The North Central Cancer Treatment Group (NCCTG), a national clinical research group sponsored by the National Cancer Institute, plans to conduct a Phase II study of brostallicin in combination with cisplatin in patients with metastatic triple-negative breast (mTNBC) cancer. These cancers are typically defined by tumors lacking expression of estrogen, progesterone receptors and without over-expression of HER2. Additionally, the majority of breast cancers that are associated with the susceptibility mutation (BRCA1) are of the triple-negative type.
BRCA1 is a tumor suppressor gene which, when mutated, is associated with the development of hereditary breast cancers. Changes in the BRCA1 status can make tumors rapidly acquire resistance to chemotherapy requiring development of new agents to effectively treat these patients. Brostallicin is a novel synthetic second-generation DNA minor groove binder with enhanced efficacy in the presence of the BRCA1 mutation and has demonstrated synergy in combination with cisplatin, an active therapeutic for this disease.
Brostallicin has also demonstrated a unique ability to retain activity in tumors that are resistant to other cancer drugs . Women with mTNBC have very limited effective treatments and based on the novel mechanism of action of brostallicin and the recognized activity of cisplatin in this disease, the combination of the two agents will be explored by the NCCTG.
In addition to standard clinical efficacy measures, biological endpoints will also be evaluated to assist in understanding the specific activity of the therapeutic in this disease.
“As we determine the underlying genetic background of disease, we believe we will be able to select the appropriate patients for testing of novel agents such as brostallicin. In the development of brostallicin, studies have indicated significant responses in particular genetic backgrounds (one being triple negative breast cancer),” said Christina Waters, Ph.D., MBA, President of CTI Europe and Systems Medicine, LLC and former Director of Scientific Development at Genomics Institute of the Novartis Research Foundation. “We are moving to a more sophisticated clinical treatment paradigm, from general cell ablation to targeted therapy, which we believe will improve patient response in select populations and decrease exposure to patients that cannot respond.”
The demonstration of tumor sensitization to brostallicin in the presence of BRCA1 suppression was completed in collaboration with Translational Genomics Research Institute (T-Gen) and Systems Medicine, LLC a wholly-owned subsidiary of the Company.
New class of cancer agent
Brostallicin is a new class of cancer drug–a synthetic DNA minor groove binding agent with a unique mechanism of action. 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). Brostallicin binds covalently to DNA within the DNA minor groove interfering with DNA division and leading to tumor cell death. Data in more than 230 patients treated in single-agent and combination phase I/II clinical trials reveal evidence of activity in patients with refractory cancer. Brostallicin has also demonstrated synergy with new targeted agents as well as established treatments for common tumor types in preclinical trials.
Minor groove binders
DNA minor groove binders such as brostallicin possess high affinity and selectivity for interaction with either GC- or AT-rich regions of DNA. All minor groove binders bind to the same DNA structure. However, brostallicin has a unique and very interesting 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, but not typically in normal cells. This gives brostallicin a novel and highly selective mechanism of action that is superior to other minor groove binding agents. Brostallicin had predictable and predominantly hematologic toxicities.
Brostallicin was discovered at Pharmacia Oncology (now Pfizer Oncology) and developed by Nerviano Medical Sciences (NMS) the largest pharmaceutical research and development facility in Italy and one of the largest oncology-focused, integrated discovery and development companies in Europe. Following a merger between Pfizer and Pharmacia, the rights to brostallicin were assigned to NMS, which continued its development and ultimately licensed worldwide rights to Systems Medicine LLC, a wholly-owned subsidiary of Seattle-based Cell Therapeutics, Inc.
- Guirouilh-Barbat J, Zhang YW, Pommier Y. Induction of glutathione-dependent DNA double-strand breaks by the novel anticancer drug brostallicin. Mol Cancer Ther. 2009 Jul;8(7):1985-94. Epub 2009 Jul 7.