SOCS3 inhibiting JAK-STAT pathway enhances oncolytic adenovirus efficacy by potentiating viral replication and T-cell activation.

Oncolytic viruses (OVs) are emerging as a potentially useful treatment for malignancies due to the capabilities of direct oncolysis and immune induction. Improving the replication of OVs is an effective approach to enhance the oncolytic effects. Here, we observed that cancer cells with deficiencies in JAK-STAT pathway showed greater sensitivity to oncolytic adenovirus (oAd), and JAK inhibitor could enhance the replication of oAd. Therefore, we constructed a novel oAd expressing SOCS3, a major negative regulator of JAK-STAT pathway, and confirmed that oAd-SOCS3 exhibited a more significant antitumor effect than oAd-Ctrl both in vitro and in vivo. Mechanistically, SOCS3 inhibited the activation of JAK-STAT pathway, resulting in stronger tumor selective replication of oAd and downregulated expression of PD-L1 on cancer cells as well. Both benefits could collectively awaken antitumor immunity. This study highlights the importance of JAK-STAT pathway in viral replication and confirms the treatment of oAd-SOCS3 in potential clinical applications.

Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation.

Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation's pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

M11: A Tropism-Modified Oncolytic Adenovirus Arming with a Tumor-Homing Peptide for Advanced Ovarian Cancer Therapies.

Oncolytic adenoviruses (OAds) have shown great promise in cancer therapy, but their efficacy has been greatly limited by poor tumor selectivity and highly off-target liver sequestration. Herein, we generated a novel "stealth" and tumor-targeting OAd vector, M0-TMTP1, by inserting TMTP1 (NVVRQ), a tumor-homing peptide specifically targeting metastasis, into the hypervariable region 5 of hexon. M0-TMTP1 exhibits increased transduction of tumor cells in vitro. In vivo biodistribution of M0-TMTP1 in an intraperitoneal disseminated ovarian cancer model showed significantly reduced virus load in major organs but apparent aggregation in tumors. The tumor-to-liver ratio of M0-TMTP1 was nearly 5,000-fold higher than that of control adenovirus M0. Furthermore, we armed M0-TMTP1 with trunked BID, a mitochondrial apoptosis protein, to obtain M11. Combining M11 with cisplatin (DDP) could induce an intensive antitumor effect in vitro and in vivo. Moreover, this combination therapy showed higher biosafety. Taken together, our results suggest that M11 represents a tumor-targeting, efficacious, and relatively nontoxic virotherapeutic agent, and these findings might offer renewed hope for tumor management.

Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer.

Refractoriness to conventional chemotherapy is a major challenge in the treatment of advanced ovarian cancer (OC). There is increasing evidence that mitochondrial priming correlates with cisplatin response in various cancers. Notably, Bim and Bid, two of the proapoptotic BH3-only proteins, are recognized as the most effective inducers of mitochondrial priming in OC. In this study, we constructed two tumor-specific oncolytic adenoviruses (Ads) coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid), respectively, and performed gain-of-function assays in nine OC cell lines. Ad-tBid exhibited significant antitumor efficacy than the controls. On addition of Ad-tBid pretreatment, mito-primed cells displayed more sensitivity to cisplatin both in vitro and ex vivo. We also found that Ad-tBid induced mitochondrial apoptosis in a Bak-dependent manner. Furthermore, a combined cisplatin plus Ad-tBid therapy markedly inhibited tumor growth in a subcutaneous xenotransplanted tumor model. In mice bearing peritoneal disseminated OC, intraperitoneal administration of Ad-tBid potentiated the antitumor effect of cisplatin. Our findings suggest that Ad-tBid enhances cisplatin response in OC cells, establishing the potential treatment of advanced OC via a combination of cisplatin and Ad-tBid.