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
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
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.Diabetology & Metabolic Syndrome, vol. 11, Jan. 2019, p. 61. Epmc, doi:10.1186/s13098-019-0456-4.
URI
https://scholars.duke.edu/individual/pub1404051
PMID
31384309
Source
epmc
Published In
Diabetol Metab Syndr
Volume
11
Published Date
Start Page
61
DOI
10.1186/s13098-019-0456-4

Abstract IA17: Non-canonical aspects of ATM and p53 signaling pathways

Authors
Kastan, MB; Scarbrough, P; Chen, J; Brown, A; Crutchley, J; Fleenor, D
MLA Citation
Kastan, Michael B., et al. “Abstract IA17: Non-canonical aspects of ATM and p53 signaling pathways.” Dna Damage Signaling, American Association for Cancer Research, 2017. Crossref, doi:10.1158/1557-3125.dnarepair16-ia17.
URI
https://scholars.duke.edu/individual/pub1288825
Source
crossref
Published In
Dna Damage Signaling
Published Date
DOI
10.1158/1557-3125.dnarepair16-ia17

Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies.

Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n = 2; IV, n = 3) B-NHL (diffuse large B-cell lymphoma, n = 4; Burkitt leukemia, n = 1) using a modified LMB-based protocol. Two achieved sustained CCR (one, CCR at 6 years; one, pulmonary death after 3 years in CCR). Two died from toxicity during induction and 1 failed induction with progressive disease. Novel therapeutic approaches which overcome drug resistance and are less toxic are needed for children with A-T and B-NHL.
Authors
Sandlund, JT; Hudson, MM; Kennedy, W; Onciu, M; Kastan, MB
MLA Citation
Sandlund, J. T., et al. “Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies.Pediatr Blood Cancer, vol. 61, no. 2, Feb. 2014, pp. 360–62. Pubmed, doi:10.1002/pbc.24696.
URI
https://scholars.duke.edu/individual/pub960540
PMID
23900766
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
61
Published Date
Start Page
360
End Page
362
DOI
10.1002/pbc.24696

Mitochondrial dysfunction in ataxia-telangiectasia.

Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease.
Authors
Valentin-Vega, YA; Maclean, KH; Tait-Mulder, J; Milasta, S; Steeves, M; Dorsey, FC; Cleveland, JL; Green, DR; Kastan, MB
MLA Citation
Valentin-Vega, Yasmine A., et al. “Mitochondrial dysfunction in ataxia-telangiectasia.Blood, vol. 119, no. 6, Feb. 2012, pp. 1490–500. Pubmed, doi:10.1182/blood-2011-08-373639.
URI
https://scholars.duke.edu/individual/pub779320
PMID
22144182
Source
pubmed
Published In
Blood
Volume
119
Published Date
Start Page
1490
End Page
1500
DOI
10.1182/blood-2011-08-373639