Michael Kahn, Ph.D.

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, Dr. 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.

Dr. 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. Dr. 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 Dr. 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, Dr. 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, Dr. 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, Dr. Kahn hopes to gain a better mechanistic comprehension of this process and potential mechanisms to intervene therapeutically.