The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner.

The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (p < 0.001) and improved pathological grade (p < 0.05) in WT but not Nrf2 KO A/J mice. Tumor burden in Nrf2 KO mice was 4.6-fold higher (p < 0.001) than in WT mice, irrespective of treatment. CDDO-Me increased the number of lung-infiltrating macrophages in WT mice but lowered CD206 expression in these cells (p < 0.0001). In summary, Nrf2 KO exacerbates lung tumorigenesis in A/J mice, and CDDO-Me promotes an Nrf2-dependent, anti-cancer macrophage phenotype.

The rexinoid V-125 reduces tumor growth in preclinical models of breast and lung cancer.

Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.

The RXR Agonist MSU42011 Is Effective for the Treatment of Preclinical HER2+ Breast Cancer and Kras-Driven Lung Cancer.

(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as a standard of care in clinical practice. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and upon ligand binding, function as transcription factors to modulate multiple cell functions. Bexarotene, the only FDA-approved RXR agonist, is still used to treat cutaneous T-cell lymphoma. (2) Methods: To test the immunomodulatory and anti-tumor effects of MSU42011, a new RXR agonist, we used two different immunocompetent murine models (MMTV-Neu mice, a HER2 positive model of breast cancer and the A/J mouse model, in which vinyl carbamate is used to initiate lung tumorigenesis) and an immunodeficient xenograft lung cancer model. (3) Results: Treatment of established tumors in immunocompetent models of HER2-positive breast cancer and Kras-driven lung cancer with MSU42011 significantly decreased the tumor burden and increased the ratio of CD8/CD4, CD25 T cells, which correlates with enhanced anti-tumor efficacy. Moreover, the combination of MSU42011 and immunotherapy (anti-PDL1 and anti-PD1 antibodies) significantly (p < 0.05) reduced tumor size vs. individual treatments. However, MSU42011 was ineffective in an athymic human A549 lung cancer xenograft model, supporting an immunomodulatory mechanism of action. (4) Conclusions: Collectively, these data suggest that the RXR agonist MSU42011 can be used to modulate the tumor microenvironment in breast and lung cancer.

The novel rexinoid MSU-42011 is effective for the treatment of preclinical Kras-driven lung cancer.

Effective drugs are needed for lung cancer, as this disease remains the leading cause of cancer-related deaths. Rexinoids are promising drug candidates for cancer therapy because of their ability to modulate genes involved in inflammation, cell proliferation or differentiation, and apoptosis through activation of the retinoid X receptor (RXR). The only currently FDA-approved rexinoid, bexarotene, is ineffective as a single agent for treating epithelial cancers and induces hypertriglyceridemia. Here, we used a previously validated screening paradigm to evaluate 23 novel rexinoids for biomarkers related to efficacy and safety. These biomarkers include suppression of inducible nitric oxide synthase (iNOS) and induction of sterol regulatory element-binding protein (SREBP). Because of its potent iNOS suppression, low SREBP induction, and activation of RXR, MSU-42011 was selected as our lead compound. We next used MSU-42011 to treat established tumors in a clinically relevant Kras-driven mouse model of lung cancer. KRAS is one of the most common driver mutations in human lung cancer and correlates with aggressive disease progression and poor patient prognosis. Ultrasound imaging was used to detect and monitor tumor development and growth over time in the lungs of the A/J mice. MSU-42011 markedly decreased the tumor number, size, and histopathology of lung tumors compared to the control and bexarotene groups. Histological sections of lung tumors in mice treated with MSU-42011 exhibited reduced cell density and fewer actively proliferating cells compared to the control and bexarotene-treated tumors. Although bexarotene significantly (p < 0.01) elevated plasma triglycerides and cholesterol, treatment with MSU-42011 did not increase these biomarkers, demonstrating a more favorable toxicity profile in vivo. The combination of MSU-42011 and carboplatin and paclitaxel reduced macrophages in the lung and increased activation markers of CD8+T cells compared to the control groups. Our results validate our screening paradigm for in vitro testing of novel rexinoids and demonstrate the potential for MSU-42011 to be developed for the treatment of KRAS-driven lung cancer.