Bcr-Abl RNA levels to monitor STI571 leukemia therapy

Project: Research project

Description

DESCRIPTION (provided by applicant): The recent discovery, validation, and accelerated FDA approval of the tyrosine kinase inhibitor STI571 (Gleevec) for the treatment of chronic myeloid leukemia (CML), the first such rationally-designed, small molecule cancer therapy, confirms the validity of the molecular targeting approach to cancer drugs. Aberrant CML cell growth is caused by the constitutive expression of the bcr-abl kinase, a chimeric fusion protein resulting from a leukemia-specific chromosomal translocation [t(9;22)]. STI571's targeted inhibition of this kinase activity specifically represses the leukemic clone without the typical toxicity of conventional nonspecific cancer drugs. Although >95% of chronic phase CML patients undergo a complete hematologic response to STI571, only a minority experience a complete cytogenetic response, the best current surrogate marker of long-term survival. After 18 months of daily STI571 therapy, approximately 28% of chronic phase patients lose their complete hematologic response. STI571 also induces an initial hematologic response in approximately 50-80% of CML patients with accelerated phase or blast crisis CML, but again these responses are typically only transient. This heterogeneity of responses suggests the pressing need for better laboratory methods to monitor and predict STI571 treatment efficacy to identify patients likely to have disease progression who may benefit from additional (more toxic) therapies. The considerable institutional resources in expertise and STI571-treated patient volume that have been built by co-investigator and STI571 co-developer Brian Druker represent a unique opportunity to develop and test novel laboratory methods to molecularly monitor STI571's treatment efficacy. This proposal's specific aims are then to: 1) validate a novel, quantitative, ultra-sensitive bcr-abl RT-PCR assay for quantifying minimal residual disease in STI571-treated patients, 2) assess whether serial bcr-abl RNA levels in STI571-treated patients can be used to predict and/or monitor clinical disease progression, and 3) establish a storage bank of clinical samples from STI571-treated patients to enable future studies of STI571 drug resistance mechanisms. As STI571 is the first of perhaps many soon-to-come molecularly targeted cancer therapies, the successful achievement of these aims will likely serve as the model by which the efficacy of other novel therapies may be similarly monitored.
StatusFinished
Effective start/end date2/14/031/31/06

Funding

  • National Institutes of Health: $151,000.00
  • National Institutes of Health: $151,000.00

Fingerprint

Leukemia
RNA
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Therapeutics
Imatinib Mesylate
Disease Progression
Neoplasms
Phosphotransferases
Leukemia, Myeloid, Chronic Phase
Blast Crisis
Genetic Translocation
Poisons
Residual Neoplasm
Myeloid Cells
Drug Resistance
Cytogenetics
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Clone Cells
Biomarkers

ASJC

  • Medicine(all)