evofosfamide (IMGS-101)

Apart HIF itself, other potential molecular targets such as prolyl-hydroxylases (PHD), von Hippel-Lindau protein (VHL), monocarboxylate transporters (MCTs), Na+ /H+ exchangers (NHEs), vacuolar ATPases (V-ATPase), anion exchangers (AEs), Na+ /HCO₃- co-transporters (NBCs), vascular endothelial growth factor (VEGF) and carbonic anhydrases were identified as being involved in tumorigenesis. HIF-1α inhibitors (topotecan, digoxin, PX-478), hypoxia-activated prodrugs (evofosfamide, apaziquone, porfiromycin, tirapazamine, banoxantrone) and carbonic anhydrase IX/XII inhibitors (SLC-0111) are either used clinically or in clinical development for the management of hypoxic breast cancers.

Functionally, reducing hypoxia with the agents TH-302 or PX-478 in the AKR model enhanced intratumoral CD8+ T cell infiltration and increased their expression of Granzyme B, IFNγ, and TNFα. Furthermore, in a preclinical ESCC model, pharmacological inhibition of HIF-1α with PX-478 synergized with anti-PD-1 therapy, leading to superior tumor control and enhanced CD8+ T cell cytotoxicity. Our study identifies HIF-1α K172 lactylation as a pivotal mechanism of hypoxia-mediated immune escape in ESCC, suggesting a therapeutic strategy to improve immunotherapy.

Targeted and molecular therapies in EWS show significant promise, particularly in rational combinations that exploit the tumor's dependence on EWS-FLI1-driven transcriptional dysregulation, DNA damage repair deficiencies, or survival signaling. Future research must prioritize biomarker-driven patient selection, integration of multiomics approaches, and multicenter prospective trials to translate these strategies into clinically meaningful improvements in EWS survival.

P2, N=35, Not yet recruiting, University Health Network, Toronto | Trial completion date: Apr 2029 --> May 2030 | Initiation date: Apr 2025 --> May 2026 | Trial primary completion date: Apr 2027 --> May 2028

To address these issues, this study engineered copper-doped ZIF-8 nanoparticles that co-deliver the hypoxia-activated prodrug TH-302 and the NQO1-targeting quinone β-lapachone, encapsulated within genetically engineered M1 macrophage membranes overexpressing CCR2 (CCR2-M)...No drug-related toxicity was observed. Thus, this rationally designed nanotherapeutic strategy significantly curtails residual tumor growth and offers a promising immunomodulatory approach to overcoming therapeutic resistance in cancer treatment after iRFA.

TH-302 shows an in vivo anti-tumour activity in chondrosarcoma. Our multimodal imaging approach allows monitoring complex exchanges between tumour cells and their neighboring under therapy.

Evofosfamide is converted into bromo-isophosphoramide mustard, a potent DNA cross-linking agent that is expected to enhance the killing of cancer cells under hypoxic conditions, where these cells typically exhibit resistance. qPCR analysis revealed that Evofosfamide was capable of restoring type I interferon signaling in hypoxic breast cancer cells, leading to the subsequent cytolytic activity of NK cells against the tumor cells. Thus, conditioning the breast cancer cells with Evofosfamide resulted in enhanced cell killing under hypoxia, further underscoring its potential as a sensitizer to target hypoxia-driven tumors.

These in vitro findings suggest that TH-302 may be efficacious in ES. This provides a rationale for further in vivo investigations into the potential of TH-302 as a treatment for ES.

Improving therapeutic outcomes for patients with lung tumors, arising either as primary lesions or metastatic colonies, is of vital clinical importance. Building on preclinical evidence for IDO1's role in promoting inflammatory neovascularization of lung tumors, this study demonstrates how the intratumoral ischemic stress elicited by IDO1 inhibition can potentiate the immunogenic cytotoxicity of ischemia-targeted agents to effectively leverage immune checkpoint blockade responsiveness to confer a synergistic survival benefit. These findings provide a novel perspective on how IDO1 inhibitors can impact tumor biology and open up new possibilities for therapeutic applications.

P2, N=35, Not yet recruiting, University Health Network, Toronto

P1/2, N=71, Recruiting, ImmunoGenesis

Combining sublethal levels of i.p. ascorbate with evofosfamide significantly prolonged tumor doubling time in MIA Paca-2 and A549b xenografts compared to either treatment alone. This improvement, however, was only observed in a subpopulation of tumors, highlighting the complexity of the oxygenation response.