Tolero Pharmaceuticals Presents Results Providing Strong Rationale for Combining Alvocidib with a Bromodomain Protein Inhibitor for the Treatment of Multiple Tumor Types
-- Data Presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting Demonstrate Convincing Justification for the Combination of Alvocidib with
Inhibitors of BET Proteins --
SALT LAKE CITY, UT - November 9, 2015 - Tolero Pharmaceuticals, Inc., today announced the presentation of nonclinical data demonstrating synergy between the CDK9 inhibitor, alvocidib, and a number of bromo and extra terminal (BET) protein inhibitors in multiple tumor models at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting in Boston, MA. Alvocidib is currently in clinical development for the treatment of frontline and relapsed/refractory acute myeloid leukemia (AML). In the results presented, the combination of CDK9 and BET protein inhibitors led to a synergistic inhibition of the super enhancer complex (SEC) in both AML and lung cancer models. The SEC is a group of transcriptional regulators that can drive oncogenesis and disease progression in many disease states, and inhibitors of the SEC are the focus of many drug development efforts.
"The strong synergy between CDK9 inhibition by alvocidib and BET inhibition further validates that alvocidib’s mechanism involves shutting down super enhancer transcriptional programs that drives initiation and progression in AML and other malignancies," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero. "We are planning a clinical development strategy to evaluate this mechanistically rationalized combination to provide the greatest impact to patients in need."
The findings were detailed in the abstract and presentation entitled, "CDK9 inhibition synergizes with BRD4 inhibitor-mediated super enhancer transcriptional repression in multiple preclinical tumor models." The study utilized cell-based and animal models of AML and lung cancer to establish that alvocidib, when combined with several different BET protein inhibitors, has potent synergistic activity. The synergy between the agents was demonstrated by using doses of alvocidib and BET inhibitors that are ineffective as single agents, yet when combined, lead to complete tumor regressions in xenograft studies, down regulation of SEC transcriptional activity, and strong induction of apoptosis in AML and lung cancer cells. These findings expand on Tolero’s previous presentations that focused on this novel combination specifically in AML. The finding that similar results were replicated in solid tumor models, such as lung cancer, suggests that the combination may be exploited in a variety of tumor types.
Currently, Tolero is initiating a biomarker-driven randomized Phase 2 clinical trial with alvocidib in combination with chemotherapy versus chemotherapy alone in patients with relapsed or refractory AML whose disease is thought to be dependent on the protein MCL-1. CDK9 tightly controls the expression of MCL-1 and the ability of alvocidib to inhibit CDK9 may make these patients more likely to respond to alvocidib treatment.
Alvocidib is a potent small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) in development as a combination therapy for frontline and relapsed/refractory AML. CDK9 is a protein critical to the regulation of gene expression including the MCL-1 gene and other important genes involved in cancer. Given the key role CDK9 de-regulation plays in expression of cancer-associated genes related to cell division and proliferation, CDK9 is an attractive target for the treatment of various cancers.
Tolero Pharmaceuticals is a clinical stage biopharmaceutical company developing treatments to improve and extend the lives of patients with serious oncological and hematological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias and anemia as well as important targets of drug resistance and transcriptional control.
Tolero Pharmaceuticals, Inc.
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