Targeting the ERß/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy.

High ERß/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.

Cancer Research Challenges and Potential Solutions in Saudi Arabia: A Qualitative Discussion Group Study.

PURPOSE: Cancer incidence in Saudi Arabia has recently shown an upward trend. Research efforts within the different cancer continuum are pivotal to strengthening control measures. Since cancer research is evolving in the country, it is crucial to understand the current challenges and implement defined interventions to overcome them. The present qualitative study aimed to assess cancer research barriers among researchers and identify potential solutions from their perspectives. METHODS: We conducted a focus group discussion among 17 Saudi-based cancer researchers from diverse research backgrounds, provinces, and institutions. We used descriptive-interpretive thematic analysis following an open-ended approach to investigate the challenges in conducting cancer research. We also captured the solutions suggested based on the researchers' experiences. RESULTS: Six major themes emerged from the analysis: requirements of the data landscape, organizational support, national research roadmap, sustainable funding, clearer policies and regulations, and capacity building. To address challenges in these areas, researchers stressed the need for improved interinstitutional collaborations, immediate availability of research materials, and unlimited and easy access to research data. CONCLUSION: Improving health research is one of the primary goals of Saudi Vision 2030. It is, therefore, essential to overcome the current challenges in cancer research, enabling research findings to inform policies related to cancer control and care provision.

Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC.

INTRODUCTION: Mounting evidence supports a role for estrogen signaling in NSCLC progression. We previously reported a seven-gene signature that predicts prognosis in estrogen receptor ß positive (ERß+) NSCLC. The signature defines a network comprised of ER and human EGFR-2/3 (HER2/HER3) signaling. METHODS: We tested the efficacy of combining the pan-HER inhibitor, dacomitinib, with the estrogen antagonist, fulvestrant, in ERß+ NSCLC models with differing genotypes. We assessed the potency of this combination on xenograft growth and survival of host mice, and the ability to reverse the gene signature associated with poor outcome. RESULTS: Synergy was observed between dacomitinib and fulvestrant in three human ERß+ NSCLC models: 201T (wild-type EGFR), A549 (KRAS mutant), and HCC827 (EGFR 19 deletion) with combination indices of 0.1-0.6. The combination, but not single agents, completely reversed the gene signature associated with poor prognosis in a mechanism that is largely mediated by activator protein 1 downregulation. In vivo, the combination also induced tumor regression and reversed the gene signature. In HCC827 xenografts treated with the combination, survival of mice was prolonged after therapy discontinuation, tumors that recurred were less aggressive, and two mechanisms of HER inhibitor resistance involving c-Met activation and PTEN loss were blocked. CONCLUSIONS: The combination of an ER blocker and a pan-HER inhibitor provides synergistic efficacy in different models of ERß+ NSCLC. Our data support the use of this combination clinically, considering its ability to induce potent antitumor effects and produce a gene signature that predicts better clinical outcomes.

Prevention of Tobacco Carcinogen-Induced Lung Tumor Development by a Novel STAT3 Decoy Inhibitor.

The STAT3 pathway is frequently overactive in non-small cell lung cancer (NSCLC), an often fatal disease with known risk factors including tobacco and chemical exposures. Whether STAT3 can be downmodulated to delay or prevent development of lung cancer resulting from an environmental exposure has not been previously tested. A circular oligonucleotide STAT3 decoy (CS3D) was used to treat mice previously exposed to the tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. CS3D contains a double-stranded STAT3 DNA response element sequence and interrupts STAT3 signaling by binding to STAT3 dimers, rendering them unable to initiate transcription at native STAT3 DNA binding sites. An intermittent course of CS3D decreased the development of airway preneoplasias by 42% at 1 week posttreatment, reduced the progression of preneoplasia to adenomas by 54% at 8 weeks posttreatment, and reduced the size and number of resulting lung tumors by 49.7% and 29.5%, respectively, at 20 weeks posttreatment. No toxicity was detected. A mutant cyclic oligonucleotide with no STAT3 binding ability was used as a control. Chemopreventive effects were independent of the KRAS mutational status of the tumors. In lungs harvested during and after the treatment course with CS3D, airway preneoplasias had reduced STAT3 signaling. Chemopreventive effects were accompanied by decreased VEGFA expression, ablated IL6, COX-2, and p-NF-κB, and decreased pulmonary M2 macrophages and myeloid-derived suppressor cells. Thus, downmodulation of STAT3 activity using a decoy molecule both reduced oncogenic signaling in the airway epithelium and favored a lung microenvironment with reduced immunosuppression.

Anti-EGFR Fibronectin Bispecific Chemically Self-Assembling Nanorings (CSANs) Induce Potent T Cell-Mediated Antitumor Responses and Downregulation of EGFR Signaling and PD-1/PD-L1 Expression.

Overexpression of the epidermal growth factor receptor (EGFR) on various cancers makes it an important target for cancer immunotherapy. We recently demonstrated that single-chain variable fragment-based bispecific chemically self-assembled nanorings (CSANs) can successfully modify T cell surfaces and function as prosthetic antigen receptors (PARs) allowing selective targeting of tumor antigens while incorporating a dissociation mechanism of the rings. Here, we report the generation of anti-EGFR fibronectin (FN3)-based PARs with high yield, rapid protein production, predicted low immunogenicity, and increased protein stability. We demonstrated the cytotoxicity of FN3-PARs successfully while evaluating FN3 affinities, CSAN valencies, and antigen expression levels. Using an orthotopic breast cancer model, we showed that FN3-PARs can suppress tumor growth with no adverse effects and FN3-PARs reduced immunosuppressive programmed cell death ligand-1 (PD-L1) expression by downregulating EGFR signaling. These results demonstrate the potential of FN3-PARs to direct selective T cell-targeted tumor killing and to enhance antitumor T cell efficacy by modulating the tumor microenvironment.