Reference Detail

Ref Type

Journal Article

PMID

(26826116)

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	5	2016 May	783-93	Mol Cancer Ther

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Trilaciclib	Trilaciclib	1	5

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Trilaciclib		G1T28	CDK4/6 Inhibitor 13	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