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Dianhydrogalactitol (VAL-083, “DAG”) is an investigational chemotherapeutic drug with preliminary anti-tumor activity. It is a “first-in-class” DNA-targeting agent with a unique bi-functional DNA cross-linking mechanism that has shown activity against a range of tumor types in prior clinical trials sponsored by the US National Cancer Institute (NCI). Dianhydrogalactitol is currently undergoing clinical trials as a potential treatment for glioblastoma multiforme (GBM), the most common and aggressive form of brain cancer  , and ovarian cancer. Dianhydrogalactitol is approved as a cancer chemotherapeutic in China for the treatment of chronic myelogenous leukemia ("CML") and lung cancer (Approval No. Guoyao Zhunzi H45021133). It has not been approved for any indication outside of China.

History
Dianhydrogalactitol was first investigated as a cancer therapy in Hungary in the 1960s and subsequently by the US National Cancer Institute (NCI) as a treatment for cancer beginning in the 1970s. NCI-sponsored clinical studies suggested promising anti-tumor activity with dianhydrogalactitol in the treatment of hematologic malignancies and a range of solid tumors, including brain tumors  , lung cancer   , ovarian cancer   and other solid tumors. Antitumor activity has been reported in clinical trials following both intravenous and oral administration of dianhydrogalactitol.

Research was eventually not pursued in the United States due to an increased focus on targeted biologic therapies during the early 1990s. Dianhydrogalactitol was subsequently approved in China for the treatment of chronic myeloid leukemia (‘CML”) and lung cancer (Approval No. Guoyao Zhunzi H45021133).

Research into dianhydrogalactitol as a chemotherapeutic agent was reactivated in 2010 and it is currently being studied in a range of indications including glioblastoma (GBM), pediatric central nervous system (CNS) tumors, non-small cell lung cancer (NSCLC) and ovarian cancer.

The U.S. FDA Office of Orphan Products has granted dianhydrogalactitol orphan drug designation for the treatment of malignant glioma, medulloblastoma and ovarian cancer. In Europe, dianhydrogalactitol has received an orphan designation for the treatment of gliomas.

Mechanism of Action
DNA is the hereditary material in humans that can replicate, or make copies of itself, in a cellular process known as mitosis. When cells divide, each new cell needs to have an exact copy of the DNA present in the original cell. When a mistake is made in the copying of DNA due to carcinogens such as sunlight (UV) damage, chemical damage, or radiation, the cell will initially attempt to repair the mistake and, if that proves impossible, the cell will be instructed to “die” via a process known as apoptosis. However, cells with DNA errors sometimes escape the body’s natural defense mechanisms resulting in DNA mutations and, ultimately, the formation of cancer. Alkylating agents are among the oldest class of cancer chemotherapies in use today. Alkylating agents bind to DNA causing damage mainly to cancer cells. The DNA damage caused by alkylating agents results in apoptosis and tumor cell death. Dianhydrogalactitol is a bi-functional DNA-targeting alkylating agent that rapidly forms interstrand DNA crosslinks at the N7 position of guanine, leading to persistent and irreversible DNA double-strand breaks and cell death. The functional groups and cytotoxic mechanism of dianhydrogalactitol differ from other DNA-targeting agents, enabling it to overcome resistance to chemotherapeutics used in the treatment of different tumors, such as the platinum-based compounds, nitrosoureas or temozolomide.