Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

Chacon, Alexander; Melucci, Alexa D.; Qin, Shuyang S.; Prieto, Peter A.

doi:10.3390/ijms22063228

Cited by 6 publications

(6 citation statements)

References 113 publications

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“…Our previous study revealed that two vitamin D analogs, calcitriol and low calcemic calcipotriol, exhibited modulatory on the A375 melanoma cells treated with dacarbazine, decreasing the half maximal inhibitory concentration (IC50, calcitriol only) for the drug, stimulating G1/G0 arrest, and causing a marked decrease in the mitochondrial transmembrane potential under given experimental conditions (30). Since the process of angiogenesis is crucial for growth, progression, and metastasis of the majority of solid tumors, including melanomas (62,63), in the current study, the effects of cediranib, an oral tyrosine kinase inhibitor (TKI) of VEGFR1-3, PDGFR, and c-KIT (64), used in combination either with 1,25(OH) 2 D 3 or with low-calcemic analog calcipotriol, were tested in the same A375 human malignant melanoma cell line, carrying the BRAF V600E mutation, very common in melanoma patients (65), which was shown to be pro-angiogenic in several human tumors (66). Selected experiments were also carried out in MNT-1, RPMI-7951, and SK-MEL-28 melanoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells

et al. 2021

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Regardless of the recent groundbreaking introduction of personalized therapy, melanoma continues to be one of the most lethal skin malignancies. Still, a substantial proportion of patients either fail to respond to the therapy or will relapse over time, representing a challenging clinical problem. Recently, we have shown that vitamin D enhances the effectiveness of classical chemotherapeutics in the human malignant melanoma A375 cell line. In search for new combination strategies and adjuvant settings to improve melanoma patient outcomes in the current study, the effects of cediranib (AZD2171), an oral tyrosine kinase inhibitor of VEGFR1-3, PDGFR, and c-KIT, used in combination either with 1,25(OH)2D3 or with low-calcemic analog calcipotriol were tested on four human malignant melanoma cell lines (A375, MNT-1, RPMI-7951, and SK-MEL-28). Melanoma cells were pretreated with vitamin D and subsequently exposed to cediranib. We observed a marked decrease in melanoma cell proliferation (A375 and SK-MEL-28), G2/M cell cycle arrest, and a significant decrease in melanoma cell mobility in experimental conditions used (A375). Surprisingly, concurrently with a very desirable decrease in melanoma cell proliferation and mobility, we noticed the upregulation of VEGFR2 at both protein and mRNA levels. No effect of vitamin D was observed in MNT-1 and RPMI-7951 melanoma cells. It seems that vitamin D derivatives enhance cediranib efficacy by modulation of VEGFR2 expression in melanoma cells expressing VEGFR2. In conclusion, our experiments demonstrated that vitamin D derivatives hold promise as novel adjuvant candidates to conquer melanoma, especially in patients suffering from vitamin D deficiency. However, further extensive research is indispensable to reliably assess their potential benefits for melanoma patients.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells

et al. 2021

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“…The use of targeted therapies and checkpoint inhibitors have significantly improved long-term outcomes. Although progress has been made in targeting melanoma with pre-requisite genotypes using small molecule inhibitors such as BRAF/MEK inhibitors, most relapse after 6 to 9 months as the majority will develop drug resistance [1]. Furthermore, 40-60% of patients with melanoma have de-novo or acquired resistance to immunotherapy leading Cancers 2021, 13, 4520 2 of 14 to disease progression [2,3].…”

Section: Introductionsmentioning

confidence: 99%

PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Chan

Brown

Reid

et al. 2021

Cancers

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Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.

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“…In recent years, peptides have displayed excellent potential as inhibitors targeting protein–protein interactions (PPIs) [ 25 , 28 ]. Compared with small molecules [ 29 ], peptide drugs can form a larger binding interface with target proteins, so they have better specificity and binding ability, and are more suitable for PPIs [ 30 ]. Therefore, it is of great significance to study peptide inhibitors for the next generation of immune checkpoint based anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Virtual Evolution of HVEM Segment for Checkpoint Inhibitor Discovery

Zhao

Miao

et al. 2021

IJMS

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Immune therapy has emerged as an effective treatment against cancers. Inspired by the PD-1/PD-L1 antibodies, which have achieved great success in clinical, other immune checkpoint proteins have drawn increasing attention in cancer research. B and T lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) are potential targets for drug development. The co-crystal structure of BTLA/HVEM have revealed that HVEM (26–38) fragment is the core sequence which directly involved on the interface. Herein, we conducted virtual evolution with this sequence by using saturation mutagenesis in silico and mutants with lower binding energy were selected. Wet-lab experiments confirmed that several of them possessed higher affinity with BTLA. Based on the best mutant of the core sequence, extended peptides with better efficacy were obtained. Furthermore, the mechanism of the effects of mutations was revealed by computational analysis. The mutated peptide discovered here can be a potent inhibitor to block BTLA/HVEM interaction and its mechanism may extend people’s view on inhibitor discovery for the checkpoint pair.

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Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

Cited by 6 publications

References 113 publications

Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells

Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells

PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Virtual Evolution of HVEM Segment for Checkpoint Inhibitor Discovery

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