From laboratory to clinic.

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

Understanding the tumor immune microenvironment (TIME) for effective therapy

Abstract Strained rings are increasingly important for the design of pharmaceutical candidates, but cross‐coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all‐carbon quaternary centers is the coupling of abundant strained‐ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel‐catalyzed cross‐electrophile approach that couples a variety of strained ring N‐hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that t‐BuBpyCamCN, an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96‐well plates.

Control of Redox‐Active Ester Reactivity Enables a General Cross‐Electrophile Approach to Access Arylated Strained Rings

With the rapid clinical development of immune checkpoint inhibitors (ICIs), the standard of care in cancer management has evolved rapidly. However, immunotherapy is not currently beneficial for all patients. In addition to intrinsic tumor factors, other etiologies of resistance to ICIs arise from the complex interplay between cancer and its microenvironment. Recognition of the essential role of the tumor microenvironment (TME) in cancer progression has led to a shift from a tumor-cell-centered view of cancer development, to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumor cells to escape detection and elimination by the immune system. Regulatory T lymphocytes (Treg), myeloid-derived suppressor cells (MDSCs), and type-2 tumor-associated macrophages (TAM2) are major components of these inhibitory cellular networks, with the ability to suppress innate and adaptive anticancer immunity. They therefore represent major impediments to anticancer therapies, particularly immune-based interventions. Recent work has provided evidence that, beyond their direct cytotoxic effects on cancer cells, several conventional chemotherapeutic (CT) drugs and agents used in targeted therapies (TT) can promote the elimination or inactivation of suppressive immune cells, resulting in enhanced antitumor immunity. In this review, we will analyze findings pertaining to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents (CT and/or TT), and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer strategies, in the era of immunotherapy. 

Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness

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.

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

Despite numerous therapeutic advances in the past decade, breast cancer is expected to cause over 42,000 deaths in the United States in 2019. Breast cancer had been considered an immunologically silent tumor; however recent findings suggest that immune cells play important roles in tumor growth even in the breast. Retinoid X receptors (RXRs) are a subclass of nuclear receptors that act as ligand-dependent transcription factors that regulate a variety of cellular processes including proliferation and differentiation; in addition, they are essential for macrophage biology. Rexinoids are synthetic molecules that bind and activate RXRs. Bexarotene is the only rexinoid approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma. Other more-potent rexinoids have been synthesized, such as LG100268 (LG268). Here, we report that treatment with LG 268, but not bexarotene, decreased infiltration of myeloid-derived suppressor cells and CD206-expressing macrophages, increased the expression of PD-L1 by 50%, and increased the ratio of CD8/CD4, CD25 T cells, which correlates with increased cytotoxic activity of CD8 T cells in tumors of MMTV-Neu mice (a model of HER2-positive breast cancer). In the MMTV-PyMT murine model of triple negative breast cancer, LG268 treatment of established tumors prolonged survival, and in combination with anti-PD-L1 antibodies, significantly (p = 0.05) increased the infiltration of cytotoxic CD8 T cells and apoptosis. Collectively, these data suggest that the use of LG268, a RXR agonist, can improve response to immune checkpoint blockade in HER2+ or triple-negative breast cancer.

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Retinoid X receptor agonist LG100268 modulates the immune microenvironment in preclinical breast cancer models

The discovery of nuclear receptors, particularly retinoid X receptors (RXR), and their involvement in numerous pathways related to development sparked interest in their immunomodulatory properties. Genetic models using deletion or overexpression of RXR and the subsequent development of several small molecules that are agonists or antagonists of this receptor support a promising therapeutic role for these receptors in immunology. Bexarotene was approved in 1999 for the treatment of cutaneous T cell lymphoma. Several other small molecule RXR agonists have since been synthesized with limited preclinical development, but none have yet achieved FDA approval. Cancer treatment has recently been revolutionized with the introduction of immune checkpoint inhibitors, but their success has been restricted to a minority of patients. This review showcases the emerging immunomodulatory effects of RXR and the potential of small molecules that target this receptor as therapies for cancer and other diseases. Here we describe the essential roles that RXR and partner receptors play in T cells, dendritic cells, macrophages and epithelial cells, especially within the tumor microenvironment. Most of these effects are site and cancer type dependent but skew immune cells toward an anti-inflammatory and anti-tumor effect. This beneficial effect on immune cells supports the promise of combining rexinoids with approved checkpoint blockade therapies in order to enhance efficacy of the latter and to delay or potentially eliminate drug resistance. The data compiled in this review strongly suggest that targeting RXR nuclear receptors is a promising new avenue in immunomodulation for cancer and other chronic inflammatory diseases.

Potential therapeutic uses of rexinoids

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

Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to prevent cancer in these high-risk patients, such as anti-estrogen drugs and radical mastectomy, are limited by lack of efficacy, undesirable toxicities, or physical and emotional challenges. We have previously shown that PARP inhibitors can significantly delay tumor development in BRCA1-deficient mice. Here, we fabricated the PARP inhibitor talazoparib (TLZ) into spacer implants (InCeT-TLZ) for localized and sustained delivery. We hypothesized that this novel formulation will provide an effective chemopreventive strategy with minimal toxicity. TLZ was released gradually over 30 days as implants degraded. InCeT-TLZ significantly decreased proliferation and increased DNA damage in the mammary glands of BRCA1-deficient mice. Notably, the number of mice that developed hyperplasia in the mammary glands was significantly lower with InCeT-TLZ treatment compared to the control group. Meanwhile, InCeT-TLZ was also better tolerated than oral TLZ, without loss of body weight or anemia. This study provides proof of concept for a novel and safe chemopreventive strategy using localized delivery of a PARP inhibitor for high-risk individuals. Future studies will directly evaluate the effects of InCeT-TLZ for preventing tumor development.

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Jessica A. Moerland

Papers

Retinoid X receptor agonist LG100268 modulates the immune microenvironment in preclinical breast cancer models

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

Potential therapeutic uses of rexinoids

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

Sustained, local delivery of the PARP inhibitor talazoparib prevents the development of mammary gland hyperplasia in Brca1-deficient mice.