IL-6 modulates immune responses and is essential for timely wound healing. As the functions mediated by IL-6 require binding to its specific receptor, IL-6Rα, it was expected that mice lacking IL-6Rα would have the same phenotype as IL-6–deficient mice. However, although IL-6Rα–deficient mice share many of the inflammatory deficits seen in IL-6–deficient mice, they do not display the delay in wound healing. Surprisingly, mice with a combined deficit of IL-6 and IL-6Rα, or IL-6–deficient mice treated with an IL-6Rα–blocking Ab, showed improved wound healing relative to mice with IL-6 deficiency, indicating that the absence of the receptor contributed to the restoration of timely wound healing, rather than promiscuity of IL-6 with an alternate receptor. Wounds in mice lacking IL-6 showed delays in macrophage infiltration, fibrin clearance, and wound contraction that were not seen in mice lacking IL-6Rα alone and were greatly reduced in mice with a combined deficit of IL-6 and IL-6Rα. MAPK activation-loop phosphorylation was elevated in wounds of IL-6Rα–deficient mice, and treatment of wounds in these mice with the MEK inhibitor U0126 resulted in a delay in wound healing suggesting that aberrant ERK activation may contribute to improved healing. These findings underscore a deeper complexity for IL-6Rα function in inflammation than has been recognized previously.

Background: Foxm1 is up-regulated in prostate adenocarcinomas and its expression correlates with the poor prognosis. Results: Conditional depletion of Foxm1 in prostate epithelial cells inhibits tumor cell proliferation, angiogenesis, and metastasis. Conclusion: Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis in mouse models. Significance: Foxm1 may play a key role in the pathogenesis of prostate cancer in human patients.

The Ron receptor tyrosine kinase is overexpressed in many cancers, including prostate cancer. In order to examine the significance of Ron in prostate cancer in vivo, we utilized a genetically engineered mouse model, referred to as TRAMP mice, that is predisposed to develop prostate tumors. In this model, we demonstrate that prostate tumors from 30-week-old TRAMP mice have increased Ron expression compared to age-matched wild-type prostates. Based on the upregulation of Ron in human prostate cancers and in this murine model of prostate tumorigenesis, we hypothesized that this receptor plays a functional role in the development of prostate tumors. To test this hypothesis, we crossed TRAMP mice with mice that are deficient in Ron signaling (TK−/−). Interestingly, TK−/− TRAMP+ mice show a significant decrease in prostate tumor mass relative to TRAMP mice containing functional Ron. Moreover, TK−/− TRAMP+ prostate tumors exhibited decreased tumor vascularization relative to TK+/+ TRAMP+ prostate tumors, which correlated with reduced levels of the angiogenic molecules VEGF and CXCL2. While Ron loss did not alter tumor cell proliferation, a significant decrease in cell survival was observed. Similarly, murine prostate cancer cell lines containing a Ron deficiency exhibited decreased levels of active NF-kappaB suggesting that Ron may be important in regulating prostate cell survival at least partly through this pathway. In total, our data show for the first time that Ron promotes prostate tumor growth, prostate tumor angiogenesis, and prostate cancer cell survival in vivo.

Current treatment strategies provide minimal results for patients with castration-resistant prostate cancer (CRPC). Attempts to target the androgen receptor have shown promise, but resistance ultimately develops, often due to androgen receptor reactivation. Understanding mechanisms of resistance, including androgen receptor reactivation, is crucial for development of more efficacious CRPC therapies. Here, we report that the RON receptor tyrosine kinase is highly expressed in the majority of human hormone-refractory prostate cancers. Further, we show that exogenous expression of RON in human and murine prostate cancer cells circumvents sensitivity to androgen deprivation and promotes prostate cancer cell growth in both in vivo and in vitro settings. Conversely, RON loss induces sensitivity of CRPC cells to androgen deprivation. Mechanistically, we demonstrate that RON overexpression leads to activation of multiple oncogenic transcription factors (namely, β-catenin and NF-κB), which are sufficient to drive androgen receptor nuclear localization and activation of AR responsive genes under conditions of androgen deprivation and support castration-resistant growth. In total, this study demonstrates the functional significance of RON during prostate cancer progression and provides a strong rationale for targeting RON signaling in prostate cancer as a means to limit resistance to androgen deprivation therapy.

Previous studies have shown that the Ron receptor is overexpressed in prostate cancer and Ron expression increases with disease severity in humans and the mouse TRAMP model. Here, the causal role of Ron overexpression in the murine prostate was examined in the development and progression of prostate cancer. Transgenic mouse strains were generated which selectively overexpressed Ron in the prostate epithelium and prostate histopathology was evaluated and compared to wild type controls. Ron overexpression led to the development of prostate intraepithelial neoplasia (mPIN) with local invasion and was associated with increases in prostate cell proliferation and decreases in cell death.

The Ron receptor tyrosine kinase is a heterodimeric, membrane-spanning glycoprotein that participates in divergent processes, including proliferation, motility, and modulation of inflammatory responses. We observed male C57BL/6 mice with a global deletion of the Ron tyrosine kinase signaling domain (TK(-/-)) to be leaner compared with control (TK(+/+)) mice under a standard diet. When fed a high-fat diet (HFD), TK(-/-) mice gained 50% less weight and were more insulin sensitive and glucose tolerant than controls. Livers from HFD TK(-/-) mice were considerably less steatotic and weighed significantly less than TK(+/+) livers. Serum cytokine levels of HFD TK(-/-) mice were also significantly altered compared with TK(+/+) mice. Fewer and smaller adipocytes were present in the TK(-/-) mice on both control and HFD and were accompanied by diminished adiponectin and peroxisome proliferator-activated receptor-γ expression. In vitro adipogenesis experiments suggested reduced differentiation in TK(-/-) embryonic fibroblasts (MEFs) that was rescued by Ron reconstitution. Likewise, signal transducer and activator of transcription (STAT)-3 phosphorylation was diminished in TK(-/-) MEFs but was increased after Ron reconstitution. The adipogenic inhibitors, preadipocyte factor 1 and Sox9, were elevated in TK(-/-) MEFs and increased in both groups after STAT3 silencing. In total, these studies document a previously unknown function for the Ron receptor in mediating HFD-induced obesity and metabolic dysregulation.

TPS5088 Background: Lesions in mCRPC are typically immunologically cold. AMG 160 binds to PSMA on cancer cells and CD3 on T cells, leading to T-cell infiltration, activation, expansion, and tumor cell killing. In a first-in-human study, AMG 160 has demonstrated a manageable safety profile with preliminary efficacy in heavily pretreated patients. Enzalutamide and abiraterone are novel hormonal therapies (NHTs) that improve survival in mCRPC and may enhance T-cell responses, but resistance occurs. Combination therapy with AMG 160 may help overcome hormonal therapy resistance and broaden use for earlier line mCRPC. Preclinical data have demonstrated enhanced activity when AMG 404, an anti-PD-1 that can overcome T-cell exhaustion, and AMG 160 are combined. The safety and efficacy of AMG 160 combinations will be evaluated. Methods: NCT04631601 will enroll ∼100 men with histologically or cytologically confirmed adenocarcinoma of the prostate. The protocol consists of 3 subprotocols. Subprotocols A and B are phase 1b, multicenter, open-label studies; subprotocol C is a phase 1b/2 study. Therapeutic combinations include AMG 160 + enzalutamide (A), AMG 160 + abiraterone (B), and AMG 160 + AMG 404 vs AMG 404 monotherapy (C). Patients who received prior PSMA radionuclide therapy may be eligible. Patients must not have received prior PSMAxCD3 bispecific therapy, prior taxane treatment (unless approved by the sponsor) across subprotocols, and prior NHT specific to the subprotocol. In subprotocol C, patients must have progressive disease on an NHT to be eligible. Patients with CNS metastases, leptomeningeal disease, or active autoimmune disease will be excluded. AMG 160 will be administered intravenously (IV). Dexamethasone (or other corticosteroids) will be administered before AMG 160 administration in cycle 1 and possibly subsequent cycles. Enzalutamide or abiraterone will be administered per label. AMG 404 will be administered IV. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 160 combinations. Subprotocol C will also evaluate the preliminary antitumor activity of AMG 404 monotherapy. Secondary objectives are to assess preliminary antitumor activity and characterize pharmacokinetics. MTD/RP2D will be established in the dose-escalation phase, and the safety and tolerability of the MTD/RP2D will be confirmed in the expansion phase. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, prostate-specific antigen (PSA) response, circulating tumor cell response, progression-free survival (radiographic, PSA, clinical), overall survival, and 68Ga-PSMA-11 and 18F-FDG PET/CT imaging. The study is currently recruiting patients. Clinical trial information: NCT04631601.

Prostate cancer is one of the leading causes of cancer-related death among men in the United States due, in part, to its aggressiveness and resistance to therapy following a remission period. Receptor tyrosine kinases are emerging as potential therapeutics in prostate cancer. One of these receptors, the Ron receptor tyrosine kinase, has been shown to be overexpressed in a variety of cancers where it modulates many cellular functions relevant to cancer such as invasion, inflammation, angiogenesis, and proliferation. Ron is expressed primarily on epithelial cells and macrophages, which are both important in regulating the prostate tumor microenvironment. Our laboratory has shown recently that crossing mice lacking the Ron receptor (Ron TK−/−) to TRAMP+ mice, which develop prostate adenocarcinomas by 30 weeks of age, leads to a significant decrease in prostate tumor mass, tumor vascularization, and proangiogenic chemokine secretion relative to TRAMP+ control mice. In addition, we have shown that loss of Ron in the myeloid lineage (monocytes and granulocytes) leads to decreases in prostate tumor establishment using an orthotopic model of prostate cancer. Given this, we therefore wished to understand what role the Ron receptor plays in specific cell types relevant to prostate cancer progression. By knocking out Ron in the prostate epithelium or myeloid lineage (monocytes, macrophages, and granulocytes) and crossing these mice onto a TRAMP background, we hope to investigate the effect of lineage-specific loss of Ron in mediating prostate cancer development and progression. We hypothesize that Ron receptor signaling in the prostate epithelium and in myeloid cells promotes prostate tumorigenesis via interdependent mechanisms. By understanding the interdependent mechanisms of Ron signaling in the prostate epithelium and myeloid lineage, our studies will identify a potential novel signaling pathway, its combined and cell-type specific role in regulating prostate tumorigenesis, and suggest novel avenues for the development of new therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A13.