TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS

Project: Research project

Description

Chronic myelogenous leukemia (CML) is a malignancy arising from a pluripotent hematopoietic stem cell. Only 20-25 percent of patients with CML are eligible for curative therapy with an allogeneic bone marrow transplant and only about half of the patients undergoing this therapy will be long term survivors. The BCR-ABL fusion protein, present in 95 percent of patients with CML, has been implicated as the cause of this disease. As the tyrosine kinase activity of ABL is required for the transforming function of the BCR-ABL fusion protein, a specific inhibitor of the ABL tyrosine kinase would seem an ideal therapy for this disorder. We have been evaluating a specific ABL tyrosine kinase inhibitor as a therapeutic agent for this disease. This inhibitor exhibits specific killing of BCR-ABL positive cell lines and is capable of selecting for BCR-ABL negative hematopoietic progenitor cells in colony forming assays of CML patient samples. In vivo antitumor activity against BCR-ABL-expressing tumors has also been demonstrated. Animal toxicology demonstrated hepatic inflammation at high doses along with mild myelosuppression, anemia, and transitional cell hyperplasia. Phase I clinical trials of this compound have begun in CML patients who have failed Interferon therapy. The goals of this proposal are to complete our Phase I clinical trials in CML patients and initiate Phase II trials in CML and other malignancies. Other experiments are proposed to optimize the conditions for in vitro purging of BCR-ABL positive hematopoietic progenitors to combine with our ongoing autologous bone marrow transplantation protocol for CML patients. This would provide an alternative treatment strategy if excess toxicity from this compound is observed in our Phase I trials. In addition, a structural analysis of the mechanism of action of the ABL tyrosine kinase inhibitor will be performed. This information would be useful for the design of more potent and specific ABL kinase inhibitors and would be helpful in the design of inhibitors of other tyrosine kinases.
StatusFinished
Effective start/end date7/9/996/30/04

Funding

  • National Institutes of Health: $117,990.00
  • National Institutes of Health: $117,990.00
  • National Institutes of Health

Fingerprint

Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Antineoplastic Agents
Protein-Tyrosine Kinases
Clinical Trials, Phase I
Hematopoietic Stem Cells
Therapeutics
Neoplasms
Pluripotent Stem Cells
Autologous Transplantation
Bone Marrow Transplantation
Toxicology
Interferons
Hyperplasia
Survivors
Anemia
Proteins
Phosphotransferases
Bone Marrow
Inflammation
Transplants

ASJC

  • Medicine(all)