Michael Kahn | City of Hope

Michael Kahn, Ph.D.

  • Professor and Associate Chair, Department of Molecular Medicine

Michael Kahn, Ph.D.

Research Focus :
  • Chemical genomics
  • Wnt signaling
Michael Kahn, Ph.D., has joined City of Hope as professor and associate chair in the Department of Molecular Medicine. He comes to us from the University of Southern California, where he was the first appointed Provost Professor, with joint appointments in the Department of Biochemistry and Molecular Biology at the Keck School of Medicine and the Department of Molecular Pharmacology and Toxicology in the School of Pharmacy. He was also the co-leader of the GI-Oncology program at the USC Norris Comprehensive Cancer Center, as well as the Center for Drug Discovery and Development at USC.
 
After completing his postdoctoral training at Columbia University with Professor Gilbert Stork, Dr. Kahn subsequently did a second postdoctoral fellowship at the Roche Institute for Molecular Biology, where he first became interested in utilizing novel chemistry to complement and enhance the investigation of complex biological signaling pathways.
 
Dr. Kahn’s research program is focused on the integration of basic science (biochemistry, cell and molecular biology and chemistry) with translational medicine. His lab utilizes a forward chemical genomic strategy to identify and validate novel pharmacologic tools to study complex signaling pathways in development and disease. Utilizing a proprietary chemical library, his lab identified the first specific CBP/β-catenin antagonist ICG-001, which has been fundamental in studies involving both normal somatic stem cell and cancer stem cell biology. From a translational perspective, these studies led to the development of the second-generation CBP/β-catenin antagonist, Wnt modulating drug, PRI-724. These efforts resulted in the clinical trials of PRI-724 in colon and pancreatic cancer, leukemia and liver fibrosis.
 
His lab is currently continuing basic research investigations concerning differential Kat3 coactivator usage (i.e. CBP versus p300) in somatic stem cell biology and cancer, regenerative medicine and aging. The lab is also investigating modulation of Wnt/β-catenin in the immune response. CBP/ β-catenin inhibitors in combination with immunotherapy may provide a significant benefit. Another area of interest to his lab is the endogenous mechanisms that control the differential usage of these coactivators and the role that the N-termini play as a nexus for the integration of a number of additional signaling pathways (e.g. Stat1/2, nuclear receptor family e.g. RAR/RXR, Vit D) with the Wnt signaling cascade. Dr. Kahn is applying this forward chemical genomic strategy to additional critical signaling cascades with the broader goal of developing novel small molecule therapeutics.
  • 2017 - present, Professor and Associate Chair, Department of Molecular Medicine, City of Hope
  • 2014 - present, Editor, Molecular Pharmacology
  • 2006 - 2017, Provost Professor, Department of Medicine and Pharmacy, University of Southern California
  • 2004 - 2005, Scientific Director, Institute for Chemical Genomics, Seattle, WA
  • 2000 - 2004, Principal Investigator, Pacific Northwest Research Institute, Seattle, WA
  • 1998 - 2000, Senior Vice-President, Molecumetics, Bellevue, WA
  • 1995 - 2006, Research Associate Professor, University of Washington
  • 1992 - 1995, Associate Professor, University of Washington
  • 1988 - 1992, Associate Professor, University of Illinois - Chicago
  • 1985 - 1988, Assistant Professor, University of Illinois - Chicago
  • 1984 - 1985, Research Associate, Hoffman-LaRoche, Nutley, NJ

Degrees

  • 1983, Yale University, Ph.D., Chemistry
  • 1978, Columbia University, B.A., Chemistry

Fellowship

  • 1982 - 1984, Postdoctoral Fellow, National Institute of Health, Professor Gilbert Stork
The laboratory of Michael Kahn, Ph.D., utilizes a forward chemical genomic strategy to identify and validate novel pharmacologic tools to study complex signaling pathways in development and disease. Utilizing a proprietary chemical library, which his team designed and synthesized, they identified the first specific CBP/β-catenin antagonist ICG-001from a cancer cell-based Wnt signaling screen.

After extensive target validation and investigations on both the mechanism of action and specificity of ICG-001, Kahn’s team has and continues to utilize this novel pharmacologic tool to investigate the enormously fundamental and complex Wnt signaling cascade, particularly in regard to stem cell and cancer stem cell biology. These efforts culminated with the entry of the second generation CBP/β-catenin antagonist PRI-724 into a first-in-human clinical trial in 2011. Of importance, PRI-724 proved to be extremely safe in patients and dose escalation continued from 40 to 1280 mg/m2 without the establishment of a maximum tolerated dose.

Kahn’s team further demonstrated that enhancing p300/β-catenin signaling utilizing CBP/catenin antagonists has beneficial effects in “repair” processes in a number of preclinical models including lung, kidney and liver fibrosis. These studies led to a phase 1 clinical trial for HCV-induced hepatic fibrosis patients with PRI-724. Of importance, not only can disease progression be halted, enhancing p300/β-catenin signaling regenerates new tissue and reverses the disease process, leading to enhanced liver function.

Although originally intended as a therapeutic agent to treat colorectal cancer, the unique and pleiotropic properties of the CBP/catenin antagonists (e.g., sparing normal somatic stem cells while forcing the differentiation and thereby the elimination of cancer stem cells) on somatic stem cells and cancer stem cells in both solid and liquid tumors, coupled with their extremely high degree of safety, both preclinically and clinically, makes them potentially ideal agents for cancer prevention strategies and therapeutic trials. These strategies could be potentially evaluated in high-risk patient cohorts (e.g., FAP, MDS patients), with the eventual goal of testing CBP/catenin antagonists as preventive agents in the general population. Kahn’s team continues to dissect the Wnt signaling cascade and differential kat3 coactivator usage, both in vitro and in vivo, with continued emphasis on somatic stem cells and cancer stem cells.

Recently, impressive results in a subset of cancers have been obtained using checkpoint immunotherapies. Still, only a subset of patients responds to these treatments. One potential mechanism of resistance was identified. In human metastatic melanoma samples, a correlation between activation of the Wnt/β-catenin signaling pathway and an absence of a T cell gene expression signature was demonstrated. Potentially, this mechanism also accounts for the limited response to checkpoint immunotherapies in CRC, particularly in MSI negative patients who generally carry APC mutations that strongly activate the Wnt signaling pathway. If this is indeed the mechanism of resistance, combining a Wnt/CBP/β-catenin inhibitor with immunotherapy may lead to a significant benefit.  

During the course of Kahn’s team’s investigations with the specific CBP/catenin antagonist ICG- 001, they discovered a very fundamental regulatory event – in both pluripotent and somatic stem cells – that controls the cell’s decision to either maintain “stemness” or initiate differentiation. This decision is governed by the choice of which of the two highly homologous Kat3 coactivators, CBP or p300, the key Wnt signaling component β-catenin partners with to drive transcription. ICG-001 is a selective CBP/β-catenin antagonist and the structurally related small molecule YH250, which they developed more recently, is a selective p300/β-catenin antagonist. His team recently demonstrated that YH250 stimulates hematopoiesis in lethally or sublethally irradiated mice. A single administration of YH250, 24 hours post-irradiation can significantly stimulate HSC proliferation, improve survival and accelerate peripheral blood count recovery. Their studies suggest that increased expansion of the remaining HSC population via symmetric nondifferentiative proliferation is at least part of the mechanism of action.

More generally, Kahn’s team is investigating the role of selective modulation of Wnt signaling on immune cell biasing and recruitment in chronic inflammatory diseases (e.g., IBD), obesity and metabolic disease and the tumor microenvironment, utilizing both their highly specific pharmacologic tools and genetic models (knockin mouse and CRISPR/Cas9 editing of p300).

In a bedside-to-bench manner, based upon findings regarding metabolic parameters in patients treated with the CBP/catenin antagonist PRI-724, Kahn’s team has initiated studies to investigate the effects of diet on differential β-catenin Kat3 coactivator usage. As diet plays an important role in both somatic stem cell biology and diseases including diabetes and cancer, Kahn hopes to gain a better mechanistic comprehension of this process and potential mechanisms to intervene therapeutically.
 
Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution
J. Org. Chem., 1978, 43, 2923
Still, W.C., Kahn, M., and Mitra, A.
 
Total Synthesis of dl-Coriolin
J. Am. Chem. Soc., 1980, 102, 2097
Danishefsky, S., Zamboni, R., Kahn, M., and Etheredge, S.J.
 
Anionic Oxy-Cope Anionic Oxy-Cope Reaction of Divinyl Cyclobutanol Pleuromutilin Model Study
Tetrahedron Lett., 1980, 21, 4547
Kahn, M.
 
Regiospecific Michael Reactions to an Enedione
Tetrahedron Lett., 1981, 22, 485
Danishefsky, S., and Kahn, M.
 
Regiospecificity in the Diels Alder Reactions of an Enedione
Tetrahedron Lett., 1981, 22, 489
Danishefsky, S., and Kahn, M.
 
The Sterospecific Total Synthesis of dl-Coriolin and dl-Coriolin D.
J. Am. Chem. Soc., 1981, 103, 3460
Danishefsky, S. Zamboni, R., Kahn, M., and Etheredge, S.J.
 
Enol Carbonates: Weakly Nucleaophilic Precursors of Site-Specific Enolates
Tetrahedron Lett., 1982, 23, 703
Danishefsky, S., Kahn, M., and Silvestri, M.
 
An Anomalous Mannich Reaction of Trimethylsilyl Enol Ether
Tetrahedron Lett., 1982, 23, 1419
Danishefsky, S., Kahn, M., and Silvestri, M.
 
A Highly Stereospecific Osmium Tetroxide Catalyzed Hydroxylation of a, b-Unsaturated Esters
Tetrahedron Lett., 1983, 24, 3951
Stork, G, and Kahn, M.
 
Control of Ring Junction Stereochemistry Via Radical Cyclization
J. Am. Chem. Soc., 1985, 107, 500
Stork, G., and Kahn, M.
 
The Design and Synthesis of a Nonpeptide Mimic an Immunosuppressing Peptide
Tetrahedron Lett., 1986, 27, 4841-4844
Kahn, M., and Devens, B.
 
Methodology for Synthesis of Mimetics of Peptide b-Turns
Tetrahedron Lett., 1987, 28, 1623-1626
Kahn, M., and Chen, B.
 
The Design and Synthesis of a Nonpeptide Mimic of Erabutoxin
Heterocycles., 1987, 25, 29-31
Kahn, M., Chen, B., and Zieske, P.
 
The Design and Synthesis of Nonpeptide Mimetics of b-Turns
J. Mol. Recog., 1988, 1, 75
Kahn, M., Wilke, S., Chen, B., and Fujita, K., Johnson, M.
 
Nonpeptide Mimetics of b-Turns: A Facile Oxidative Intramolecular Cycloaddition of an Azodicarbonyl System
J. Am. Chem. Soc., 1988, 110, 1638-1639
Kahn, M., Wilke, S., Chen, B., and Fujita, K.
 
  • 1990 - 1995, American Heart Association Established Investigator
  • 1991 - 1993, Camille and Henry Dreyfuss Teacher Scholar
  • 1986 - 1991, Camille and Henry Dreyfuss Distinguished Young Faculty Fellow
  • 1987 - 1992, NSF Presidential Young Investigator
  • 1986 - 1989, Searle Scholar
  • 1987 - 1989, American Cancer Society Faculty Fellow
  • 1989, American Cyanamid Faculty Award
  • 1989, University Scholar - University of Illinois
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