Tolero Pharmaceuticals announces preclinical data supporting development of TP-1287 and TP-3654 for MYC-dependent triple-negative breast cancer
SALT LAKE CITY, Oct. 23, 2017 /PRNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing treatments for hematological diseases, today announced preclinical data supporting development of TP-1287 and TP-3654 in triple negative breast cancer. TP-1287 is an oral prodrug form of alvocidib, and TP-3654 is Tolero's second-generation, selective PIM kinase inhibitor. Key findings from cell culture models suggest that dual therapy with alvocidib and TP-3654 showed a 100% reduction in Myc protein expression. Further, combining TP-1287 and TP-3654 resulted in a 58.3% reduction of tumor growth in a xenograft model.
These and other preclinical data will be presented at the 2017 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Philadelphia. Posters will be on display from 12:30 to 4:00 p.m. EDT on October 29 in Hall E of the Pennsylvania Convention Center.
"There is a significant need for new therapies aimed at triple negative breast cancer, as patients and physicians are currently limited only to chemotherapy," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals. "Although the complexities of this cancer pose a unique therapeutic challenge, we are encouraged by these pre-clinical findings suggesting the potential of TP-1287 and TP-3654 in triple negative breast cancer. We look forward to further exploring this hypothesis."
Recent data suggest that PIM regulation of the Myc protein may play a role in the mediation of triple negative breast cancer. TP-3654 is a second-generation, selective PIM kinase inhibitor and alvocidib is an inhibitor of cyclin-dependent kinase 9 (CDK9), a protein important to the regulation of Myc. An oral prodrug form of alvocidib, TP-1287, was also evaluated in this preclinical study.
In a triple negative breast cancer cell line, TP-3654 as a single agent reduced relative Myc protein expression by 74%, while alvocidib alone reduced expression by 71%. The combination of TP-3654 and alvocidib reduced detectable expression 100%, as measured by standard immunoblotting, at concentrations of 100 nM with a 3-hour treatment. TP-3654 and TP-1287 were tested in the same cell line during subsequent in vivo xenograft tests. TP-3654 (150 mg/kg) reduced tumor growth (%TGI) 40.7%, while TP-1287 (3.75 mg/kg) reduced tumor growth 11.6%. The combined agents reduced tumor growth by 58.3% at day 18. The associated abstract is available on the AACR-NCI-EORTC meeting website: http://www.abstractsonline.com/pp8/#!/4557/presentation/498.
Tolero will also present preclinical data evaluating the potential of its PKM2 inhibitor, TP-1454, at the AACR-NCI-EORTC meeting. PKM2 has been the focus of research to determine its utility as a target for cancer treatment. Data from the preclinical study evaluating TP-1454 suggest that PKM2 is a potential therapeutic target for multiple cancers that warrants further clinical evaluation. The associated abstract is available on the meeting website: http://www.abstractsonline.com/pp8/#!/4557/presentation/344.
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9). Phase II studies are underway for patients with relapsed or refractory MCL-1-depenedent acute myeloid leukemia, or AML, in combination with cytarabine and mitoxantrone. Clinical studies are being initiated to evaluate alvocidib in combination with (7+3) in treatment-naive patients with AML.
MCL-1 is a protein, which, in cancers, serves to block the induction of cell death (apoptosis) and may drive resistance to chemotherapy. Data from previous trials suggest that certain tumors are dependent upon the MCL-1 protein to survive, making it a rational target. These data indicate that 25%-35% of acute myeloid leukemia patients have tumors with such dependency, and that treatment with a regimen containing alvocidib, which inhibits production of the MCL-1 protein through blockage of CDK9, may be of benefit to these patients.
About Tolero Pharmaceuticals, Inc.
Tolero is a clinical-stage biopharmaceutical company researching and developing treatments to improve and extend the lives of patients with oncological and hematological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias, anemia, and solid tumors, as well as targets of drug resistance and transcriptional control. Tolero is based in the United States and is a wholly owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., a pharmaceutical company based in Japan.
Additional information about the company and its product pipeline can be found at www.toleropharma.com.
Tolero Forward-Looking Statements
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Tolero's business. Tolero undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.