Targeting SOX9 in Colorectal Cancer Promotes Differentiation and Cancer Cell Death

Assays to support the identification and optimization of SOX9 inhibitors as a therapeutic approach to CRC treatment.

Therapeutics

Project Overview

Microsatellite stable (MSS) CRC represents 85% of CRC cases and is characterized by high SOX9 expression and WNT pathway dependency.
Developing a new treatment regimen that targets SOX9 and/or promotes intestinal differentiation in cancer cells may be an interesting therapeutic strategy.
Scientists at Dana-Farber have developed assays to identify optimize SOX9 inhibitors.
Dana-Farber is interested in collaborations to further develop these SOX9 inhibitors.

Technology

Disrupting the balance between stem cell and differentiation programs is a defining property of colorectal cancer (CRC). Specifically, aberrant stem cell-like activity prevents intestinal differentiation, allowing cancer cells to survive, persist, and grow. Genomic alterations that activate WNT signaling are the initiating events in sporadic CRC, usually loss-of-function APC mutations, shifting the homeostasis away from differentiation and toward excessive proliferation.

SRY-Box transcription factor 9 (SOX9) is an early marker of colorectal cancer development. SOX9 serves as a functional biomarker in that its activity is necessary for premalignant colorectal lesions to form. It is a key developmental transcription factor that guides cell fate decisions during developmental and adult homeostasis in diverse tissue. In the intestines, inactivation of SOX9 led to impaired Paneth cell differentiation in genetically engineered mouse models. SOX9 may be important in blocking the differentiation of stem cells.

Scientists at Dana-Farber have developed assays to support the identification and optimization of SOX9 inhibitors. Preclinical data support the development of SOX9 inhibitors as frontline treatment for microsatellite (MSS) colorectal cancer. SOX9 overexpression is associated with poor survival in CRC patients. The discovery that SOX9 is a key blocker of CRC cell differentiation opens the possibility for direct targeting of this mechanism with small molecules. Promoting cancer cell differentiation is a therapeutic strategy particularly well suited for CRC because of the biology of the disease.

Figure 1 – Schematic for Generating Next-Generation of Colorectal Cancer Therapeutics from the Sethi lab

Further Details:

Liang, X; Duronio, G; Yang, Y; Bala, P; Hebbar, P; Spisak, S; Singh, H; Zhang, Y; Xie, Y; Cejas, P; Long, HW; Bass, AJ; Sethi, NS†. An enhancer driven stem cell-like program mediated by SOX9 blocks intestinal differentiation in colorectal cancer. Gastroenterology (2022) 162(1): 209-22 PMID: 34571027. PMCID: PMC10035046.
Bala, P*; Rennhack, J*; Aitymbayev, D; Morris, C; Moyer, S; Duronio, GN; Doan, P; Li, Z; Liang, X; Hornick, J; Yurgelun, M.; Hahn, WC; Sethi, NS†. Aberrant cell state plasticity mediated by development reprogramming precedes colorectal cancer initiation. Science Advances (2023) 9 (13): 1-17 PMCID: PMC10058311.

Team Members: Nilay Sethi, MD, PhD, Sandor Spisak, PhD

Applications

Patient selection: patients with higher SOX9 nuclear expression in CRC tissue can be measured by SOX9 IHC and selected for potential treatment with SOX9 inhibitors.
Inactivating SOX9 prevents adenoma formation in well-established in vivo models.
Disrupting SOX9 and its downstream target PROM1 can induce differentiation and hinder primary tumor growth in several colorectal cancer models, providing proof-ofconcept for the development of therapeutics that restore intestinal differentiation in colorectal cancer.
A new therapeutic approach to CRC treatment.

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in collaborating with the investigator to further develop these SOX9 inhibitors.

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