Benjamin Alman

Positions:

James R. Urbaniak, M.D., Distinguished Professor of Orthopedic Surgery

Orthopaedic Surgery
School of Medicine

Professor of Orthopaedic Surgery

Orthopaedic Surgery
School of Medicine

Chair of Orthopaedic Surgery

Orthopaedic Surgery
School of Medicine

Professor in Cell Biology

Cell Biology
School of Medicine

Professor in Pediatrics

Pediatrics
School of Medicine

Professor in the Department of Pathology

Pathology
School of Medicine

Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Co-Director of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1986

Thomas Jefferson University, Sidney Kimmel Medical College

Grants:

Rejuvenating fracture repair: The role of the macrophage and Beta-catenin

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

Stable Isotope Resolved Metabolomics to Interrogate the Interactions between Stroma and Desmoid Tumors

Awarded By
Desmoid Tumor Research Foundation, Inc.
Role
Principal Investigator
Start Date
End Date

IPA - Janet Prvu Bettger

Awarded By
Durham Veterans Affairs Medical Center
Role
Principal Investigator
Start Date
End Date

Collaboration for a Cure: Identifying new Therapeutic Targets for Desmoid Tumors

Awarded By
Desmoid Tumor Research Foundation, Inc.
Role
Principal Investigator
Start Date
End Date

Targeting Tumor Initiating Cell in Undifferentiated Pleomorphic Sarcoma

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

Publications:

Efficacy of auranofin as an inhibitor of desmoid progression.

Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of β-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of β-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.
Authors
Ito, K; Nishida, Y; Hamada, S; Shimizu, K; Sakai, T; Ohkawara, B; Alman, BA; Enomoto, A; Ikuta, K; Koike, H; Zhang, J; Ohno, K; Imagama, S
MLA Citation
Ito, Kan, et al. “Efficacy of auranofin as an inhibitor of desmoid progression.Sci Rep, vol. 12, no. 1, July 2022, p. 11918. Pubmed, doi:10.1038/s41598-022-15756-9.
URI
https://scholars.duke.edu/individual/pub1526508
PMID
35831372
Source
pubmed
Published In
Scientific Reports
Volume
12
Published Date
Start Page
11918
DOI
10.1038/s41598-022-15756-9

In desmoid-type fibromatosis cells sorafenib induces ferroptosis and apoptosis, which are enhanced by autophagy inhibition.

INTRODUCTION: Desmoid-type fibromatosis (DTF) is a rare, soft tissue tumour. Sorafenib, a multikinase inhibitor, has demonstrated antitumour efficacy in DTF patients. Little is known about the underlying molecular mechanisms, which are crucial to know to further optimize systemic treatments. Here we investigated the molecular effects of sorafenib exposure on DTF and stromal cells, with an emphasis on cell death mechanisms. MATERIAL AND METHODS: DTF primary cell cultures, with known CTNNB1 status, and primary stromal cell cultures, derived from DTF tissue, were exposed to clinically relevant concentrations of sorafenib in the presence or absence of inhibitors of ferroptosis, apoptosis and autophagy. Cell viability was determined after 24 and 48 h using MTT assays. Annexin V/PI staining, lipid peroxidation analysis and immunoblotting were performed to assess apoptosis, ferroptosis and autophagy. RESULTS: Exposure to sorafenib caused a significant, concentration- and time-dependent decrease in cell viability in all primary DTF and stromal cell cultures. Inhibitors of ferroptosis and apoptosis protected against sorafenib-mediated cytotoxicity implicating that both cell death mechanisms are activated. Annexin V/PI stainings and lipid peroxidation analyses confirmed induction of apoptosis and ferroptosis, respectively. Autophagy inhibition enhanced the cytotoxic effect of sorafenib and led to a stronger induction of apoptosis and ferroptosis. CONCLUSION: This study identified ferroptosis and apoptosis as mechanisms for the sorafenib induced cell death in DTF cells as well as stromal cells. Furthermore, autophagy inhibition enhanced the cytotoxic effects of sorafenib. Knowledge of the mechanisms by which sorafenib affects DTF at a cellular level may help to optimize its clinical efficacy and mitigate toxic effects.
Authors
Schut, A-RW; Vriends, ALM; Sacchetti, A; Timbergen, MJM; Alman, BA; Al-Jazrawe, M; Grünhagen, DJ; Verhoef, C; Sleijfer, S; Wiemer, EAC
MLA Citation
Schut, Anne-Rose W., et al. “In desmoid-type fibromatosis cells sorafenib induces ferroptosis and apoptosis, which are enhanced by autophagy inhibition.Eur J Surg Oncol, vol. 48, no. 7, July 2022, pp. 1527–35. Pubmed, doi:10.1016/j.ejso.2022.02.020.
URI
https://scholars.duke.edu/individual/pub1511821
PMID
35221159
Source
pubmed
Published In
Eur J Surg Oncol
Volume
48
Published Date
Start Page
1527
End Page
1535
DOI
10.1016/j.ejso.2022.02.020

Distinct Roles of Glutamine Metabolism in Benign and Malignant Cartilage Tumors With IDH Mutations.

Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant, respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Authors
Zhang, H; Puviindran, V; Nadesan, P; Ding, X; Shen, L; Tang, YJ; Tsushima, H; Yahara, Y; Ban, GI; Zhang, G-F; Karner, CM; Alman, BA
MLA Citation
Zhang, Hongyuan, et al. “Distinct Roles of Glutamine Metabolism in Benign and Malignant Cartilage Tumors With IDH Mutations.J Bone Miner Res, vol. 37, no. 5, May 2022, pp. 983–96. Pubmed, doi:10.1002/jbmr.4532.
URI
https://scholars.duke.edu/individual/pub1512781
PMID
35220602
Source
pubmed
Published In
J Bone Miner Res
Volume
37
Published Date
Start Page
983
End Page
996
DOI
10.1002/jbmr.4532

The origins and roles of osteoclasts in bone development, homeostasis and repair.

The mechanisms underlying bone development, repair and regeneration are reliant on the interplay and communication between osteoclasts and other surrounding cells. Osteoclasts are multinucleated monocyte lineage cells with resorptive abilities, forming the bone marrow cavity during development. This marrow cavity, essential to hematopoiesis and osteoclast-osteoblast interactions, provides a setting to investigate the origin of osteoclasts and their multi-faceted roles. This Review examines recent developments in the embryonic understanding of osteoclast origin, as well as interactions within the immune environment to regulate normal and pathological bone development, homeostasis and repair.
Authors
Yahara, Y; Nguyen, T; Ishikawa, K; Kamei, K; Alman, BA
MLA Citation
Yahara, Yasuhito, et al. “The origins and roles of osteoclasts in bone development, homeostasis and repair.Development, vol. 149, no. 8, Apr. 2022. Pubmed, doi:10.1242/dev.199908.
URI
https://scholars.duke.edu/individual/pub1520473
PMID
35502779
Source
pubmed
Published In
Development
Volume
149
Published Date
DOI
10.1242/dev.199908

How to Assess Quality in an Increasingly Diverse Health-Care System: AOA Critical Issues Symposium.

Authors
Obremskey, W; Alman, B; Vail, TP; Suk, M; Russell, G
MLA Citation
Obremskey, William, et al. “How to Assess Quality in an Increasingly Diverse Health-Care System: AOA Critical Issues Symposium.J Bone Joint Surg Am, Jan. 2022. Pubmed, doi:10.2106/JBJS.21.00307.
URI
https://scholars.duke.edu/individual/pub1526732
PMID
35041622
Source
pubmed
Published In
J Bone Joint Surg Am
Published Date
DOI
10.2106/JBJS.21.00307