As an alternative to surgery, radiotherapy, and chemotherapy, tumor therapy via the immune pathway has made significant advances in recent years. Among the targeted drugs of immuno-oncology (IO), Ab drugs have become the focus of research due to their excellent therapeutic abilities. Small molecule targeted drugs, another growing category, are also used in tumor therapy in various ways, making up for the shortcomings of Ab drugs.
Therapies targeting the cancer pathway
Cancer is primarily caused by dysregulation of cell cycle homeostasis and enhanced resistance to apoptosis. Besides, in the process of tumor development, a variety of inhibitory signals appear, leading to the proliferation of immune cells and weakened effect function. Current small-molecule drugs that target these molecules fall into the following categories:
- BRAF inhibitors
BRAF is a proto-oncogene, and mutation of BARF (V600E) can lead to tumorigenesis. Two Phase I studies have shown that BRAF/MEK inhibition increases CD8 T cell infiltration by inducing immunogenic cell death (ICD) to produce pro-inflammatory signaling, while damage-associated molecular patterns (DAMPs) activate T cell effector functions. (NCT01656642, NCT02130466)
The presence of immunosuppressive signals in TME is an obstacle to BRAF/MEK-targeted therapy. Combining ICI drugs may be a way to improve efficacy. In the trial, the combination with anti-PD-1 antibodies fails to reach the clinical endpoint, and there may be overlapping toxicity that increases the incidence of treatment-related adverse events.
- VEGF-VEGFR pathway inhibitors
Vascular endothelial growth factor (VEGF) stimulates angiogenesis, and high levels of VEGF in TME recruit immunosuppressive cell subsets. Blocking VEGF-VEGFR can effectively exert antitumor effects, especially against highly vascularized tumors.
Several clinical trials conducted in combination with PD-1 Ab drugs have shown good overall effects.
Cytokines play a key role in maintaining intercellular communication, especially in the production and regulation of immune function.
Many popular cytokines, including TNFα and IL-2, have not been shown to have antitumor properties in preclinical trials. Dose-limiting toxicity caused by the systemic administration of drugs is a critical reason.
Therapies targeting tumor metabolic pathways
The metabolic function of tumor cells is extremely active, and the demand for oxygen and nutrients is greatly increased. By reshaping TME, large quantities of metabolites can inhibit the effect function of T cells, further promoting tumor growth.
At present, small molecule drugs targeting metabolic pathways are being intensively studied and multiple drugs are now in advanced clinical development.
- Glutamine, arginine metabolic pathways
Tumor cells meet their energy needs by enhancing glycolysis and by the breakdown of glutamine to compete with T cells for nutrients. Targeting this pathway with small molecule inhibitors can effectively suppress tumor growth and promote immune cell infiltration in preclinical models.
Arginine is also competed for by tumor and T cells, and high levels of arginine-degrading enzymes expressed by myeloid-derived suppressor cells (MDSCs) in TMEs boost the need for arginine. Fortunately, a variety of small molecule arginine inhibitors have been developed.
- Adenosine metabolic pathways
Adenosine is a potent immunosuppressant produced in large quantities by a variety of tumors. It mediates immunosuppression by binding to GPCR, A2aR, and A2bR on immune cells.
A2aR has a high affinity for adenosine. Small molecule inhibitors targeting A2aR alone were previously the major direction for research. However, the current focus shifts to dual inhibition of A2aR/A2bR, which may be more effective in inhibiting adenosine signal transduction. But the resulting toxic effects need to be considered. If the concentration of adenosine in TME is too high, targeting A2bR with low affinity alone may be a safer strategy.
- Kynurenine metabolic pathways
Tumor cells catalyze tryptophan decomposition to produce kynurenine through IDO1 and TDO. They are combined with AHR to inhibit T cell effect function while promoting the development of Treg and MDSC cells.
An IDO1 inhibitor, echo-301, showed acceptable early clinical data but no significant benefit in phase III trials (NCT02862457). TDO and IDO2 can also degrade tryptophan, which is the compensatory mechanism of this pathway and may also be the cause of tumor insensitivity to IDO1.
References
1. Offringa R et al. The expanding role for small molecules in immuno-oncology. Nat Rev Drug Discov. 2022 Nov;21(11):821-840.
2. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022 Jan;12(1):31-46.
3. Low V et al. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment. Sci Signal. 2022 Nov 8;15(759):eabj4220.