Myelosuppression continues to represent the major dose-limiting toxicity of cancer chemotherapy, resulting in considerable morbidity and mortality along with frequent reductions in chemotherapy dose intensity, which may compromise disease control and survival. G-Zero Therapeutics, with operations in the Research Triangle Park of North Carolina, has developed a novel approach to attenuate the hematologic toxicity of chemotherapy. This approach relies on the administration of novel small molecule kinase inhibitors around the time of chemotherapy administration. These compounds in turn induce a cell cycle arrest of the early hematopoietic stem and progenitor cells (HSPC) through the inhibition of cyclin dependent kinases 4 and 6 (CDK4/6) that govern the G1-S transition of the cell cycle of HSPC. We have termed this arrest "pharmacological quiescence" (or PQ throughout), which is protective as non-cycling cells are resistant to DNA damaging agents. Specifically, PQ enhances the per cell survival of HSPC by augmenting the repair of DNA damage following exposure to chemotherapy. Enhanced survival of HSPC in turn translates into markedly reduced acute hematologic toxicity. G-Zero has shown in mice that the PQ approach can significantly protect all hematopoietic cell lineages (including red cells, platelets, granulocytes and lymphocytes) from chemotherapy-induced DNA damage. G-Zero has licensed from the University of North Carolina the broad intellectual property developed in Dr. Sharpless' lab at UNC surrounding the use of PQ for chemoprotection. In addition, G-Zero is developing its own proprietary series of CDK4/6 drug candidates, from which we have identified GZ38-1 as our lead candidate. In this proposal, we seek to extend our proof- of-concept results using our own proprietary CDK4/6 inhibitors, by demonstrating in vivo efficacy and safety of GZ38-1. In Phase I, we will determine the efficacy of novel chemotherapeutic regimens incorporating GZ38-1 and standard SCLC chemotherapeutic agents in Small Cell Lung Cancer xenograft models. In Phase II, we will pursue pharmaceutical chemistry development of GZ38-1 for future IND-enabling GLP studies. We believe work described in this proposal will lead to a commercially valuable approach to prevent chemotherapy-induced myelosuppression that is protected by G-Zero's broad intellectual property: a simple and non- toxic therapeutic that will provide protectio of all hematopoietic cell lineages following exposure to chemotherapeutic DNA-damaging agents.
Public Health Relevance Statement: Public Health Relevance: Myelosuppression continues to represent the major dose-limiting toxicity of cancer chemotherapy, resulting in considerable morbidity and mortality along with frequent reductions in chemotherapy dose intensity, which may compromise disease control and survival. G-Zero Therapeutics is developing a novel approach and proprietary CDK4/6 series to attenuate the hematologic toxicity of chemotherapy and protect all hematopoietic cell lineages (red cells, platelets, granulocytes and lymphocytes) from chemotherapy-induced DNA damage.
Project Terms: Acute; Adverse effects; alpha-Thalassemia; Attenuated; base; Blood Platelets; Bone Marrow; Bone Pain; Boxing; Cancer Etiology; Cancer Model; Cancer Patient; cancer therapy; Canis familiaris; Cell Cycle; Cell Cycle Arrest; Cell Lineage; Cell Survival; Cells; Cessation of life; Chemoprotection; chemotherapeutic agent; chemotherapy; Chemotherapy-Oncologic Procedure; clinical application; CSF3 gene; Cyclin-Dependent Kinase 4; Cytotoxic Chemotherapy; Data; Development; Disease; disorder control; DNA Damage; DNA Repair; Dose; Dose-Limiting; drug candidate; Drug Formulations; Dysmyelopoietic Syndromes; Erythrocytes; Erythropoietin; Exposure to; FDA approved; Fever; Funding; Future; G1/S Transition; granulocyte; Growth Factor; Hematopoietic; Human; in vivo; inhibitor/antagonist; Injectable; Intellectual Property; Investigation; Ionizing radiation; kinase inhibitor; Lead; Licensing; lung small cell carcinoma; Lymphocyte; Malignant Neoplasms; Molecular Genetics; Morbidity - disease rate; Mortality Vital Statistics; Mus; Myelosuppression; North Carolina; novel; novel strategies; operation; Pharmaceutical Chemistry; Phase; prevent; public health relevance; Rattus; Regimen; Research; Resistance; Risk; Safety; Series; Small Business Innovation Research Grant; small molecule; stem; Stem cells; Therapeutic; Thrombosis; Time; Toxic effect; Toxicity due to chemotherapy; Toxicology; Translating; tumor; tumor progression; Universities; Work; Xenograft Model
