A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors

Mody, Kabir; Mansfield, Aaron S.; Vemireddy, Lalitha Padmanabha; Nygren, Peter; Gulbo, Joachim; Borad, Mitesh J.

doi:10.1007/s10637-018-0703-9

Cited by 32 publications

(33 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A phase I study was initiated to evaluate VLX600 in patients with advanced solid tumors, however due to slow recruitment the trial was terminated early. In total 19 patients were enrolled, all received at least one dose of VLX600 and the drug was well-tolerated at all doses (192). The study was underpowered so no efficacy endpoints were met, and the maximum tolerated dose and recommended phase II dose could not be determined.…”

Section: Iron Chelationmentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

View full text Add to dashboard Cite

Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

show abstract

Section: Iron Chelationmentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

View full text Add to dashboard Cite

show abstract

“…26 VLX has shown promising results preventing tumor cell proliferation in vitro 27 and displayed a high-safety profile in clinical studies. 28 Finally, to decrease the activity of PPARγ, we selected HX531, a compound that blocks the activity of RXR (part of the heterodimer PPARγ/RXR). 29 Although HX531 is not yet FDA-approved, it has shown promising results for diabetes type 2 treatment.…”

Section: Selection Of Drugsmentioning

confidence: 99%

Re-polarization of immunosuppressive macrophages to tumor-cytotoxic macrophages by repurposed metabolic drugs

et al. 2021

View full text Add to dashboard Cite

M2-like tumor-associated macrophages promote tumor progression by establishing an immunosuppressive tumor microenvironment. The phenotype and activity of immunosuppressive macrophages are related to their mitochondrial metabolism. Thus, we studied if drugs targeting mitochondrial metabolic pathways can repolarize macrophages from M2 into an M1-like phenotype or can prevent M0-to-M2 polarization. The drugs selected are clinically approved or in clinical trials and target M2-specific metabolic pathways: fatty acid oxidation (Perhexiline and Trimetazidine), glutaminolysis (CB-839), PPAR activation (HX531), and mitochondrial electron transport chain (VLX-600). Murine bone marrow-derived macrophages were either polarized to M2 using IL-4 in the presence of the drugs or polarized first into M2 and then treated with the drugs in presence of IFN-γ for re-polarization. Targeting both fatty acid oxidation with Perhexiline or the electron transport chain with VLX-600 in the presence of IFN-γ, impaired mitochondrial basal, and maximal respiration and resulted in M2 to M1-like re-polarization (increased iNOS expression, NO production, IL-23, IL-27, and TNF-α secretion), similar to LPS+IFN-γ re-polarization. Moreover, drug-induced macrophage re-polarization resulted in a strong tumor-cytotoxic activity. Furthermore, the polarization of M0-to M2-like macrophages was impaired by CB-839, Trimetazidine, HX531, and Perhexiline, while Hx531 and Perhexiline also reduced MCP-1 secretion. Our results show that by targeting cell metabolism, macrophages could be re-polarized from M2-into an anti-tumoral M1-like phenotype and that M0-to-M2 polarization could be prevented. Overall, this study provides rational for the use of clinically applicable drugs to change an immunosuppressive tumor environment into a proinflammatory tumor environment that could support cancer immunotherapies.

show abstract

“…Interestingly, the concentrations of VLX600 that are selectively cytotoxic to BRCA1-deficient and NNMT-overexpressing cells are readily achieved in patients treated with this agent. For example, a phase I trial of VLX600 as a single agent found plasma C max concentrations of 1 to 2 mmol/L in humans (25), well above the 30 to 100 nmol/L concentrations used in the current studies (Fig. 3).…”

Section: Discussionmentioning

confidence: 46%

BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents

et al. 2019

View full text Add to dashboard Cite

BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression.Significance: Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer.

show abstract

A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors

Cited by 32 publications

References 24 publications

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Re-polarization of immunosuppressive macrophages to tumor-cytotoxic macrophages by repurposed metabolic drugs

BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents

Contact Info

Product

Resources

About