Tumor Suppression by Retinoic Acid Pathway Inhibition

Targeting retinoic acid (RA) synthesizing enzymes or RA receptors with small molecules boosts the immune system towards a tumor rejection response

Problem:
Hepatocellular carcinoma (HCC) is the most common liver cancer globally. In the US alone, 33 000 patients are diagnosed yearly, 27 000 of which will die. Once metastasized, HCC shows a grim 5-year survival rate of 2%. Though immunotherapy has shown promise against several cancer types, it has thus far shown poor efficacy against HCC. There remains an unmet clinical need for better therapies against HCC.

Solution:
Researchers at the Perelman School of Medicine found that the RA pathway is crucial in modulating the immune response against tumors. Dr. Haldar and his team have found that inhibiting this pathway, either alone or combined with immunotherapy, promotes a tumor-rejecting immune response.

Technology Overview:
The use of small molecule inhibitors targeting RA signaling or RA synthesis in tumor cells promotes the differentiation of immune cells able to detect and kill tumor cells. Notably, Dr. Haldar’s team found that the RA receptor inhibitor BMS493 combined with immune checkpoint blockade significantly reduced tumor growth in mice. Similarly, compounds investigated by colleagues were found to inhibit a key enzyme of RA synthesis (RALDH1) and to restrain HCC growth in vitro.

Advantages:

Efficient against aggressive cancers such as HCC
Targets a specific isoform (RALDH1) to minimize side-effects from broader range inhibitors (e.g. that inhibit RALDH1, 2 and 3)
Synergizes with immune checkpoint blockade (ICB) therapy to reduce ICB-resistant tumor size by over 50%

Stage of Development:

Target Identified
Preclinical Discovery

Overview of retinoic acid (RA) pathway in solid tumor biology and compound #86 mechanism of action. Many solid tumors produce high levels of RA that inhibit the formation of tumor-suppressive dendritic cells (DCs) through activation of the RA and retinoid X (RX) receptors. It instead promotes the differentiation of tumor-permissive macrophages, thus allowing tumor persistence and growth. When RA synthesis (by targeting RALDH1 with C-86) and/or signaling (by inhibiting RAR/RXR) is inhibited, monocytes differentiate into DCs that activate T cells, which in turn kill tumors such as hepatocellular carcinoma (HCC). Shifting the tumor microenvironment balance through inhibition of RA production is therefore desirable from a therapeutic perspective. Moreover, this approach can be combined to checkpoint inhibitors to enhance immune checkpoint blockage therapy.