A New Class of Cancer Drug

Brostallicin (bräst-al-iss-in) is a small molecule chemotherapeutic agent with a unique mechanism of action. It is a new class of cancer drug—a synthetic DNA minor groove binding agent. Most cytotoxic agents bind DNA’s major groove, have little sequence-specificity, and are severely toxic to normal tissues (including topoisomerase inhibitors, such as camptothecins and anthracyclines).

DNA minor groove binders such as brostallicin possess high affinity and selectivity for interaction with DNA. All minor groove binders bind to the same DNA structure. However, brostallicin has a unique and very interesting mechanism of action.

A Novel and Unique Mechanism of Action

Brostallicin binds to DNA only in the presence of glutathione (GSH) and glutathione S-transferase (GST), which are produced to a greater extent in cancer cells than in normal cells.

This gives brostallicin a novel and highly selective mechanism of action that is superior to other minor groove binding agents.

By binding to the minor groove, brostallicin provides a new target to interfere with cell division and lead to tumor cell death. Brostallicin is potently synergistic (in preclinical studies) in combination with standard cytotoxic agents as well as newer targeted therapies.

Brostallicin has a unique ability to retain activity in tumors that are resistant to other cancer drugs. Additionally, its anti-tumor activity remains high in the presence of a number of critical cancer causing genetic abnormalities that cause resistance to standard anti-cancer agents. This activity profile makes it of extreme interest in designing trials to test its activity in targeted patients with certain genetic abnormalities, such as mismatch-repair mutations in inherited breast, ovarian, and colorectal cancers that are generally resistant to treatment.

Brostallicin Clinical Research

Phase I and phase II clinical trials have been conducted with brostallicin in both Europe and the US involving more than 230 patients in single agent and combination trials.

Brostallicin has been generally well tolerated with mild to moderate, reversible myelosuppression being the primary adverse event. It has had predictable and predominantly hematologic toxicities, which rarely required growth factor support. Responses have been reported in non-small cell lung cancer and in head and neck cancer.

Clinical Trials

In 2010, the North Central Cancer Treatment Group started a phase II study of brostallicin in combination with cisplatin in patients with triple-negative metastatic breast cancer patients in first, second, third or fourth line therapy. Enrollment is expected to be complete in early 2012. In addition to standard clinical efficacy measures, biological endpoints also will be evaluated to assist in understanding brostallicin’s activity in this disease.