HIF-2𝛂 Inhibitor
Transcription factor
Cancer cell intrinsic target; potential non-oncology indications
HIF-2α is a master transcriptional regulator of multiple genes involved in tumor progression.1
AXL Inhibitor
Tyrosine kinase
Cancer cell intrinsic target
AXL overexpression is associated with tumor resistance to chemotherapy and immunotherapy drugs.2
PI3Kγ Inhibitor
Glycolipid kinase
Immune (TAM, MDSC) target
PI3Kγ is required for the immunosuppressive activity of tumor-infiltrating macrophages and myeloid-derived suppressor cells.3
PAK4 Inhibitor
Serine kinase
Cancer cell intrinsic target
PAK4 overexpression is responsible for T cell exclusion from immune desert tumors.4
Anti-TIM-3 Antibody
Immune Checkpoint
Cancer cell intrinsic and immune (T cell) target
TIM-3 is an immune checkpoint highly overexpressed by leukemic cells (eg, MDS, AML) and exhausted T cells.5
AML, acute myeloid leukemia; HIF-2𝛂, hypoxia-inducible factor 2-alpha; MDS, myelodysplastic syndromes; PAK-4, p21-activated kinase 4; PI3Kγ, phosphatidylinositol 3-kinase-gamma; TIM-3, T cell immunoglobulin and mucin-domain containing-3.
References: 1. Murugesan T, Rajajeyabalachandran G, Kumar S, Nagaraju S, Kumar S. Targeting HIF-2α as therapy for advanced cancers. Drug Discov Today. 2018;23(7):1444-1451. 2. Axelrod HD, Valkenburg KC, Amend SR, et al. AXL is a putative tumor suppressor and dormancy regulator in prostate cancer. Mol Cancer Res. 2019;17(2):356-369. 3. Foubert P, Kaneda MM, Varner JA. PI3Kγ activates integrin α4 and promotes immune suppressive myeloid cell polarization during tumor progression. Cancer Immunol Res. 2017;5(11):957-968. 4. Abril-Rodriguez G, Torrejon DY, Liu W, et al. PAK4 inhibition improves PD-1 blockade immunotherapy. Nature Cancer. 2020;1:46-58. 5. Toshio A, Tamura H, Ishibashi M, et al. Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget. 2017;8(51):88904-88917.
