Studies Show Potential Progress Toward Identifying Specific Tumor Types
Cell Therapeutics and Systems Medicine announced new preclinical data from several of its drug candidates during the 19th annual AACR-NCI-EORTC Symposium.
"These studies show potential progress toward identifying specific tumor types with a higher likelihood of demonstrating response to anti-cancer compounds early in clinical development and are critical to our goal of a highly focused clinical development strategy," said Jack W. Singer, M.D., Chief Medical Officer of CTI.
A new class of thienopyrimidine Src inhibitors demonstrates potent growth suppression of imatinib resistant Ba/F3 cells harboring a wide range of BCR-ABL mutations, including the CML relevant T315I (Abstract #B238)
Spyro Mousses, Ph.D., Senior Investigator and Director, Cancer Drug Development Laboratory at the Translational Genomics Research Institute (TGen) presented preclinical data that showed two thienopyrimidine Src inhibitors work in imantinib-resistant tumors, including the most frequent mutation leading to relapse. The study showed the Src inhibitors retained potent and non-selective cytotoxicity (at sub-micromolar concentrations) in cell lines previously shown to be susceptible and resistant to imatinib, including the T315I mutant cell line. The data suggest that the thienopyrimidine Src inhibitors may represent a new class of drugs with in vitro activity against chronic myelogenous leukemia (CML) variants with BCR-ABL mutations, warranting their exploration as potential new treatments for patients with imatinib-resistant forms of cancer. Preliminary in vitro data suggest these compounds are selective for Src.
"Continued development of these compounds is warranted to more extensively evaluate their selectivity and toxicity and gain further insight into the molecular mechanism by which these new Src inhibitors retain potent activity against all tested imatinib resistant BCR-ABL mutants, including the BCR-ABL T315I mutant, which is generally refractory to other Src and Aurora Kinase inhibitors," said Mousses.
Antitumor activity of brostallicin on human prostatic cancer: role of combination with hypomethylating agents (Abstract #A288)
Data were presented that show brostallicin, when combined with hypomethylating agents such as zebularine, may convert resistant tumors into tumors sensitive to brostallicin. The data suggest that interaction between zebularine and brostallicin could be beneficial to patients with prostate cancer and that the use of other hypomethylating agents in combination with brostallicin should be explored. The study results support a potential clinical trial of zebularine in combination with brostallicin.
Brostallicin induces DNA damage measured by histone H2AX phosphorylation independently of the nucleotide excision repair pathways. (Abstract #B77)
Yves Pommier, M.D., Ph.D., Chief of the Laboratory of Molecular Pharmacology at the Center for Cancer Research at the NCI evaluated various cell lines known to be differentially sensitive to ecteinascidin 743 (a minor groove binder). Data showed that brostallicin retained potent cytotoxicity in the submicromolar range in cell lines previously identified to be resistant to ecteinascidin 743. In addition, the study showed brostallicin is less dependent on the nucleotide excision repair (NER) gene than ecteinascidin 743 and that cells selected for resistance to ecteinascidin 743 showed no cross resistance to brostallicin. The study also suggested gamma-H2AX, a major regulator of cellular responses to DNA damage, could be considered a pharmacodynamic biomarker for the clinical development of brostallicin.
Occurrence and mode of the interaction between brostallicin and the human glutathione transferases GSTP1-1 and GSTM2-2 (Abstract #C249)
Data were also presented on the mechanism of action of brostallicin and its interaction with glutathione transferases. "It is well established that both glutathione and glutathione S-transferase are overexpressed in many types of cancer cells in comparison to normal tissues and are also involved in the mechanism of resistance to several antitumor drugs," noted Robert B. MacArthur, Pharm.D., Vice President of Clinical and Regulatory Affairs for Systems Medicine. "It is also known that brostallicin's activity is enhanced in the presence of both glutathione and glutathione S-transferase and that tumor cells expressing relatively high levels of glutathione and glutathione S-transferase are more susceptible to brostallicin's antitumor activity."
These data establish for the first time that brostallicin interacts with each enzyme in a different manner. "Several human tumors display increased levels of Pi and Mu class of glutathione S-transferase and these data support the value of targeting those tumors in the development of brostallicin," MacArthur concluded.
Brostallicin, a novel synthetic second-generation DNA minor groove binder, has potent cancer killing activity and has demonstrated synergism in combination with standard cytotoxic agents as well as with newer targeted therapies in preclinical experimental tumor models. Brostallicin binds covalently to DNA within the DNA minor groove interfering with DNA division and leading to tumor cell death. More than 200 patients have been treated with brostallicin in single-agent and combination studies. Brostallicin had predictable and predominantly hematologic toxicities. Activity was demonstrated in a number of solid tumor types. A phase II study of brostallicin in relapsed/refractory soft tissue sarcoma met its pre-defined activity and safety hurdles and resulted in a first-line phase II study that is currently being conducted by the European Organization for Research and Treatment of Cancer (EORTC).
Brostallicin was discovered at Pharmacia 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.