Michael Kastan

Positions:

William and Jane Shingleton 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:

The Role of USP22 in Prostate Cancer Development and Progression

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

Evaluation of kinase inhibitors

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
End Date

Cancer Center Support Grant

Administered By
Duke Cancer Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

C30 Canine Pilot Research

Administered By
Duke Cancer Institute
Awarded By
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
End Date

Cellular Stress Response Signaling Pathways

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

Publications:

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. 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

Chromatin perturbations during the DNA damage response in higher eukaryotes.

The DNA damage response is a widely used term that encompasses all signaling initiated at DNA lesions and damaged replication forks as it extends to orchestrate DNA repair, cell cycle checkpoints, cell death and senescence. ATM, an apical DNA damage signaling kinase, is virtually instantaneously activated following the introduction of DNA double-strand breaks (DSBs). The MRE11-RAD50-NBS1 (MRN) complex, which has a catalytic role in DNA repair, and the KAT5 (Tip60) acetyltransferase are required for maximal ATM kinase activation in cells exposed to low doses of ionizing radiation. The sensing of DNA lesions occurs within a highly complex and heterogeneous chromatin environment. Chromatin decondensation and histone eviction at DSBs may be permissive for KAT5 binding to H3K9me3 and H3K36me3, ATM kinase acetylation and activation. Furthermore, chromatin perturbation may be a prerequisite for most DNA repair. Nucleosome disassembly during DNA repair was first reported in the 1970s by Smerdon and colleagues when nucleosome rearrangement was noted during the process of nucleotide excision repair of UV-induced DNA damage in human cells. Recently, the multi-functional protein nucleolin was identified as the relevant histone chaperone required for partial nucleosome disruption at DBSs, the recruitment of repair enzymes and for DNA repair. Notably, ATM kinase is activated by chromatin perturbations induced by a variety of treatments that do not directly cause DSBs, including treatment with histone deacetylase inhibitors. Central to the mechanisms that activate ATR, the second apical DNA damage signaling kinase, outside of a stalled and collapsed replication fork in S-phase, is chromatin decondensation and histone eviction associated with DNA end resection at DSBs. Thus, a stress that is common to both ATM and ATR kinase activation is chromatin perturbations, and we argue that chromatin perturbations are both sufficient and required for induction of the DNA damage response.
Authors
Bakkenist, CJ; Kastan, MB
MLA Citation
Bakkenist, Christopher J., and Michael B. Kastan. “Chromatin perturbations during the DNA damage response in higher eukaryotes..” Dna Repair (Amst), vol. 36, Dec. 2015, pp. 8–12. Pubmed, doi:10.1016/j.dnarep.2015.09.002.
URI
https://scholars.duke.edu/individual/pub1090047
PMID
26391293
Source
pubmed
Published In
Dna Repair (Amst)
Volume
36
Published Date
Start Page
8
End Page
12
DOI
10.1016/j.dnarep.2015.09.002

Preface

Authors
Niederhuber, JE; Armitage, JO; Doroshow, JH; Kastan, MB; Tepper, JE
MLA Citation
Niederhuber, J. E., et al. Preface. 2013. Scopus, doi:10.1016/B978-1-4557-2865-7.00114-4.
URI
https://scholars.duke.edu/individual/pub1097427
Source
scopus
Published Date
Start Page
ix
DOI
10.1016/B978-1-4557-2865-7.00114-4

Multiple roles of ATM in monitoring and maintaining DNA integrity.

The ability of our cells to maintain genomic integrity is fundamental for protection from cancer development. Central to this process is the ability of cells to recognize and repair DNA damage and progress through the cell cycle in a regulated and orderly manner. In addition, protection of chromosome ends through the proper assembly of telomeres prevents loss of genetic information and aberrant chromosome fusions. Cells derived from patients with ataxia-telangiectasia (A-T) show defects in cell cycle regulation, abnormal responses to DNA breakage, and chromosomal end-to-end fusions. The identification and characterization of the ATM (ataxia-telangiectasia, mutated) gene product has provided an essential tool for researchers in elucidating cellular mechanisms involved in cell cycle control, DNA repair, and chromosomal stability.
Authors
Derheimer, FA; Kastan, MB
MLA Citation
Derheimer, Frederick A., and Michael B. Kastan. “Multiple roles of ATM in monitoring and maintaining DNA integrity..” Febs Lett, vol. 584, no. 17, Sept. 2010, pp. 3675–81. Pubmed, doi:10.1016/j.febslet.2010.05.031.
URI
https://scholars.duke.edu/individual/pub779321
PMID
20580718
Source
pubmed
Published In
Febs Letters
Volume
584
Published Date
Start Page
3675
End Page
3681
DOI
10.1016/j.febslet.2010.05.031

A message from the editor

Authors
Kastan, MB
MLA Citation
Kastan, M. B. “A message from the editor.” Molecular Cancer Research, vol. 5, no. 11, Nov. 2007.
URI
https://scholars.duke.edu/individual/pub779336
Source
scopus
Published In
Molecular Cancer Research : Mcr
Volume
5
Published Date