Complementary Approaches for Military Women with Chronic Pelvic Pain: A Randomized Trial.

Introduction: Active duty (AD) women suffer with chronic pelvic pain (CPP) while providers tackle diagnoses and treatments to keep them functional without contributing to the opioid epidemic. The purpose of this randomized trial was to determine the effectiveness of noninvasive, self-explanatory mindfulness-based stress reduction (MBSR) or self-paced healthy lifestyle (HL) interventions on CPP in AD women. Methods: A 6-week, interventional prospective study with AD women aged 21-55 years at Mountain Home (MTHM), Idaho, was conducted. Women were randomly assigned to MBSR (N = 21) or HL (N = 20) interventions. The primary outcome was pain perception. The secondary outcomes were depression and circulating cytokine levels. Results: Women in the MBSR group exhibited reduced pain interference (p < 0.01) and depression (p < 0.05) alongside decreased interleukin (IL)-4 (p < 0.05), IL-6 (p < 0.05), eotaxin (p < 0.05), monocyte chemoattractant protein-1 (p = 0.06), and interleukin-1 receptor antagonist (IL-1ra) (p < 0.01) and increased vascular endothelial growth factor (p < 0.05). Women in the HL group did not have changes in pain; however, they did exhibit reduced depression (p < 0.05) alongside decreased granulocyte-macrophage colony-stimulating factor (p < 0.05) and increased tumor necrosis factor alpha (p < 0.05), stromal cell-derived factor-1 (p < 0.01), and IL-1ra (p < 0.01). Conclusions: AD women receiving MBSR or HL had reduced depression scores and altered circulating cytokine levels; however, only those receiving MBSR had reduced pain perception. Findings support MBSR as an effective and viable behavioral treatment for AD women suffering from CPP and provide premise for larger randomized controlled studies. Clinical Trial Registration: MOCHI-An RCT of mindfulness as a treatment for CPP in AD Women NCT04104542 (September 26, 2019).

Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.

Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer.

PURPOSE: The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER. METHODS: The pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo). RESULTS: G1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib. CONCLUSIONS: These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.

Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer.

Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinically useful anti-tumor responses when targeting a single metabolic pathway, they can also serve as targetable metabolic vulnerabilities that can be therapeutically exploited. Previously, we demonstrated that inhibition of estrogen-related receptor alpha (ERRα) significantly disrupts mitochondrial metabolism and that this results in substantial antitumor activity in animal models of breast cancer. Here we show that ERRα inhibition interferes with pyruvate entry into mitochondria by inhibiting the expression of mitochondrial pyruvate carrier 1 (MPC1). This results in a dramatic increase in the reliance of cells on glutamine oxidation and the pentose phosphate pathway to maintain nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis. In this manner, ERRα inhibition increases the efficacy of glutaminase and glucose-6-phosphate dehydrogenase inhibitors, a finding that has clinical significance.

A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product.

Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that differences in rate-controlling enzymes during the Warburg effect (WE), the most prominent hallmark of cancer cell metabolism, can be used to predict a response to targeting glucose metabolism. We establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH, an enzyme we characterize to have differential control properties over metabolism during the WE. With machine learning and integrated pharmacogenomics and metabolomics, we demonstrate that KA efficacy is not determined by the status of individual genes, but by the quantitative extent of the WE, leading to a therapeutic window in vivo. Thus, the basis of targeting the WE can be encoded by molecular principles that extend beyond the status of individual genes.

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer.

The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC). Recently, however, it has been reported that CYP17 inhibitors can interact directly with the androgen receptor (AR). A phase I study recently reported that seviteronel, a CYP17 lyase-selective inhibitor, ædemonstrated a sustained reduction in prostate-specific antigen in a patient with CRPC, and another study showed seviteronel's direct effects on AR function. This suggested that seviteronel may have therapeutically relevant activities in addition to its ability to inhibit androgen production. Here, we have demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor-bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC.

ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer.

Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.

Myeloid-derived suppressor cells regulate T cell and B cell responses during autoimmune disease.

MDSCs are a heterogeneous group of myeloid cells that suppress T cell activity in cancer and autoimmune disease. The effect of MDSCs on B cell function is not clear. Using the CIA model of autoimmune disease, we found an increase in M-MDSCs in the periphery of WT mice with CIA compared with naïve mice. These MDSCs were absent from the periphery of CCR2(-/-) mice that developed exacerbated disease. M-MDSCs, isolated from immunized mice, inhibited autologous CD4(+) T cell proliferation. The M-MDSC-mediated suppression of T cell proliferation was NO and IFN-γ dependent but IL-17 independent. Furthermore, we demonstrated for the first time that M-MDSCs from CIA mice also inhibited autologous B cell proliferation and antibody production. The suppression of B cells by M-MDSCs was dependent on the production of NO and PGE2 and required cell-cell contact. Administration of M-MDSCs rescued CCR2(-/-) mice from the exacerbated CIA phenotype and ameliorated disease in WT mice. Furthermore, adoptive transfer of M-MDSCs reduced autoantibody production by CCR2(-/-) and WT mice. In summary, M-MDSCs inhibit T cell and B cell function in CIA and may serve as a therapeutic approach in the treatment of autoimmune arthritis.