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HMBD-001 in Advanced HER3 Positive Solid Tumours

ABSTRACT: This clinical trial is evaluating a drug called HMBD-001 (an anti-HER3 monoclonal antibody) in patients with advanced HER3 positive solid tumours. The main aims are to find out the maximum dose of HMBD-001 that can be given safely to patients alone and in combination with other anti-cancer agents, more about the potential side effects of HMBD-001 and how these can be treated and what happens to HMBD-001 inside the body and how it affects cancer cells.

DISEASE(S): Endometrial Cancer,Cervical Cancer,Triple Negative Breast Neoplasms,Hepatocellular Carcinoma (hcc),Melanoma,Bladder Cancer,Triple Negative Breast Cancer,Head And Neck Neoplasms,Pancreatic Cancer,Endometrial Neoplasms,Non-small Cell Lung Cancer (nsclc),Ras Wild Type Colorectal Cancer,Neoplasms, Squamous Cell,Ovarian Cancer,Carcinoma, Squamous Cell,Oesophageal Cancer,Gastric Cancer,Squamous Cell Cancer Of The Head And Neck,Castration-resistant Prostate Cancer

PROVIDER: 2390619 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:RRx-001 (also known as ABDNAZ, 1-bromoacetyl-3,3-dinitroazetidine) is a novel aerospace-derived compound currently under investigation in several ongoing Phase II studies. In a Phase I trial, it demonstrated anti-cancer activity and evidence of resensitization to formerly effective therapies in heavily pre-treated patients with relapsed/refractory solid tumors. With a pharmacologically unprecedented dinitroazetidine scaffold, RRx-001 generates reactive oxygen and nitrogen species (ROS and RNS) and nitric oxide (NO), elicits changes in intracellular redox status, modulates tumor blood flow, hypoxia and vascular function and triggers apoptosis in cancer cells. Here, the effect of RRx-001 on the epigenome of SCC VII cancer cells was investigated. RRx-001 at 0.5 and 2 μM significantly decreased global DNA methylation, i.e., 5-methylcytosine levels, in SCC VII cells determined by analysis with an enzyme-linked immunosorbent assay (ELISA). Consistently, 0.5-5 μM RRx-001 significantly decreased Dnmt1 and Dnmt3a protein expression determined using Western blot in a dose- and time-dependent manner. In addition, global methylation profiling identified differentially methylated genes in SCC VII cells treated with 0.5, 2, and 5 μM RRx-001 compared to control cells. Twenty-three target sites were hypomethylated and 22 hypermethylated by >10% in the presence of at least two different concentrations of RRx-001. Moreover, RRx-001 at 2 μM significantly increased global acetylated histone H3 and H4 levels in SCC VII cells after 24 hour treatment determined by a fluorometric assay, suggesting that RRx-001 regulates global acetylation in cancer cells. These results demonstrate that, in contrast to the traditional “one drug one target” paradigm, RRx-001 has multi(epi)target features, which contribute to its anti-cancer activity and may rationalize the resensitization to previously effective therapies observed in clinical trials and serve as a unifying mechanism for its anticancer activity.

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HMBD-001 in Advanced HER3 Positive Solid Tumours

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