Delving into the Latest Updates on INGN-241 with Synapse

Overview

Basic Info

Drug Type

Gene therapy

Synonyms

Adenoviral-mda7, Mda 7 gene therapy, AD-MDA7

+ [1]

Target

IL-24

Action

stimulants

Mechanism

IL-24 stimulants(Interleukin 24 stimulants)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesDigestive System Disorders+ [2]

Active Indication-

Inactive Indication

Advanced cancerBreast CancerHead and Neck Neoplasms+ [3]

Originator Organization

The Trustees of Columbia University in The City of New York

Active Organization-

Inactive Organization

Introgen Therapeutics, Inc.

The Trustees of Columbia University in The City of New York

Baylor University Medical Center

+ [2]

License Organization-

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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We examined the combinatory antitumor effects of adenoviruses expressing human mda-7/IL-24 gene (Ad-mda-7) and chemotherapeutic agents on nine kinds of human esophageal carcinoma cells. All the carcinoma cells expressed the melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) receptor complexes, IL-20R2 and either IL-20R1 or IL-22R1, and were susceptible to Ad-mda-7, whereas fibroblasts were positive only for IL-20R2 gene and resistant to Ad-mda-7-mediated cytotoxicity. Sensitivity of these esophageal carcinoma cells to Ad-mda-7 was however lower than that to Ad expressing the wild-type p53 gene. We thereby investigated a possible combination of Ad-mda-7 and anticancer agents and found that Ad-mda-7 with 5-fluorouracil (5-FU), cisplatin, mitomycin C or etoposide produced greater cytotoxic effects than those by Ad-mda-7 or the agent alone. Half-maximal inhibitory concentration values of the agents in respective cells were decreased by the combination with Ad-mda-7. Cell cycle analyses showed that Ad-mda-7 and 5-FU increased G2/M-phase and S-phase populations, respectively, and the combination augmented sub-G1 populations. Ad-mda-7-treated cells showed cleavages of caspase-8, -9 and -3 and poly (ADP-ribose) polymerase, but the cleavage levels were not different from those of the combination-treated cells. Ad-mda-7 treatments upregulated Akt phosphorylation but suppressed IκB-α levels, whereas 5-FU treatments induced phosphorylation of p53 and extracellular signal-regulated protein kinases 1 and 2. Molecular changes caused by the combination were similar to those by Ad-mda-7 treatments, but the Ad-mda-7-mediated upregulation of Akt phosphorylation decreased with the combination. These data collectively suggest that Ad-mda-7 induced apoptosis despite Akt activation and that the combinatory antitumor effects with 5-FU were produced partly by downregulating the Ad-mda-7-induced Akt activation.

01 Dec 2013·Cancer gene therapyQ2 · MEDICINE

Heat-shock protein 90 inhibitors synergistically enhance melanoma differentiation-associated gene-7-mediated cell killing of human pancreatic carcinoma

Q2 · MEDICINE

Article

Author: Chada, S ; Kawamura, K ; Ma, G ; Tagawa, M ; Hu, J ; Zhang, Z ; Liu, H ; Shingyoji, M ; Zhang, F ; Kang, S ; Li, Q ; Shan, B ; Jiang, Y ; Wang, S ; Qi, Y

Pancreatic cancer is one of the intractable diseases and an effective therapeutic strategy is required to improve the prognosis. We examined possible antitumor effects of adenoviruses expressing melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda-7) and a heat-shock protein 90 (Hsp90) inhibitor to human pancreatic carcinoma cells. Ad-mda-7 and an Hsp90 inhibitor, geldanamycin (GA), produced cytotoxic effects, and a combinatory use of Ad-mda-7 and GA further achieved synergistic effects. Administration of N-acetyl-L-cysteine, an inhibitor of reactive oxygen species, eliminated Ad-mda-7- and GA-mediated cytotoxicity. Ad-mda-7 augmented phosphorylated AKT levels but GA did not influence the phosphorylation. GA-treated cells showed cleavage of poly-(ADP-ribose) polymerase but not caspase-3, and upregulated Hsp70 and LC3A/B II levels, whereas Ad-mda-7-treated cells did not. GA treatments augmented ubiquitination and markedly increased melanoma differentiation-associated gene-7 (MDA-7) expression levels. These findings suggest that Ad-mda-7-mediated cytotoxicity is dependent on reactive oxygen species but independent of apoptosis or autophagy, and that GA-mediated cytotoxicity was linked with caspase-independent apoptosis and/or autophagy. A mechanism underlying the combinatory effects of Ad-mda-7 and GA remained complex and the synergism is attributable to multiple factors including increased MDA-7 protein stability by GA.

01 Feb 2010·Cancer researchQ1 · MEDICINE

PERK–Dependent Regulation of Ceramide Synthase 6 and Thioredoxin Play a Key Role inmda-7/IL-24–Induced Killing of Primary Human Glioblastoma Multiforme Cells

Q1 · MEDICINE

Article

Author: Dent, Paul ; Ogretmen, Besim ; Grant, Steven ; Curiel, David T. ; Spiegel, Sarah ; Mitchell, Clint ; Fisher, Paul B. ; Sarkar, Devanand ; Yacoub, Adly ; Lesniak, Maciej S. ; Hamed, Hossein A. ; Dash, Rupesh ; Allegood, Jeremy ; Broaddus, William C.

Abstract:

Melanoma differentiation associated gene-7(mda-7) encodes IL-24, a cytokine that can selectively trigger apoptosis in transformed cells. Recombinant mda-7 adenovirus (Ad.mda-7) effectively kills glioma cells, offering a novel gene therapy strategy to address deadly brain tumors. In this study, we defined the proximal mechanisms by which Ad-mda-7 kills glioma cells. Key factors implicated included activation of the endoplasmic reticulum stress kinase protein kinase R–like endoplasmic reticulum kinase (PERK), Ca++ elevation, ceramide generation and reactive oxygen species (ROS) production. PERK inhibition blocked ceramide or dihydroceramide generation, which were critical for Ca++ induction and subsequent ROS formation. Activation of autophagy and cell death relied upon ROS formation, the inhibition of which ablated Ad.mda-7–killing activity. In contrast, inhibiting TRX induced by Ad.MDA-7 enhanced tumor cytotoxicity and improved animal survival in an orthotopic tumor model. Our findings indicate that mda-7/IL-24 induces an endoplasmic reticulum stress response that triggers production of ceramide, Ca2+, and ROS, which in turn promote glioma cell autophagy and cell death. Cancer Res; 70(3); 1120–9

100 Deals associated with INGN-241

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Head and Neck Neoplasms	Phase 3	United States	Introgen Therapeutics, Inc.	-
Head and Neck Neoplasms	Phase 3	-	The Trustees of Columbia University in The City of New York	-
Head and Neck Neoplasms	Phase 3	-	GSK Plc	-
Melanoma	Phase 2	United States	Introgen Therapeutics, Inc.	01 Mar 2005
Advanced cancer	Phase 1	United States	Baylor University Medical Center	01 May 2004
Advanced cancer	Phase 1	United States	US Oncology, Inc.	01 May 2004
Advanced cancer	Phase 1	United States	Introgen Therapeutics, Inc.	01 May 2004
Breast Cancer	Preclinical	United States	Introgen Therapeutics, Inc.	-
Breast Cancer	Preclinical	-	The Trustees of Columbia University in The City of New York	-
Breast Cancer	Preclinical	-	GSK Plc	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASGCT2007	Phase 1/2	Neoplasms	22	INGN 241	yuvgmkeqpu(gzscrvoulq) = Patients treated with INGN 241 had increases in CD8 + T-cells jajxboqeax (dppwjzhjuo ) View more	Positive	01 May 2007
INGN 241 (ASGCT2003)	Phase 1	Advanced cancer	18	INGN 241 (Ad-mda7)	isklnznwpx(qgotnzvxlu) = pain at the injection site, transient low grade fever and mild flu-like symptoms wubzwybctb (oltwyhuzps ) View more	Positive	01 May 2003