CLINICAL STUDIES OF SIGNAL TRANSDUCTION INHIBITORS

Project: Research project

Project Details

Description

DESCRIPTION: (Applicant's Description)

Regulated cell signaling is critical in neoplastic cell transformation and
proliferation. Novel anticancer agents interrupting different points in
cell signaling pathways are entering the clinic. Rapamycin is a novel
immunosuppressive agent targeting a single protein mTOR, which appears to
function in a previously unrecognized signal transduction pathway necessary
for G1/S phase cell cycle transition. Rapamycin has anti-proliferative
activity in a variety of tumor cell types.

This application utilizes rapamycin and its analogues as a focus in
developing a career in clinical developmental therapeutics. The applicant
proposes to: 1. utilize the rapamycin analogues as a model for the
development of anticancer agents inhibiting intracellular signaling
pathways. a. Rapamycin analogues with growth inhibitory activity will enter
clinical trials shortly. Anti-proliferative effects have been seen in cell
types which express EGF and PDGF receptors. Preliminary studies, however,
indicate that the critical growth factor determining the sensitivity of
tumor cells to the rapamycin analogues is IGF. In these clinical studies,
the dependence of tumor sensitivity on EGF, PDGF, and IGF expression will be
tested in tumor tissue samples (immunohistochemistry) and patient serum
(serum immunoassay). b. Content of the target protein mTOR and one of its
putative targets p70K in tumor tissue samples will be assayed via
immunoblotting. Results will be correlated with tumor response to
rapamycin. c. Since these agents are predominantly cytostatic, combination
regimens will be tested initially in vitro utilizing clonogenic assays. The
novel signal transduction regulator mTOR, which is the target of these
agents, stimulates cell proliferation via a ras-independent pathway. Thus
candidate drugs for combination studies will include (I) other cell
signaling agents interfering with the ras pathway such as the farnesylation
inhibitors, and (ii) classical cytotoxic agents which are non-cycle
dependent such as the platinum analogues. 2. improve expertise in clinical
drug development research through attending courses in biostatistics, phase
I clinical trial design, involvement in pharmacokinetic/drug metabolism
analyses, scientific meetings (Gordon Conference, AACR special meetings,
EORTC-NCI new drug symposia).
StatusNot started