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

Commentary on "Participation of p53 Protein in the Cellular Response to DNA Damage".

Authors
Kastan, MB
MLA Citation
Kastan, Michael B. “Commentary on "Participation of p53 Protein in the Cellular Response to DNA Damage"..” Cancer Res, vol. 76, no. 13, July 2016, pp. 3663–65. Pubmed, doi:10.1158/0008-5472.CAN-16-1560.
URI
https://scholars.duke.edu/individual/pub1136098
PMID
27371738
Source
pubmed
Published In
Cancer Res
Volume
76
Published Date
Start Page
3663
End Page
3665
DOI
10.1158/0008-5472.CAN-16-1560

Erratum: Development of a cell-based, high-throughput screening assay for atm kinase inhibitors (Journal of Biomolecular Screening (2014) 19:4 (538-546) DOI:10.1177/1087057113520325)

Authors
Guo, K; Anang, A; Shelat, R; Guy, K; Kastan, MB
MLA Citation
Guo, K., et al. “Erratum: Development of a cell-based, high-throughput screening assay for atm kinase inhibitors (Journal of Biomolecular Screening (2014) 19:4 (538-546) DOI:10.1177/1087057113520325).” Journal of Biomolecular Screening, vol. 19, no. 10, Jan. 2014. Scopus, doi:10.1177/1087057114559509.
URI
https://scholars.duke.edu/individual/pub1053579
Source
scopus
Published In
J Biomol Screen
Volume
19
Published Date
Start Page
1418
DOI
10.1177/1087057114559509

Chloroquine Activates ATM and Improves Hematopoietic Recovery and Survival of Mice following Low Dose-rate Radiation

Authors
DeWeese, TL; Lim, Y; Hedayati, M; Merchant, A; Zhang, Y; Yu, HM; Kastan, MB; Matsui, W
MLA Citation
DeWeese, T. L., et al. “Chloroquine Activates ATM and Improves Hematopoietic Recovery and Survival of Mice following Low Dose-rate Radiation.” International Journal of Radiation Oncology*Biology*Physics, vol. 81, no. 2, Elsevier BV, Oct. 2011, pp. S191–92. Crossref, doi:10.1016/j.ijrobp.2011.06.343.
URI
https://scholars.duke.edu/individual/pub888480
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
81
Published Date
Start Page
S191
End Page
S192
DOI
10.1016/j.ijrobp.2011.06.343

Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis.

Despite great interest in cancer chemoprevention, effective agents are few. Here we show that chloroquine, a drug that activates the stress-responsive Atm-p53 tumor-suppressor pathway, preferentially enhances the death of Myc oncogene-overexpressing primary mouse B cells and mouse embryonic fibroblasts (MEFs) and impairs Myc-induced lymphomagenesis in a transgenic mouse model of human Burkitt lymphoma. Chloroquine-induced cell death in primary MEFs and human colorectal cancer cells was dependent upon p53, but not upon the p53 modulators Atm or Arf. Accordingly, chloroquine impaired spontaneous lymphoma development in Atm-deficient mice, a mouse model of ataxia telangiectasia, but not in p53-deficient mice. Chloroquine treatment enhanced markers of both macroautophagy and apoptosis in MEFs but ultimately impaired lysosomal protein degradation. Interestingly, chloroquine-induced cell death was not dependent on caspase-mediated apoptosis, as neither overexpression of the antiapoptotic protein Bcl-2 nor deletion of the proapoptotic Bax and Bak affected chloroquine-induced MEF death. However, when both apoptotic and autophagic pathways were blocked simultaneously, chloroquine-induced killing of Myc-overexpressing cells was blunted. Thus chloroquine induces lysosomal stress and provokes a p53-dependent cell death that does not require caspase-mediated apoptosis. These findings specifically demonstrate that intermittent chloroquine use effectively prevents cancer in mouse models of 2 genetically distinct human cancer syndromes, Burkitt lymphoma and ataxia telangiectasia, suggesting that agents targeting lysosome-mediated degradation may be effective in cancer prevention.
Authors
Maclean, KH; Dorsey, FC; Cleveland, JL; Kastan, MB
MLA Citation
Maclean, Kirsteen H., et al. “Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis..” J Clin Invest, vol. 118, no. 1, Jan. 2008, pp. 79–88. Pubmed, doi:10.1172/JCI33700.
URI
https://scholars.duke.edu/individual/pub779333
PMID
18097482
Source
pubmed
Published In
The Journal of Clinical Investigation
Volume
118
Published Date
Start Page
79
End Page
88
DOI
10.1172/JCI33700