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|Ref Type||Journal Article|
|Authors||Bisi JE, Sorrentino JA, Roberts PJ, Tavares FX, Strum JC|
|Title||Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Chemotherapy-induced myelosuppression continues to represent the major dose-limiting toxicity of cytotoxic chemotherapy, which can be manifested as neutropenia, lymphopenia, anemia, and thrombocytopenia. As such, myelosuppression is the source of many of the adverse side effects of cancer treatment including infection, sepsis, bleeding, and fatigue, thus resulting in the need for hospitalizations, hematopoietic growth factor support, and transfusions (red blood cells and/or platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to chemotherapy dose reductions, therefore limiting therapeutic dose intensity, and reducing the antitumor effectiveness of the treatment. Currently, the only course of treatment for myelosuppression is growth factor support which is suboptimal. These treatments are lineage specific, do not protect the bone marrow from the chemotherapy-inducing cytotoxic effects, and the safety and toxicity of each agent is extremely specific. Here, we describe the preclinical development of G1T28, a novel potent and selective CDK4/6 inhibitor that transiently and reversibly regulates the proliferation of murine and canine bone marrow hematopoietic stem and progenitor cells and provides multilineage protection from the hematologic toxicity of chemotherapy. Furthermore, G1T28 does not decrease the efficacy of cytotoxic chemotherapy on RB1-deficient tumors. G1T28 is currently in clinical development for the reduction of chemotherapy-induced myelosuppression in first- and second-line treatment of small-cell lung cancer. Mol Cancer Ther; 15(5); 783-93. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Trilaciclib||G1T28||CDK4/6 Inhibitor 12||Trilaciclib (G1T28) is a small molecule that inhibits CDK4/6, resulting in reversible cell-cycle arrest, and potentially reduces myelosuppression induced by chemotherapeutics (PMID: 26826116, PMID: 31575503).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|RB1 loss||lung small cell carcinoma||resistant||Trilaciclib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, RB1-deficient small cell lung cancer cell lines were resistant to Trilaciclib (G1T28) in culture and in xenograft models (PMID: 26826116).||26826116|
|RB1 loss||lung small cell carcinoma||sensitive||Topotecan + Trilaciclib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Trilaciclib (G1T28) and Hycamtin (topotecan) inhibited tumor growth in RB1-deficient small cell lung cancer cell line xenograft models, with greater efficacy than Hycamtin (topotecan) alone (PMID: 26826116).||26826116|