Gang Yin

The Anti-FRα Antibody–Drug Conjugate Luveltamab Tazevibulin Demonstrates Efficacy in Non–Small Cell Lung Cancer Preclinical Models and Induces Immunogenic Cell Death

Abstract Luveltamab tazevibulin is a folate receptor α (FRα)–targeting antibody–drug conjugate currently being evaluated in phase I and II/III clinical trials in endometrial and ovarian cancers (NCT03748186 and NCT05870748), respectively. In this study, we report non–small cell lung cancer (NSCLC) as an additional cancer subtype enriched for FRα expression. In patient-derived xenograft models of NSCLC, FRα-expressing tumors demonstrated robust tumor growth inhibition following luveltamab tazevibulin treatment, demonstrating its potential use for NSCLC treatment. Luveltamab tazevibulin was additionally identified as a potent inducer of immunogenic cell death (ICD). In in vitro cell killing assays, luveltamab tazevibulin induced all three hallmarks of ICD—high mobility group box 1 release, ATP release, and surface exposure of calreticulin. Furthermore, in in vivo vaccination studies, injection of luveltamab tazevibulin–treated tumor cells established protective immunity against subsequent tumor challenge. Consistent with ICD induction, luveltamab tazevibulin treatment in tumor-bearing mice also altered tumor immune cell infiltrate and activation, demonstrating its ability to modulate the tumor immune microenvironment. Given the success of immune checkpoint therapy in NSCLC and luveltamab tazevibulin’s ability to potentiate the immune response, we evaluated the combination therapy of luveltamab tazevibulin with immune checkpoint blockade in syngeneic mouse models and demonstrated that combination treatment results in enhanced efficacy compared with either monotherapy alone. This improved activity with combination therapy was associated with increased tumoral infiltration of CD8+ T cells. In conclusion, the work presented here provides rationale for evaluating luveltamab tazevibulin in NSCLC either as monotherapy or in combination with immune checkpoint blockade.

Comprehensive network analysis of dysregulated genes revealed MNX1‐AS1/hsa‐miR‐4697‐3p/HOXB13 axis in ovarian cancer chemotherapy response

AbstractPoor chemotherapy response is the main obstacle of ovarian cancer (OC) treatment. Platinum‐refractory and ‐resistant patients are associated with a worse outcome than platinum‐sensitive and partially sensitive patients, but the comprehensive similarities and differences among them are not yet clear. In this study, we analyzed the data of patients with different chemotherapy response in The Cancer Genome Atlas. We found a minority of altered genes were overlapped in refractory and resistant groups, as did the enriched pathways and Gene Ontology terms. We noticed that the neural signaling and drug metabolism enzymes were more significantly enriched and the protein–protein interaction supported these results. The transcription analysis highlighted PDX1 as the common and central transcription factor in both refractory and resistant groups. The competing endogenous RNA (ceRNA) network shared no common ceRNA pairs, indicating a major difference in noncoding RNA post‐transcriptional regulation. In the end, we validated the expression, regulation, binding, and effect on chemotherapy response for selected MNX1‐AS1/hsa‐miR‐4697‐3p/HOXB13 in OC cell lines. Our study offered a novel and comprehensive insight into chemotherapy response, and potential targets for improving chemotherapy response in OC.

Hotair promotes the migration and proliferation in ovarian cancer by miR-222-3p/CDK19 axis

AbstractPrevious studies in our laboratory have reported that miR-222-3p was a tumor-suppressive miRNA in OC. This study aims to further understand the regulatory role of miR-222-3p in OC and provide a new mechanism for its prevention and treatment. We first found that miR-222-3p inhibited the migration and proliferation of OC cells. Then, we observed CDK19 was highly expressed in OC and inversely correlated with miR-222-3p. Besides, we observed that miR-222-3p directly binds to the 3′-UTR of CDK19 and inhibits CDK19 translation, thus inhibiting OC cell migration and proliferation in vitro and repressed tumor growth in vivo. We also observed the inhibitory effect of Hotair on miR-222-3p in OC. In addition, Hotair could promote the proliferation and migration of OC cells in vitro and facilitate the growth and metastasis of tumors in vivo. Moreover, Hotair was positively correlated with CDK19 expression. These results suggest Hotair indirectly up-regulates CDK19 through sponging miR-222-3p, which enhances the malignant behavior of OC. This provides a further understanding of the mechanism of the occurrence and development of OC.

Have you ever heard of Human Papillomavirus (HPV) vaccine? The awareness of HPV vaccine for college students in China based on meta-analysis