Future investigative directions for novel therapeutic targets in head and neck cancer

Abstract

Areas covered: Here we describe novel agents, their mechanism(s) of action, preclinical results, and ongoing clinical trials in HNSCC.

Expert opinion: Established therapeutic targets in HNSCC include EGFR (cetuximab) and PD-1 (pembrolizumab and nivolumab). Despite the detection of many other possible targets in HNSCC cell lines and patient tumors, no other therapies have successfully advanced to date. Identification of predictive biomarkers may guide the use of targeted agents and combination therapies. Clinical trials supported by strong preclinical data in relevant models are more likely to advance treatment options.

Keywords: HNSCC; PI3K inhibitors; breakthough designation; immunotherapy; radiation therapy.

Figure 1:. Anti-PD1 combination therapy with novel agents.

Schematic diagram of novel agents currently being tested in HNSCC clinical trials in combination with the FDA-approved PD-1 (programed death protein 1) blocking antibodies, nivolumab and pembrolizumab. Checkpoint inhibitor immunotherapy aims at blocking T cell inactivation by using antibodies that target PD-1 and prevent it from binding to its ligand, PD-L1. PD-1 inhibition prevents activation of SHP2 (Src homology domain phosphatase 2) and dephosphorylation of PI3K (phosphoinositide 3-kinase), allowing for TCR (T cell receptor) and the co-stimulatory receptor CD28 to promote signals (Bcl-xL, IL-2, and IFNγ) for T cell activation and tumor cell destruction. Tumor proliferation and tumor angiogenesis are other key mechanisms in tumor progression. Tumor growth can occur through aberrant signaling in various pathways. EGFR (epidermal growth factor receptor) signals through several downstream signaling pathways including PI3K/AKT or the Ras/Raf/MAPK pathway to promote tumor growth. TGFβ (transforming growth factor beta) and its receptors TGFβRI/II crosstalk with EGFR signaling though PI3K/AKT pathway to stimulate tumor growth. Wnt binds to its receptor, Frizzled, and the Frizzled complex then binds to another membrane protein, LRG5 (leucine rich repeats containing G protein-coupled receptor 5), to activate Ras/MAPK signaling, leading to tumor cell proliferation. Aurora kinase is involved in cell division and interacts with receptor tyrosine kinases like EGFR to enhance tumor growth. IDO1 (indoleamine 2,3-dioxygenase 1) metabolizes tryptophan to kynurenine stimulating nucleotide synthesis and cell division. ATR (ataxia telangiectasia and rad3-related) kinase is involved in the DNA damage repair process. The following agents inhibit these pathways and are being investigated in combination with anti-PD-1 in HNSCC: BMS-986205, a small molecule inhibitor targeting IDO1; MCLA-158, a bispecific antibody that interacts with both EGFR and LGR5; BCA101, a bispecific antibody that binds EGFR and TGFβ; ipatasertib, a small molecule inhibitor targeting all isoforms of AKT; alisertib, a small molecule inhibitor targeting Aurora kinase; and BAY1895344, a small molecule inhibitor targeting ATR. Tumor angiogenesis is driven by tumor-secreted VEGF (vascular endothelial growth factor) binding to its receptor VEGFR on endothelial cells to promote vessel formation. Sitravatinib is a small molecule inhibitor that targets multiple receptor tyrosine kinases including VEGF. MHC indicates major histocompatibility complex. Created in BioRender. Woerner, L. (2024) BioRender.com/o07f863

Figure 2:. Anti-CTLA-4 inhibitors in combination with anti-PD1/PDL1.

Schematic diagram of anti-CTLA-4 agents being studied in combination with anti-PD-1 or anti-PD-L1 in clinical trials for treatment of HNSCC. T cells express PD-1 receptor that binds to PD-L1 on tumor cells, inducing inhibitory signaling on TCR (T cell receptor) and the co-stimulatory receptor CD28, thereby blocking T cell effector activity. T cells express the checkpoint protein CTLA-4 (cytotoxic T lymphocyte antigen 4), which interacts with CD80/CD86 on antigen presenting cells (APCs), leading to naive T cell activation. The combination of anti-PD1 agents, durvalumab and nivolumab, and anti-PD-L1 agents, ipilimumab or tremelimumab, aims to relieve the inhibition imposed by these checkpoint proteins and enhance T cell activation and effector function. Created in BioRender. Woerner, L. (2024) BioRender.com/m72z037

Figure 3:. Novel blocking antibodies against the LAG-3, TIM-3, or TIGIT co-inhibitory checkpoint receptors.

Antibodies targeting LAG-3 (lymphocyte activation gene 3), TIM-3 (T-cell immunoglobulin and mucin-domain-containing 3), or TIGIT (tyrosine-based inhibitory motiff), are being investigated in clinical trials as shown in the schematic diagram. T cells express LAG-3, TIM-3, and TIGIT which interact with MHCII (major immunohistochemistry complex II), CAECAM-1 (carcinoembryonic antigen-related cell adhesion molecule 1), and CD155/112, respectively, on tumor cells leading to inhibition of T cell activation. Relatlimab is an antibody targeting LAG-3. BGB-A425 is an antibody targeting TIM-3 and LBL-007 is an antibody targeting LAG-3 and are being tested together in HNSCC. FS118 is a bispecific antibody that binds and inhibits LAG-3 and PD-L1. Tiragolumab is a blocking antibody against TIGIT. Created in BioRender. Woerner, L. (2024) BioRender.com/q75f403

Figure 4:. Inhibitors targeting components of the PI3K pathway in clinical trials for HNSCC therapy.

As shown, EGFR and HER2/3/4 (human epidermal growth factor receptor) homodimerize or heterodimerize and signal through downstream pathways including the Ras/Raf/MAPK pathway and the PI3K/AKT/mTOR pathway. Novel small molecule inhibitors targeting PI3K or HER receptors have been developed to reduce tumor growth. HM781–36B binds to and inhibits all members of the EGFR/HER protein family. Duvelisib targets PI3Kδ/γ isoforms and is being tested in combination with docetaxel. BKM120 (burpelisib) is a small molecule inhibitor of PI3Kα/β/δ/γ that was evaluated in combination with cetuximab, an EGFR inhibitor. BYL719 (alpelisib) is a small molecule inhibitor of PI3Kα and is being tested in combination with cetuximab and radiation therapy. PF-05212384 (gedatolisib), a PI3K and mTOR inhibitor, was tested in combination with paclitaxel and carboplatin in solid tumors. Farnesyltransferase attaches an isoprenyl group to Ras localizing Ras to the plasma membrane to activate downstream molecules. Tipifarnib is a farnesyltransferase inhibitor that is being investigated with BYL719 in HNSCC tumors with HRAS and/or PI3K activating mutations. HGF (hepatocyte growth factor) binds to c-Met and activates Ras/Raf/MAPK and PI3K/AKT/mTOR pathways like EGFR signaling. Ficlatuzumab is an HGF antibody being tested in combination with cetuximab. Created in BioRender. Woerner, L. (2024) BioRender.com/g97p168