoing ovarian suppression therapy. Bone and joint problems can affect their quality of life and treatment adherence. Thus, the management of bone health is of clinical importance for this population. Objective: This study aimed to systematically develop a multicomponent bone health management intervention for women with breast cancer and assess the acceptability of the intervention program. Methods: The Rebuilding Osteo Strength with Exercise (ROSE) program for women with breast cancer was developed based on biological mechanisms, patient needs, evidence-based practices, theories, and stakeholder consensus using the Medical Research Council framework. An open-pilot study and post-intervention interviews were conducted to assess the acceptability of the ROSE program. Results: The ROSE program consisted of 6 modules, which integrated progressive exercise, bone health education, and behavior change strategies. Eight eligible patients were recruited during the open-pilot study, and all participants considered the program acceptable. Six patients accepted the post-intervention interview. Four themes emerged from the post-intervention interview: perceived benefits of participating, barriers to adherence, facilitators to adherence, and suggestions for optimization. Conclusions: The ROSE program is an acceptable bone health intervention program for women with breast cancer. Future refinements will be made before efficacy testing. Trial registration: The study was retrospectively registered with the Chinese Clinical Trial Registry, registration number ChiCTR2300072208.

Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82

Abstract Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome caused by germline pathogenic variants in the fumarate hydratase (FH) gene. Affected individuals are at risk for developing cutaneous and uterine leiomyomas and aggressive FH-deficient renal cell carcinoma (RCC) with a papillary histology. Due to a disrupted tricarboxylic acid cycle, FH-deficient kidney cancers rely on aerobic glycolysis for energy production, potentially creating compensatory metabolic vulnerabilities. This study conducted a high-throughput drug screen in HLRCC cell lines, which identified a critical dependency on nicotinamide adenine dinucleotide (NAD), a redox cofactor produced by the biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). Human HLRCC tumors and HLRCC-derived cell lines exhibited elevated NAMPT expression compared with controls. FH-deficient HLRCC cells, but not FH-restored HLRCC or normal kidney cells, were sensitive to NAMPT inhibition. HLRCC cell line viability was significantly decreased in both 2D and 3D in vitro cultures in response to the clinically relevant NAMPT inhibitor OT-82. NAMPT inhibition in vitro significantly decreased the total amount of NAD+, NADH, NADP, NADPH, and poly-ADP-ribose levels, and the effects of NAMPT inhibition could be rescued by the downstream NAD precursor nicotinamide mononucleotide (NMN), confirming the on-target activity of OT-82. Moreover, NAMPT inhibition by OT-82 in two HLRCC xenograft models resulted in severely reduced tumor growth. OT-82 treatment of HLRCC xenograft tumors in vivo inhibited glycolytic flux as demonstrated by reduced lactate/pyruvate ratio in hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging experiments. Overall, our data define NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated RCC.

miR‐425 regulates ovarian cancer proliferation, metastasis, and apoptosis by repressing PAK4 expression

AbstractAimTo explore the biological function of miR‐425/PAK4 axis in proliferation, metastasis, and apoptosis of ovarian cancer (OC) cells.MethodsqRT‐PCR and Western blot were adopted to examine miR‐425 and PAK4 expressions in OC tissues and cell lines. Cell counting kit‐8 (CCK‐8) and BrdU assays were applied to detect the proliferation ability of OC cells, and Transwell assay was adopted to assess the migration and invasion of OC cells. Flow cytometry was employed to evaluate the apoptosis of OC cells. The interaction between miR‐425 and PAK4 was predicted and verified by bioinformatics analysis and dual luciferase reporter gene assay, respectively.ResultsmiR‐425 was reduced in OC tissues and cell lines, and its underexpression was in evident correlation with the shorter overall survival time of OC patients. miR‐425 impeded OC cell proliferation, migration, and invasion, and accelerated apoptosis. Additionally, PAK4 was validated as the target of miR‐425, and the cotransfection of PAK4 reversed the antitumor effect of miR‐425.ConclusionmiR‐425 suppresses the proliferation, migration, and invasion of OC cells and enhances apoptosis via inhibiting PAK4, and it is expected to be a prognostic indicator and therapeutic target for the patients with OC.