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DRUG:

evofosfamide (IMGS-101)

i
Other names: IMGS-101, TH 302, HAP-302, TH-302, HAP TH-302, TH302-cpd, IMGS 101, IMGS101, HAP 302, HAP302, TH302
Company:
ImmunoGenesis
Drug class:
Alkylating agent
Related drugs:
6ms
Pharmacologic Ascorbate Induces Transient Hypoxia Sensitizing Pancreatic Ductal Adenocarcinoma to a Hypoxia Activated Prodrug. (PubMed, Free Radic Biol Med)
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.
Journal
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CAT (Catalase)
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evofosfamide (IMGS-101)
9ms
Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma. (PubMed, Int J Biol Sci)
The hypoxia-activated anti-PKM2 Ab safely confers a strong inhibitory effect on HCC with improved selectivity. This provides a promising strategy to overcome the on-target off-tumor toxicity of Ab therapeutics; and highlights an advanced approach to precisely kill HCC in combination with HAP TH-302.
Journal
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PKM (Pyruvate Kinase M1/2)
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evofosfamide (IMGS-101)
1year
Reprint of: Detection and Impact of Hypoxic Regions in Multicellular Tumor Spheroid Cultures formed by Head and Neck Squamous Cell Carcinoma Cells Lines. (PubMed, SLAS Discov)
In HNC MCTSs, hypoxic cytotoxicity ratios for the hypoxia activated prodrugs (HAP) evofosfamide and tirapazamine were much smaller than have been reported for uniformly hypoxic 2D monolayers in gas chambers, and many viable cells remained after HAP exposure. Cells in solid tumors and MCTSs experience three distinct O microenvironments dictated by their distances from blood vessels or MCTS surfaces, respectively; oxic, hypoxic, or intermediate levels of hypoxia. These studies support the application of more physiologically relevant in vitro 3D models that recapitulate the heterogeneous microenvironments of solid tumors for preclinical cancer drug discovery.
Journal • IO biomarker
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HIF1A (Hypoxia inducible factor 1, alpha subunit)
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HIF1A expression
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evofosfamide (IMGS-101) • Tirazone (tirapazamine)
1year
Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism. (PubMed, Cancers (Basel))
Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism.
Journal
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HIF1A (Hypoxia inducible factor 1, alpha subunit) • PDK1 (Pyruvate Dehydrogenase Kinase 1)
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HIF1A expression
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temozolomide • evofosfamide (IMGS-101)
1year
TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer. (PubMed, J Nanobiotechnology)
TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • GZMB (Granzyme B)
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HIF1A expression
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evofosfamide (IMGS-101)
1year
Hypoxia-activated prodrug and anti-angiogenic therapy cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration. (PubMed, JCI Insight)
Blockade of the CCL9-CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302 and anti-VEGFR-2 with ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization, and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.
Journal
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KRAS (KRAS proto-oncogene GTPase) • CD8 (cluster of differentiation 8)
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KRAS G12D • KRAS G12 • TP53 R172H
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evofosfamide (IMGS-101)
1year
Radiomic-Based Prediction of Lesion-Specific Systemic Treatment Response in Metastatic Disease. (PubMed, Int J Radiat Oncol Biol Phys)
Predicting lesion-specific responses using radiomic features represents a paradigm shift. Lesion-specific radiomic models indicate a 2 to 3-fold increase in predictive capacity in comparison to a no-skill classifier. These models, although preliminary, achieved a strong predictive value and could be used to predict lesion-specific treatment response.
Journal • Metastases
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doxorubicin hydrochloride • evofosfamide (IMGS-101)
over1year
Doxorubicin combined with Trabectedin in systemic first-line M+/recurrent leiomyosarcoma patients. (PubMed, Curr Opin Oncol)
In the first-line setting, the results of this trial were pivotal for numerous reasons; Doxorubicin-Trabectedin is the first combination that has been proven to be more effective in terms of PFS, ORR and trend of OS compared with doxorubicin alone; moreover, it is clear that trials regarding soft tissue sarcoma should strive to be histology-driven.
Journal
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gemcitabine • docetaxel • doxorubicin hydrochloride • ifosfamide • Yondelis (trabectedin) • Lartruvo (olaratumab) • evofosfamide (IMGS-101)
almost2years
IDO1 inhibition sensitizes metastatic lung tumors to hypoxia/ER stress targeting agent-induced cell death (AACR 2023)
Similarly, when WT 4T1 tumor-bearing mice were administered GSK2656157 together with the IDO1 inhibitors Epacadostat, Indoximod or Navoximod, the attenuated neovascularization and elevated regional hypoxia in lung metastases elicited by IDO1 inhibition was accompanied by an increased level of tumor cell death. Co-administration of the hypoxia-activated prodrug Evofosfamide with Epacadostat likewise resulted in elevated metastatic tumor cell death. This contrasts with results obtained with the non-targeted cytotoxic agent Carboplatin that elicited comparable levels of metastatic tumor cell death regardless of Epacadostat co-administration. Altogether, these data establish the potential to benefit treatment in tumor settings where IDO1 inhibition enhances intra-tumoral hypoxia through neovascular regression by facilitating the ability of hypoxia-targeting agents to effectively eliminate tumor cells in a more targeted manner than can be achieved with conventional chemotherapy.
Metastases
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IFNG (Interferon, gamma) • IL6 (Interleukin 6)
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carboplatin • epacadostat (INCB024360) • indoximod (NLG8189) • evofosfamide (IMGS-101) • navoximod (NLG919)
2years
Assessment of hypoxia-targeting therapy for gastrointestinal lymphoma in dogs: Preclinical test using murine models. (PubMed, Res Vet Sci)
In contrast, evofosfamide (Evo) releases a DNA-alkylating moiety within hypoxic tumor regions, suggesting that Evo could serve as a hypoxia-targeting drug in canine lymphoma...Our data showed that Evo showed significantly higher tumor growth potential and fewer adverse events in three type of murine models compared to lomustine; CeeNu (CCNU). Additionally, Evo suppressed the expression of HIF-1α protein in tumor tissues, suggesting that it may preferentially target and inhibit tumor cells in a hypoxic region. The evidence presented here supports the favorable preclinical evaluation that Evo may be effective for GIL in dogs.
Preclinical • Journal
|
HIF1A (Hypoxia inducible factor 1, alpha subunit)
|
HIF1A expression
|
lomustine • evofosfamide (IMGS-101)
over2years
Hypoxia-targeting therapy for intestinal T-cell lymphoma in dogs: Preclinical study using 3D in vitro models. (PubMed, Vet Comp Oncol)
We assessed the effects of evofosfamide (Evo; hypoxia-activated prodrug) on cell lines cultured under hypoxic conditions...Additionally, Evo downregulated HIF-1α expression in cell lines cultured under hypoxia, suggesting that Evo might inhibit cell growth by inactivating HIF-1α-dependent cell signalling. Our results revealed the preclinical antitumor activity of Evo and provide a rationale for treatment strategies for dogs with ITL.
Preclinical • Journal
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HIF1A (Hypoxia inducible factor 1, alpha subunit)
|
HIF1A expression
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evofosfamide (IMGS-101)
over2years
Multicellular tumor spheroids of LNCaP-Luc prostate cancer cells as in vitro screening models for cytotoxic drugs. (PubMed, Am J Cancer Res)
For docetaxel, this resistance increased with the spheroid growth stage, whereas the activity of TH-302 was potentiated by the hypoxic environment. In conclusion, the development of LNCaP-Luc cell MCTS provides a simple model mimicking a microtumor; it appears to be particularly well-suited to the validation of new therapeutic approaches targeting proliferation and the microenvironment.
Preclinical • Journal
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VEGFA (Vascular endothelial growth factor A)
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FOLH1 expression
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docetaxel • evofosfamide (IMGS-101)
almost3years
Targeting HIF-1α/NOTCH1 pathway eliminates CD44 cancer stem-like cell phenotypes, malignancy, and resistance to therapy in head and neck squamous cell carcinoma. (PubMed, Oncogene)
Moreover, inhibition of these signaling proteins using shRNA or Evofosfamide (Evo) development for cancer treatment, reversed chemoresistance in vitro and in vivo. Taken together, our results indicated that targeting HIF-1α attenuated NOTCH1-induced stemness, which regulates responses to chemotherapy or radiotherapy and malignancy in CD44 HNSCCs. HIF-1α/NOTCH1 signaling may represent a target for HNSCC treatment.
Journal
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NOTCH1 (Notch 1) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • CD44 (CD44 Molecule)
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CD44 expression • HIF1A expression
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evofosfamide (IMGS-101)
almost3years
Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment (AACR 2022)
While these studies highlight hypoxia reduction as therapeutically tractable, we lack complete understanding of the contribution of the tumor vasculature to hypoxia reduction therapy, as well as the downstream consequences of hypoxia reduction on the cellular composition of the tumor microenvironment and the responsiveness to immunotherapy.We used a transplantable, orthotopic pancreatic tumor model derived from Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre mice and a syngeneic prostate tumor model to study tumor responses to hypoxia-reduction, anti-angiogenic therapy, and combination immunotherapy.We find that Evofosfamide with anti-VEGFR-2 (DC101) significantly extends mouse survival. Put together, these data indicate that targeted hypoxic reduction with anti-angiogenic therapy remodels the pancreatic tumor microenvironment. In this setting, CD40 agonist over PD-1 blockade provides an additive benefit in prolonging mouse survival.
PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8) • CD40 (CD40 Molecule) • PDX1 (Pancreatic And Duodenal Homeobox 1)
|
PD-L1 expression • KRAS G12D • KRAS G12
|
DC101 • evofosfamide (IMGS-101)
almost3years
Detection and impact of hypoxic regions in multicellular tumor spheroid cultures formed by head and neck squamous cell carcinoma cells lines. (PubMed, SLAS Discov)
In HNC MCTSs, hypoxic cytotoxicity ratios for the hypoxia activated prodrugs (HAP) evofosfamide and tirapazamine were much smaller than have been reported for uniformly hypoxic 2D monolayers in gas chambers, and many viable cells remained after HAP exposure. Cells in solid tumors and MCTSs experience three distinct O microenvironments dictated by their distances from blood vessels or MCTS surfaces, respectively; oxic, hypoxic, or intermediate levels of hypoxia. These studies support the application of more physiologically relevant in vitro 3D models that recapitulate the heterogeneous microenvironments of solid tumors for preclinical cancer drug discovery.
Journal • IO biomarker
|
HIF1A (Hypoxia inducible factor 1, alpha subunit)
|
HIF1A expression
|
evofosfamide (IMGS-101) • Tirazone (tirapazamine)
3years
18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition. (PubMed, Clin Cancer Res)
The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.
Journal • PD(L)-1 Biomarker • IO biomarker
|
IFNG (Interferon, gamma) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • GZMB (Granzyme B)
|
evofosfamide (IMGS-101)
3years
Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy (SITC 2021)
Results We find that anti-VEGFR-2 (DC101) in combination with TH-302 demonstrates a cooperative benefit to combat both orthotopically implanted pancreatic cancer and transplantable prostate cancer. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted hypoxia reduction with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC.
PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • CD40 (CD40 Molecule)
|
PD-L1 expression
|
DC101 • evofosfamide (IMGS-101)
over3years
SUNitinib and EVOfosfamide (TH-302) in systemic treatment-naïve patients with G1/G2 metastatic pancreatic neuroendocrine tumors, the GETNE-1408 trial. (PubMed, Oncologist)
Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in panNETs, reaching a median ORR of 17.6% and median PFS of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs resistance to antiangiogenic agents with other therapies with a safer profile.
Clinical • Journal
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PTEN (Phosphatase and tensin homolog) • ATRX (ATRX Chromatin Remodeler) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • DAXX (Death-domain associated protein)
|
PTEN mutation
|
sunitinib • evofosfamide (IMGS-101) • Zymafos (palifosfamide)
over3years
Chitosan oligosaccharide decorated liposomes combined with TH302 for photodynamic therapy in triple negative breast cancer. (PubMed, J Nanobiotechnology)
The impressive synergistic antitumor effects, together with the superior fluorescence imaging capability, good biocompatibility and minor side effects confers the liposomes with potential for future translational research in the diagnosis and CD44-overexpressing cancer therapy, especially TNBC.
Journal
|
CD44 (CD44 Molecule)
|
evofosfamide (IMGS-101)
over3years
Monitoring Treatment Efficacy of Antiangiogenic Therapy Combined With Hypoxia-Activated Prodrugs Online Using Functional MRI. (PubMed, Front Oncol)
Twenty-four tumor-bearing mice were randomly divided into four groups and injected with bevacizumab combined with TH-302 (A), bevacizumab (B), TH-302 (C), or saline (D) on days 1, 4, 7, 10 and 13. Anti-angiogenic agents combined with HAP can inhibit tumor growth effectively. In addition, IVIM-DWI and BOLD-MRI can be used to monitor the tumor microenvironment, including perfusion, hypoxia, cell apoptosis and proliferation, in a noninvasive manner.
Clinical • Journal
|
HIF1A (Hypoxia inducible factor 1, alpha subunit) • CD31 (Platelet and endothelial cell adhesion molecule 1)
|
Avastin (bevacizumab) • evofosfamide (IMGS-101)
almost4years
Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma. (PubMed, Oncogene)
Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.
Journal
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DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
Chr t(4;14) • DKK1 overexpression
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evofosfamide (IMGS-101)