Cyclacel Pharmaceuticals disclosed promising preclinical results of its drug candidate, CYC065, for the treatment of B-cell lymphoma in a poster presentation at the recent American Association for Cancer Research (AACR) annual meeting in New Orleans. The presentation was titled, “CYC065, a novel CDK2/9 inhibitor, is an effective inducer of cell death and synergizes with BCL2 and BET inhibitors in B-cell lymphoma, including double-hit lymphomas.”
Cancer in its various forms is fundamentally a condition of tissue growth regulation. The transformation of a normal cell into a cancer cell requires an alteration in the genes that regulate cell growth and differentiation. This occurs through a chain reaction of accumulated errors, allowing the cell to escape the rules governing normal tissue growth.
Double hit B-cell lymphomas, characterized by concurrent rearrangement of regulating genes named MYC and BCL2, have a poorer prognosis than diffuse large B-cell lymphomas (DLBCL). As such, limiting the formation and accumulation of genetic errors at early stages through the use of inhibitors could halt the production of cancer cells.
CYC065 is an inhibitor for enzymes called cyclin-dependent kinases (CDKs), particularly CDK2 and CDK9, known to play important roles in cancer cell growth, survival, metastatic spread, and DNA repair. The anti-cancer activity of CYC065 was evaluated separately and in combination with the Bcl-2 inhibitor, venetoclax (ABT-199, Venclexta), and BET (Bromodomain and Extra-Terminal) inhibitors in B-cell lymphoma cell lines.
Preclinical results showed that a brief exposure to CYC065 suffices to decrease cellular MYC levels, usually overexpressed in many types of cancer. CYC065 also decreased levels of the protein-coding gene Mcl-1, involved in cell death, but did not influence Bcl-2 levels. When CYC065 was combined with venetoclax or BET inhibitors, synergistic effects were observed.
“CYC065 is currently in a Phase 1 clinical trial to evaluate its safety, pharmacokinetic and pharmacodynamic activity in patients with solid tumors and lymphomas,” Spiro Rombotis, president and chief executive officer of Cyclacel, said in a press release. “Data presented at AACR highlights its potential as an agent to treat hematological malignancies, such as B-cell lymphoma. Data from this study are particularly important as they validate the mechanism of action of CYC065, which is reducing MYC and Mcl-1 levels, both of which can be elevated in B-cell lymphoma. The study also suggests that CYC065 may be used effectively in combination with other targeted anti-tumor agents in lymphomas.
“In parallel with collecting preclinical data, we continue to enroll patients in the Phase 1 trial and look forward to reporting initial results from the clinical study,” he said.
More information on the trial, being conducted at the Dana-Farber Cancer Institute in Massachusetts, is available through its clinical trials.gov website (NCT02552953).