Everardo Macias

Overview:

The overarching goal of the Macias lab is to gain basic mechanistic insights into clinically relevant actionable molecular targets with the eventual goal of aiding to reduce prostate cancer-specific mortality.

Our group integrates human cancer genomic data, functional genomic loss of function screens and pre-clinical in vitro and in vivo mouse models in order to identify, prioritize and validate potential therapeutic targets. Recently, we conducted a functional genomic kinome screen in obese and calorie restricted mice that identified various orphan kinases that are essential for tumor growth in an obese and lean host environment. We are steadily adapting drug development discovery capabilities and lead compound optimization strategies for increased target engagement, efficacy and drug like properties via collaboration with medicinal chemists and structural biologists. In parallel, we are conducting basic mechanistic studies to determine the mechanism of action, including live cell imaging phenotypic gain and loss of function genetic studies and various omic approaches.

Positions:

Assistant Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

North Carolina State University

Grants:

Genetic screen of calorie restricted and western diet essential kinases in prostate cancer

Administered By
Pathology
Awarded By
Prostate Cancer Foundation
Role
Principal Investigator
Start Date
End Date

Targeting Ribosomal Biogenesis in Prostate Cancer

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Prostate Cancer and Obesogenic Factors

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Targeting NUAK2 to mitigate obesity-enhanced prostate cancer growth and metastasis

Administered By
Pathology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Publications:

Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.
Authors
Schirmer, AU; Driver, LM; Zhao, MT; Wells, CI; Pickett, JE; O'Bryne, SN; Eduful, BJ; Yang, X; Howard, L; You, S; Devi, GR; DiGiovanni, J; Freedland, SJ; Chi, J-T; Drewry, DH; Macias, E
MLA Citation
Schirmer, Amelia U., et al. “Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.Mol Ther, Aug. 2021. Pubmed, doi:10.1016/j.ymthe.2021.08.029.
URI
https://scholars.duke.edu/individual/pub1494995
PMID
34450249
Source
pubmed
Published In
Molecular Therapy : the Journal of the American Society of Gene Therapy
Published Date
DOI
10.1016/j.ymthe.2021.08.029

Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer

Authors
Macias, E; Cho, J; Rosowicz, D; Heidari, Z; You, S; Maravilla, EJ; Chi, J-T; Freedland, SJ
MLA Citation
Macias, Everardo, et al. “Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer.” Molecular and Cellular Biology / Genetics, American Association for Cancer Research, 2019. Crossref, doi:10.1158/1538-7445.am2019-3590.
URI
https://scholars.duke.edu/individual/pub1416900
Source
crossref
Published In
Molecular and Cellular Biology / Genetics
Published Date
DOI
10.1158/1538-7445.am2019-3590

Abstract 862: Inhibition of Hippo tumor suppressors MST1/2 slows prostate cancer cell proliferation and invasion

Authors
Schirmer, A; Stokes, AB; Maravilla, EJ; Fu, W; Macias, E
MLA Citation
Schirmer, Amelia, et al. “Abstract 862: Inhibition of Hippo tumor suppressors MST1/2 slows prostate cancer cell proliferation and invasion.” Molecular and Cellular Biology / Genetics, American Association for Cancer Research, 2019. Crossref, doi:10.1158/1538-7445.am2019-862.
URI
https://scholars.duke.edu/individual/pub1416901
Source
crossref
Published In
Molecular and Cellular Biology / Genetics
Published Date
DOI
10.1158/1538-7445.am2019-862

NUAK2 inhibition for prostate cancer.

Authors
Fu, W; Zhao, M; Schirmer, A; Maravilla, EJ; Yoon, J; You, S; Freedland, SJ; Macias, E
MLA Citation
Fu, Weiwei, et al. “NUAK2 inhibition for prostate cancer.Molecular Cancer Research, vol. 18, no. 8, 2020, pp. 46–46.
URI
https://scholars.duke.edu/individual/pub1457301
Source
wos-lite
Published In
Molecular Cancer Research : Mcr
Volume
18
Published Date
Start Page
46
End Page
46

27-Hydroxycholesterol Impairs Plasma Membrane Lipid Raft Signaling as Evidenced by Inhibition of IL6-JAK-STAT3 Signaling in Prostate Cancer Cells.

We recently reported that restoring the CYP27A1-27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti-prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6-JAK-STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6-JAK-STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation. IMPLICATIONS: Collectively, these data show that modulation of intracellular cholesterol by 27HC can inhibit IL6-JAK-STAT signaling and may synergize with STAT3-targeted compounds.
Authors
Dambal, S; Alfaqih, M; Sanders, S; Maravilla, E; Ramirez-Torres, A; Galvan, GC; Reis-Sobreiro, M; Rotinen, M; Driver, LM; Behrove, MS; Talisman, TJ; Yoon, J; You, S; Turkson, J; Chi, J-T; Freeman, MR; Macias, E; Freedland, SJ
MLA Citation
Dambal, Shweta, et al. “27-Hydroxycholesterol Impairs Plasma Membrane Lipid Raft Signaling as Evidenced by Inhibition of IL6-JAK-STAT3 Signaling in Prostate Cancer Cells.Mol Cancer Res, vol. 18, no. 5, May 2020, pp. 671–84. Pubmed, doi:10.1158/1541-7786.MCR-19-0974.
URI
https://scholars.duke.edu/individual/pub1432447
PMID
32019810
Source
pubmed
Published In
Mol Cancer Res
Volume
18
Published Date
Start Page
671
End Page
684
DOI
10.1158/1541-7786.MCR-19-0974