2019 — 2021 |
Wu, Boyang |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Maoa and Ar Reciprocal Crosstalk in Prostate Cancer @ Washington State University
Project Summary/Abstract Prostate cancer (PC) is the most common non-skin cancer in American men, with a lifetime incidence of 1 in 7, and also the second leading cause of cancer death in American men. Androgen receptor (AR) is the primary oncogenic driver of PC growth, survival and progression. AR-directed therapy is currently the principal treatment regimen. Despite initial response rates exceeding 90%, PC eventually relapses and progresses to fatal castration-resistant PC (CRPC), where reactivation of AR signaling occurs in a low-androgen environment. Recent introduction of FDA-approved next-generation antiandrogens, including enzalutamide (ENZ) and abiraterone acetate (ABI), have improved the CRPC treatment landscape, but emergence of drug resistance remains nearly universal, with no AR-targeted therapeutic options afterwards. These dismal facts underscore the pressing clinical need to identify new molecular targets and develop effective therapies to combat advanced PC. Through integrated analysis of publicly available clinical PC data sets coupled with functional studies in AR-positive PC cells, we propose monoamine oxidase A (MAOA), which synergizes with AR to promote PC, as an ideal therapeutic candidate to complement AR-targeted therapy in CRPC. We identified a novel reciprocal interaction between MAOA and AR in PC cells. MAOA expression is induced by androgen treatment; and conversely, MAOA silencing significantly reduces AR activity by lowering AR target gene expression and responsiveness to androgen stimulation in PC cells under both androgen-replete and depleted conditions as well as in a CRPC xenograft model. We showed significant positive co-expression of MAOA and AR target genes (PSA, TMPRSS2, NKX3.1) in multiple clinical data sets, including CRPC. Importantly, we found MAOA genomic amplification and/or epigenetic activation in 64% of samples in a CRPC data set, reinforced by elevated MAOA protein expression in our CRPC patient cohort. Additionally, we demonstrated that inhibition of MAOA by genetic or pharmacological approaches enhanced the growth-inhibiting effects of ENZ and ABI in androgen-sensitive, CR and antiandrogen-resistant PC cells. Based on these findings, we will test the hypothesis that MAOA synergizes with AR through reciprocal crosstalk and convergent downstream signaling to amply MAOA/AR effects promoting AR-driven PC growth and progression, and that co-targeting MAOA/AR is an actionable, effective strategy to treat CRPC and reverse antiandrogen drug resistance. To address this hypothesis, three aims are proposed. In Aim 1, we will elucidate the mechanistic basis of MAOA- AR reciprocal interaction in PC cells. In Aim 2, we will characterize the role of MAOA in regulating the development and progression of CRPC in xenograft models. In Aim 3, we will determine the efficacy of MAOA inhibitors for treating CRPC and reversing resistance to next-generation antiandrogens in vitro and in vivo. These studies will provide fundamental innovative insights into AR regulation in CRPC and illuminate a path toward the development of new combination therapy for advanced PC.
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0.931 |
2021 |
Wu, Boyang |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Deciphering Mechanisms of Tumor-Stromal Interactions in Prostate Cancer @ Washington State University
Project Summary/Abstract Prostate cancer (PC) affects 1 in 9 men and causes nearly 30,000 yearly deaths in the United States. Understanding the PC tumor microenvironment (TME) is essential for optimizing cancer prevention and care. Unlike highly mutable tumor cells, non-cancerous stromal cells in the TME, consisting primarily of cancer associated fibroblasts (CAFs), are a genetically stable and attractive therapeutic target in PC, with reduced risk of acquired resistance from genetic changes. Our long-term goals are to elucidate the molecular mechanisms governing stromal support of PC growth and progression, and identify potential druggable therapeutic targets in the stromal compartment to disrupt tumor-stromal interactions. We recently found that monoamine oxidase B (MAOB), a mitochondrial oxidative enzyme responsible for degrading monoamine neurotransmitters and dietary amines, is highly induced in PC stromal cells compared to normal prostate stromal cells in patient samples, PTEN-knockout (KO) transgenic mice and primary cultures of patient-derived CAFs. Stromal MAOB expression further increases during disease progression toward castration resistance and neuroendocrine differentiation, compared to hormone-naïve disease. Our epidemiological studies revealed that men taking MAOB inhibitors for neurological disorders such as depression tend to have a lower incidence of PC. Functional studies showed that MAOB ablation in prostate stromal cells profoundly suppressed co-cultured PC cell proliferation/invasion and co-inoculated xenograft/allograft prostate tumor growth in mice. Mechanistically, gene profiling, bioinformatics and phenotypic analyses indicate that stromal MAOB heightens cellular reactive oxygen species (ROS) levels and chemotaxis/chemokine secretion, particularly CXCL13. Based on these new findings, we hypothesize that the elevated expression of MAOB in PC stromal cells promotes adjacent epithelial PC development and progression, and that targeting MAOB and its downstream effectors in stromal cells is an effective strategy to treat PC. In Aim 1, we will determine the functional role of MAOB in stromal activation and its contribution to tumor growth and progression in tissue recombinant xenograft immunocompromised mice and MAOB-KO immunocompetent mice. In Aim 2, we will investigate the molecular mechanism by which MAOB mediates tumor-stromal communication in PC, specifically dissecting how Twist1 cooperates with TGF?1/Smad3/4 by ROS to activate CXCL13 and how the CXCL13/CXCR5 paracrine axis impacts PC cell behaviors and associated novel signaling pathways in the context of MAOB. We will also establish the relevance of our mechanistic findings in a large collection of human PC samples and assess correlations with disease status. In Aim 3, we will evaluate the efficacy of MAOB inhibitors for treating PC, including castration-resistant PC, in xenograft and syngeneic mouse prostate tumor models. These studies have tremendous biological, pathological and clinical implications for the future application of clinical MAOB inhibitors and development of TME-targeted therapies to complement existing tumor cell-centric PC therapies.
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0.931 |