RESUMEN
Tumor hypoxia plays an important role in controlling tumor progression through signaling pathways related to the transcription factor HIF-1. In addition to enhancing migration, promoting angiogenesis and regulating metabolism, the hypoxic environment also affects immune function. In this hypoxic microenvironment an immunosuppressive milieu is established, where HIF-1 upregulates the expression of PD-L1, a key regulator of the immune response. We have found that elevated expression of PD-L1 correlates with increased HIF-1 levels in cancer cell lines and clinical samples. Thus, the co-inhibition of HIF-1 and PD-1/PD-L1 offers promising therapeutic possibilities. In this review we have examined the limitations of HIF-1 and PD-1/PD-L1 inhibition as monotherapy, explored their combined benefits and evaluated the feasibility of targeting PD-L1 with HIF-1 inhibitors.
Asunto(s)
Antígeno B7-H1 , Neoplasias , Receptor de Muerte Celular Programada 1 , Hipoxia Tumoral , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Hipoxia Tumoral/efectos de los fármacos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
Antibody-Drug Conjugates (ADCs) and Small Molecule-Drug Conjugates (SMDCs) represent successful examples of targeted drug-delivery technologies for overcoming unwanted side effects of conventional chemotherapy in cancer treatment. In both strategies, a cytotoxic payload is connected to the tumor homing moiety through a linker that releases the drug inside or in proximity of the tumor cell, and that represents a key component for the final therapeutic effect of the conjugate. Here, we show that the replacement of the Val-Ala-p-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-p-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the cyclo[DKP-isoDGR] αVß3 integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the "kiss-and-run" protocol, and the relative potency were clearly consistent with the expression of the αVß3 integrin receptor in the considered cancer cell lines. In vitro enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15 min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems.
RESUMEN
BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are among the most abundant malignancies worldwide. Patients with recurrent/metastatic disease undergo combination chemotherapy containing cetuximab, the monoclonal antibody used against the epidermal growth factor receptor (EGFR). Cetuximab augments the effect of chemotherapy; however, a significant number of patients show therapy resistance. The mechanism of resistance is yet to be unveiled, although extracellular alterations of the receptor have been reported, and their role in cetuximab failure has been proposed. AIMS: Here, we investigate possible effects of the multi-exon deletion variant (EGFRvIII), and the single nucleotide polymorphism EGFR R521K on cetuximab efficacy. RESULTS: Our results show that in HNSCC patients, the EGFRvIII allele frequency is under 1%; therefore, it cannot lead to common resistance. EGFR R521K, present in 42% of the patients, is investigated in vitro in four HNSCC cell lines (two wild-type and two heterozygous for EGFR R521K). While no direct effect is found to be related to the EGFR status, cells harboring R521K show a reduced sensitivity in ADCC experiments and in vivo xenograft experiments. However, this preclinical difference is not reflected in the progression-free or overall survival of HNSCC patients. Furthermore, NK cell and macrophage presence in tumors is not related to EGFR R521K. DISCUSSION: Our results suggest that EGFR R521K, unlike reported previously, is unable to cause cetuximab resistance in HNSCC patients; therefore, its screening before therapy selection is not justifiable.