Michael Kastan

Positions:

William and Jane Shingleton Distinguished Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Director of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Professor of Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1984

Washington University in St. Louis

Ph.D. 1984

Washington University in St. Louis

Grants:

Using bacterial CRISPR/Cas endonucleases to selectively eliminate HPV-transformed cells in vivo

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Development and Validation of Novel Therapeutic Targets in Anal Cancer

Administered By
Medicine, Medical Oncology
Awarded By
The Farrah Fawcett Foundation
Role
Collaborator
Start Date
End Date

The role of ATM in Metabolic Stress Responses

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The role of ATM in Metabolic Stress Responses

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Metabolic Sensing and Stress Response Deficit in Ataxia Telangiectasia

Administered By
Pharmacology & Cancer Biology
Awarded By
A-T Children's Project
Role
Principal Investigator
Start Date
End Date

Publications:

Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in childhood and early adulthood. An adolescent girl with minimal neurological symptoms was diagnosed with A-T 8 years after completing therapy for T-cell acute lymphoblastic leukemia, following a diagnosis of ATM-mutated breast cancer in her mother. We highlight the importance of recognizing ATM mutations in T-cell acute lymphoblastic leukemia, appreciating the phenotypic heterogeneity of A-T, and defining optimal cancer screening in A-T patients.
Authors
Sze, S-GK; Lederman, HM; Crawford, TO; Wangler, MF; Lewis, AM; Kastan, MB; Dibra, HK; Taylor, AMR; Wechsler, DS
MLA Citation
Sze, Sei-Gyung K., et al. “Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.J Pediatr Hematol Oncol, Nov. 2019. Pubmed, doi:10.1097/MPH.0000000000001672.
URI
https://scholars.duke.edu/individual/pub1421634
PMID
31743320
Source
pubmed
Published In
Journal of Pediatric Hematology/Oncology
Published Date
DOI
10.1097/MPH.0000000000001672

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.

Background: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007.
Authors
McGill, JB; Johnson, M; Hurst, S; Cade, WT; Yarasheski, KE; Ostlund, RE; Schechtman, KB; Razani, B; Kastan, MB; McClain, DA; de Las Fuentes, L; Davila-Roman, VG; Ory, DS; Wickline, SA; Semenkovich, CF
MLA Citation
McGill, Janet B., et al. “Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.Diabetol Metab Syndr, vol. 11, 2019, p. 61. Pubmed, doi:10.1186/s13098-019-0456-4.
URI
https://scholars.duke.edu/individual/pub1404051
PMID
31384309
Source
pubmed
Published In
Diabetol Metab Syndr
Volume
11
Published Date
Start Page
61
DOI
10.1186/s13098-019-0456-4

ATM functions at the peroxisome to induce pexophagy in response to ROS.

Peroxisomes are highly metabolic, autonomously replicating organelles that generate reactive oxygen species (ROS) as a by-product of fatty acid β-oxidation. Consequently, cells must maintain peroxisome homeostasis, or risk pathologies associated with too few peroxisomes, such as peroxisome biogenesis disorders, or too many peroxisomes, inducing oxidative damage and promoting diseases such as cancer. We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to ROS, ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy. These data reveal an important new role for ATM in metabolism as a sensor of ROS that regulates pexophagy.
Authors
Zhang, J; Tripathi, DN; Jing, J; Alexander, A; Kim, J; Powell, RT; Dere, R; Tait-Mulder, J; Lee, J-H; Paull, TT; Pandita, RK; Charaka, VK; Pandita, TK; Kastan, MB; Walker, CL
MLA Citation
Zhang, Jiangwei, et al. “ATM functions at the peroxisome to induce pexophagy in response to ROS.Nat Cell Biol, vol. 17, no. 10, Oct. 2015, pp. 1259–69. Pubmed, doi:10.1038/ncb3230.
URI
https://scholars.duke.edu/individual/pub1087777
PMID
26344566
Source
pubmed
Published In
Nat Cell Biol
Volume
17
Published Date
Start Page
1259
End Page
1269
DOI
10.1038/ncb3230

Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair.

Recruitment of DNA repair factors and modulation of chromatin structure at sites of DNA double-strand breaks (DSBs) is a complex and highly orchestrated process. We developed a system that can induce DSBs rapidly at defined endogenous sites in mammalian genomes and enables direct assessment of repair and monitoring of protein recruitment, egress, and modification at DSBs. The tight regulation of the system also permits assessments of relative kinetics and dependencies of events associated with cellular responses to DNA breakage. Distinct advantages of this system over focus formation/disappearance assays for assessing DSB repair are demonstrated. Using ChIP, we found that nucleosomes are partially disassembled around DSBs during nonhomologous end-joining repair in G1-arrested mammalian cells, characterized by a transient loss of the H2A/H2B histone dimer. Nucleolin, a protein with histone chaperone activity, interacts with RAD50 via its arginine-glycine rich domain and is recruited to DSBs rapidly in an MRE11-NBS1-RAD50 complex-dependent manner. Down-regulation of nucleolin abrogates the nucleosome disruption, the recruitment of repair factors, and the repair of the DSB, demonstrating the functional importance of nucleosome disruption in DSB repair and identifying a chromatin-remodeling protein required for the process. Interestingly, the nucleosome disruption that occurs during DSB repair in cycling cells differs in that both H2A/H2B and H3/H4 histone dimers are removed. This complete nucleosome disruption is also dependent on nucleolin and is required for recruitment of replication protein A to DSBs, a marker of DSB processing that is a requisite for homologous recombination repair.
Authors
Goldstein, M; Derheimer, FA; Tait-Mulder, J; Kastan, MB
MLA Citation
Goldstein, Michael, et al. “Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair.Proc Natl Acad Sci U S A, vol. 110, no. 42, Oct. 2013, pp. 16874–79. Pubmed, doi:10.1073/pnas.1306160110.
URI
https://scholars.duke.edu/individual/pub965197
PMID
24082117
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
110
Published Date
Start Page
16874
End Page
16879
DOI
10.1073/pnas.1306160110

RADIATION THERAPY AND ADJUVANT CHEMOTHERAPY IN A PATIENT WITH A HIGH GRADE GLIOMA AND UNDERLYING ATAXIA TELANGIECTASIA

Authors
DeWire, MD; Pananandiker, ASP; Ellison, DE; McKinnon, PJ; Kastan, MB; Gajjar, A
MLA Citation
DeWire, M. D., et al. “RADIATION THERAPY AND ADJUVANT CHEMOTHERAPY IN A PATIENT WITH A HIGH GRADE GLIOMA AND UNDERLYING ATAXIA TELANGIECTASIA.” Neuro Oncology, vol. 12, no. 6, OXFORD UNIV PRESS INC, 2010, pp. II87–II87.
URI
https://scholars.duke.edu/individual/pub888451
Source
wos
Published In
Neuro Oncology
Volume
12
Published Date
Start Page
II87
End Page
II87