Synergistic compositions and method of using modulators of Ah-R activity and synergistic compounds to treat cancer
Background Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. When activated by the binding of a wide range of both endogenous and exogenous small molecules, AhR signaling influences cellular outcomes in different developmental, immunological, and cancer-related contexts. Once activated, AhR translocates from the cytosol into the nucleus and heterodimerizes with AhR Nuclear Translocator (ARNT). Binding of the AhR/ARNT complex to specific promoter sequences recruits other transcriptional regulators to modulate the expression of downstream target genes. Benzimidazoisoquinolines (BBQs) are a novel class of AhR ligand compounds. Accumulating evidence indicates that the AhR can have anti-tumorigenic effects depending on the biological activity of the ligands. Research has revealed a subset of cancer cell lines that were dependent on AhR for their growth and survival. Furthermore, recent studies showed that AhR exhibits tumor-suppressive effects against multiple cancers. As the fate of cancer cells can be influenced via AhR signaling, the AhR has been suggested as a molecular target for cancer drug development. Triple-negative breast cancer (TNBC) represents a group of breast cancers defined by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression, and lack of human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are frequently aggressive, highly metastatic, and are recalcitrant to the targeted therapies employed in hormone positive and HER2-amplified breast cancers. Despite being superficially classified by the absence of these important immunohistochemical markers, TNBC is highly heterogeneous, and different subtypes exhibit wide variabilities in their molecular features, and response to therapies. Targeted treatments for TNBC are lacking. A clinical need therefore exists to identify novel therapeutic vulnerabilities for this subtype of cancer.
Technology Description This technology provides AhR ligands useful for treating cancer in a subject by administering a therapeutically effective amount of an AhR ligand compound, sometimes with the further introduction of synergizing compounds and/or chemotherapeutic agents. The inventors discovered that the AhR ligand compounds 10/11-Cl-BBQ and their analogs, when used to activate AhR, have growth inhibitory effects against lung, breast and liver cancer cells. AhR translocates within the cell once activated, and can then recruit other transcriptional regulators to modulate the expression of target genes, thus having the potential for anti-tumorigenic effects.
Cell viability versus treatment showing the effects of using 11-Cl-BBQ alone and in combination with Evoxine or in combination with Citropten, establishing that these combinations have synergistic effects
Features & Benefits
Applications
Opportunity OSU is seeking a licensee to develop and commercialize the synergistic combinations and methods envisioned by this invention.
Status Patent publication W02024081428